Conditions: Gout Chronic Hyperuricemia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 152
Healthy volunteers: no

Brief summary:
This is an open label multicenter study to evaluate the safety and tolerability of multiple doses (3 monthly IV infusions) of SEL-212 ( a combination of pegsiticase (SEL-037) and SVP-rapamycin (SEL-110)) followed by multiple doses (2 monthly IV infusions) of pegsiticase (SEL-037) alone for a total of 5 treatment cycles in subjects with symptomatic gout and hyperuricemia. Additional participants will be treated with multiple doses ( 5 monthly IV infusions) of pegsiticase (SEL-037) alone.

Participants will be monitored for safety endpoints through the 5th treatment cycle plus 30 days .Pharmacokinetic samples will be drawn at pre-determined time points in addition to weekly serum uric acid levels.

Detailed description:
This is an open label multicenter study to evaluate the safety and tolerability of multiple doses (3 monthly IV infusions) of SEL-212 ( a combination of pegsiticase ( SEL-037, also known as pegadricase) and SVP-rapamycin (SEL-110)) followed by multiple doses (2 monthly IV infusions) of pegsiticase (SEL-037) alone for a total of 5 treatment cycles in participants with symptomatic gout and hyperuricemia. Additional participants will be treated with multiple doses (5 monthly IV infusions) of pegsiticase (SEL-037) alone.

Uricase is an enzyme that converts uric acid to the readily soluble allantoin that is then excreted and SEL-110 is designed to prevent unwanted anti-drug-antibodies (ADAs) from forming. All participants will be monitored for safety and tolerability to drug throughout the study on a weekly schedule. Pharmacokinetic and pharmacodynamic parameters will at specific timepoints to monitor for continued efficacy. Pharmacodynamic parameters measured include uric acid levels and levels of ADAs.

The study duration per enrolled participant will be approximately 6 months including a 1 month screening period followed by 5 treatment cycles and an end of treatment visit which will occur 30 days after the last IV infusion .

Arms:
arm 1: Pegadricase 0.2 mg/kg intravenous (IV) every 28 days for 5 treatments arm 2: Pegadricase 0.4 mg/kg intravenous (IV) every 28 days for 5 treatments arm 3: Pegadricase 0.2 mg/kg IV plus SEL-110 0.05 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.2 mg/kg IV every 28 days for 2 treatments arm 4: Pegadricase 0.4 mg/kg IV plus SEL-110 0.05 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.4 mg/kg IV every 28 days for 2 treatments arm 5: Pegadricase 0.2 mg/kg IV plus SEL-110 0.08 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.2 mg/kg IV every 28 days for 2 treatments arm 6: Pegadricase 0.4 mg/kg IV plus SEL-110 0.08 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.4 mg/kg IV every 28 days for 2 treatments arm 7: Pegadricase 0.2 mg/kg IV plus SEL-110 0.1 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.2 mg/kg IV every 28 days for 2 treatments arm 8: Pegadricase 0.4 mg/kg IV plus SEL-110 0.1 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.4 mg/kg IV every 28 days for 2 treatments arm 9: Pegadricase 0.4 mg/kg IV plus SEL-110 0.125 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.4 mg/kg IV every 28 days for 2 treatments arm 10: Pegadricase 0.2 mg/kg IV plus SEL-110 0.15 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.2 mg/kg IV every 28 days for 2 treatments arm 11: Pegadricase 0.4 mg/kg IV plus SEL-110 0.15 mg/kg IV every 28 days for 3 treatments, followed by pegadricase 0.4 mg/kg IV every 28 days for 2 treatments arm 12: Pegadricase 0.2 mg/kg IV plus SEL-110 0.15 mg/kg IV every 28 days for 5 treatments arm 13: Pegadricase 0.2 mg/kg IV plus SEL-110 0.10 mg/kg IV every 28 days for 1 treatment followed by pegadricase 0.2 mg/kg IV plus SEL-110 0.15 mg/kg IV every 28 days for 4 treatments arm 14: Pegadricase 0.2 mg/kg IV plus SEL-110 0.1 mg/kg IV every 28 days for 5 treatments

Interventions: intervention 1: SEL-212 intervention 2: SEL-037 intervention 3: SVP-rapamycin (SEL-110)
Intervention descriptions: intervention 1: SEL-212, biologic intervention 2: SEL-037, biologic intervention 3: SVP-rapamycin, biologic

Protocol document:
Prot_000.pdf: 
••
6;::.:
SELECTA
.-
Biosciences
STUDY DRUG:
SEL-212 (a combination of SEL-037
and SEL-ll 0)
STUDY NUMBER:
SEL-212/201
VERSION:
7.1
EFFECTIVE
DATE:
March 19,2018
An Open Label Phase II Multiple Dose Safety,
Pharmacokinetic
and Pharmacodynamics
Study of SEL-212
Followed by Open Label Administration
of SEL-037 in
Subjects with Symptomatic
Gout and Elevated Blood Uric
Acid
Approver(s):
Sponsor:
Selecta Biosciences
480 Arsenal Way, Building One
Watertown,
MA 02472
USA
Tel: 617-923-1400
Fax: 617-924-3454
Signature:
Date:
Earl E. Sands MD
Chief Medical Officer
Kei Kishimoto, Ph.D.
Chief Scientific Officer


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
2 
 
 
  
 
SELECTA BIOSCIENCES CLINICAL STUDY PROTOCOL 
An Open Label Phase II Multiple Dose Safety, 
Pharmacokinetic and Pharmacodynamics Study of SEL-212 
Followed by Open Label Administration of SEL-037 in 
Subjects with Symptomatic Gout and  
Elevated Blood Uric Acid  
 
 
 
STUDY NUMBER: SEL-212/201 
 
CONTACT INFORMATION 
Sponsor: Selecta Biosciences 
480 Arsenal Way, Building One 
Watertown, MA 02472 
Tel: 617-923-1400 
Fax: 617-924-3454 
Email: clinicaltrials@selectabio.com  
Clinical Study Leader: Earl E. Sands MD 
Chief Medical Officer  
Selecta Biosciences 
480 Arsenal Way, Building One 
Watertown, MA 02472 
Tel: 617-231-8105 
Fax: 617-924-3454 
Email: ssands@selectabio.com 
Medical Contact: Ray Dawkins, MD 
Senior Medical Director, Clinical Division 
INC Research/inVentiv Health 
1001 Winstead Dr. 
Cary, NC 275133201 
Tel: 919-413-2250 
Email: ray.dawkins@inventivhealth.com 
 
Pharmacovigilance: INC Research Safety and Pharmacovigilance 
Fax Number: 001-877-464-7787 
In case of issues with fax, Email: 
INCDrugSafety@INCResearch.com 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
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3 
 
 
  
 
INVESTIGATOR’S AGREEMENT 
I agree: 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
To conduct the study in compliance with applicable regulatory requirements, this protocol, any future 
amendments, and with any other study conduct procedures provided by Selecta Biosciences. (Sponsor). 
• 
Not to implement any changes to the protocol without agreement from the Sponsor and prior review and 
written approval from the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), 
except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of 
the study (where permitted by all applicable regulatory requirements). 
• 
That I am thoroughly familiar with the appropriate use of the study drug(s), as described in this protocol, 
and any other information provided by the Sponsor including, but not limited to, the following: the current 
Investigator’s Brochure (IB) or equivalent document, any IB supplement as applicable, or any approved 
product label as applicable. 
• 
That I am aware of, and will comply with, “good clinical practices” (GCP) and all applicable regulatory 
requirements. 
• 
That I will provide full and unencumbered access to source documents and medical records needed for the 
Sponsor, representatives of the Sponsor and regulatory authorities to verify source data and related 
documentation with respect to this trial. 
• 
To ensure that all persons assisting me with the study are adequately informed about the Sponsor study 
drug(s) and of their study-related duties and functions as described in the protocol. 
• 
That I have been informed that certain regulatory authorities require the Sponsor to obtain and supply, as 
necessary, details about the Investigator’s ownership interest in the Sponsor or the study drug, and more 
generally about his/her financial ties with the Sponsor. The Sponsor will use and disclose the information 
solely for the purpose of complying with regulatory requirements. 
Hence I: 
• 
Agree to supply Selecta Biosciences with any necessary information regarding ownership interest and 
financial ties (including those of my spouse and dependent children); 
• 
Agree to promptly update this information if any relevant changes occur during the course of the study and 
for 1 year following completion of the study; and  
• 
Agree that Selecta Biosciences may disclose any information it has about such ownership interests and 
financial ties to regulatory authorities. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
                                                                                                                                                
 
 
Signature of Investigator   
 
 
 
 
 
 
 
 
Date 
 
 


Study: SEL-212/201 
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1. 
SYNOPSIS 
 
Name of Investigational Products: 
SEL-212 (a combination of SEL-037 and SEL-110) 
SEL-110 and SEL-037 
Name of Active Ingredient: 
SEL-037 (pegsiticase, Recombinant Pegylated Candida Urate Oxidase) 
SEL-110 (a nanoparticle composed of PLA (poly(D,L-lactide)) and PLA-PEG (poly(D,L—
lactide)-block-poly (ethylene-glycol)) encapsulating rapamycin) 
Title of Study: An Open Label Phase II Multiple Dose Safety, Pharmacokinetic and 
Pharmacodynamics Study of SEL-212 Followed by Open Label Administration of SEL-037 in 
Subjects with Symptomatic Gout and Elevated Blood Uric Acid 
Study center(s): 12-18 
Principal Investigator:  TBD 
Study period:  
Estimated date first patient enrolled: October, 2016 
Estimated date last patient completed: September, 2018 
Phase of development: 2 
 
Objectives:  
Primary: 
• 
To assess the safety and tolerability of multiple intravenous infusions of SEL-212  
 
Secondary:  
• 
To assess the pharmacokinetics (PK), pharmacodynamics (PD) (ability to reduce 
circulating uric acid) and immunogenicity (anti-uricase, anti-PEG and anti-pegsiticase 
antibodies) of SEL-037 after multiple IV infusions of SEL-037 with or without multiple 
doses of SEL-110. 
 
• 
To assess the pharmacokinetics (PK) of rapamycin after multiple IV infusions of SEL-
110 with multiple IV infusions of SEL-037. 
 
Exploratory: 
• To assess the effect on uric acid deposits and/or total body uric acid deposited as 
measured by Dual Energy Computed Tomography scan of multiple doses of SEL-037 
alone or multiple doses of SEL-212 plus additional doses of SEL-037. 
 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
5 
 
 
  
 
Methodology: (Part A) Open label multiple dose study of a combination drug (SEL-212) 
combined with an open label multiple dose study of a single drug (SEL-037) followed by (Part 
B) an open label administration of a single drug (SEL-037).  Part C will involve patients naïve to 
SEL-212 who are treated with multiple doses of the combination drug (SEL-212). 
 
Number of patients (planned): In Part A and Part B, approximately 100 subjects will be 
divided into 11 dosing cohorts, each consisting of 6-20 subjects. Cohorts 1-10 are closed to 
enrollment but are permitted to be re-opened to increase the enrollment to the maximum total 
number of subjects permitted. Cohorts 11 and 12 will continue enrolling up to 20 subjects per 
cohort. Cohort 1 will receive SEL-037 (pegsiticase alone, 0.2 mg/kg). Cohort 2 will receive 
SEL-037 (pegsiticase alone, 0.4 mg/kg), Cohort 3 will receive SEL-212 (with 0.05 mg/kg of 
SEL-110 + 0.2 mg/kg pegsiticase), Cohort 4 will receive SEL-212 (with 0.05 mg/kg of SEL-
110 + 0.4 mg/kg pegsiticase), Cohort 5 will receive SEL-212 (with 0.08 mg/kg of SEL-110 + 
0.2 mg/kg pegsiticase), Cohort 6 will receive SEL-212 (with 0.08 mg/kg of SEL-110 + 0.4 
mg/kg pegsiticase), Cohort 7 will receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.2 mg/kg 
pegsiticase), Cohort 8 will receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase), Cohort 10 will receive SEL-212 (with 0.125 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase, Cohort 11 will receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.2 mg/kg 
pegsiticase), and Cohort 12 will receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase. (Note: Cohort 9 is intentionally omitted from this protocol in order to maintain 
the cohort numbering convention of associating even numbered cohorts with the 0.4 mg/kg 
SEL-037 dose.)  
 
In Part C, up to 40 patients naïve to SEL-212 will be enrolled. Patients enrolled in Cohort 13 will 
receive SEL-212 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037). Patients enrolled in Cohort 15 
will receive an initial induction dose of SEL-212 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037) 
and, then, four subsequent doses of SEL-212 (0.10 mg/kg SEL-110 + 0.2 mg/kg SEL-037). 
Patients enrolled in Cohort 17 will receive SEL-212 (0.10 mg/kg SEL-110 + 0.2 mg/kg 
SEL-037). (Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to 
maintain the cohort numbering convention of associating odd numbered cohorts with the 0.2 
mg/kg SEL-037 dose.) 
 
Subjects who withdraw early or have significant protocol deviations or compliance issues 
may be replaced at the discretion of the Sponsor to complete the objectives of the clinical 
study and maintain the integrity of the data set. 
 
 
 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
6 
 
 
  
 
Overall scheme of trial (Part A and Part B) 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering 
convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
 
Overall scheme of trial (Part C) 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the cohort 
numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose. 
SEL-037 (0.2 mg/kg)
Cohort 1 Part A
SEL-037 (0.4 mg/kg)
Cohort 2 Part A
SEL-212 (0.05 + 0.2 mg/kg)
Cohort 3 Part A
SEL-212 (0.05 + 0.4 mg/kg)
Cohort 4 Part A
SEL-037 (0.2 mg/kg)
Cohort 1 Part B
SEL-037 (0.4 mg/kg)
Cohort 2 Part B
SEL-037 (0.2 mg/kg)
Cohort 3 Part B
SEL-037 (0.4 mg/kg)
Cohort 4 Part B
SEL-212 (0.08 + 0.2 mg/kg)
Cohort 5 Part A
SEL-212 (0.08 + 0.4 mg/kg)
Cohort 6 Part A
SEL-037 (0.2 mg/kg)
Cohort 5 Part B
SEL-037 (0.4 mg/kg)
Cohort 6 Part B
SEL-212 (0.1 + 0.2 mg/kg)
Cohort 7 Part A
SEL-212 (0.1 + 0.4 mg/kg)
Cohort 8 Part A
SEL-037 (0.2 mg/kg)
Cohort 7 Part B
SEL-037 (0.4 mg/kg)
Cohort 8 Part B
SEL-212 (0.125 + 0.4 mg/kg)
Cohort 10 Part A
SEL-037 (0.4 mg/kg)
Cohort 10 Part B
SEL-212 (0.15 + 0.4 mg/kg)
Cohort 12 Part A
SEL-037 (0.4 mg/kg)
Cohort 12 Part B
Cohort
SEL-110
SEL-037
1 (Closed)
NA
0.2 mg/kg
2 (Closed)
NA
0.4 mg/kg
3 (Closed)
0.05 mg/kg
0.2 mg/kg
4 (Closed)
0.05 mg/kg
0.4 mg/kg
5 (Closed)
0.08 mg/kg
0.2 mg/kg
6 (Closed)
0.08 mg/kg
0.4 mg/kg
7 (Closed)
0.1 mg/kg
0.2 mg/kg
8 (Closed)
0.1 mg/kg
0.4 mg/kg
10 (Closed)
0.125 mg/kg
0.4 mg/kg
11
0.15 mg/kg
0.2 mg/kg
12
0.15 mg/kg
0.4 mg/kg
SEL-212 (0.15 + 0.2 mg/kg)
Cohort 11 Part A
SEL-037 (0.2 mg/kg)
Cohort 11 Part B
SEL-212 
(0.1 + 0.2 mg/kg)
Cohort 15 Part C
Cohort
SEL-110
SEL-037
13
0.15 mg/kg
0.2 mg/kg
15 
(first/induction dose)
0.15 mg/kg
0.2 mg/kg
15
(4 subsequent doses)
0.1 mg/kg
0.2 mg/kg
17
0.1 mg/kg
0.2 mg/kg
SEL-212
(0.15 + 0.2 mg/kg)
Cohort 13 Part C
SEL-212 
(0.15 + 0.2 mg/kg)
Cohort 15 Part C
SEL-212
(0.1 + 0.2 mg/kg)
Cohort 17 Part C


Study: SEL-212/201 
Version: 7.1 
Effective Date  
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7 
 
 
  
 
Diagnosis and main criteria for inclusion/exclusion: 
Inclusion Criteria: 
1. Has provided written informed consent prior to the conduct of any study specific 
procedures and continues to provide consent; 
2. Understands and is willing and able to comply with study requirements, including 
the schedule of follow-up visits, and has demonstrated compliance with study 
requirements during Screening; 
3. At the Screening Visit male age 21 - 75, inclusive or female age 21-75 of non-child 
bearing potential; 
4. Has at the Screening Visit a serum uric acid ≥ 6 mg/dL, with established or 
symptomatic gout which is defined as having at least ONE of any of the 3 following 
factors: 
a. ≥ 1 tophus 
b. 1 gout flare within the last 6 months 
c. Chronic gouty arthropathy 
5. The use of allopurinol, febuxostat (Uloric®), or probenecid as uric acid-lowering 
therapy is permissible if dosing has been stable for at least the month prior to the 
Screening Visit and remains stable during the Screening Phase (i.e., no initiation, 
change in dose or discontinuation 1 month prior to screening and during screening). 
6. Is negative for anti-PEG antibodies at the Screening Visit; 
7. Has not participated in a clinical trial within 30 days of the Screening Visit and 
agrees to not participate in a clinical trial for the duration of the study; 
8. Negative serology for HIV-1/-2 and negative antibodies to hepatitis C; 
9. Has adequate venous access and able to receive IV therapy; 
10. If applicable, has fully recovered from any prior surgery; 
11. Is not presently receiving any vaccination scheme or have received a live virus 
vaccine in the previous 6 months. 
Exclusion criteria 
1. History of anaphylaxis or severe allergic reactions; 
2. History of any allergy to pegylated products, including peginterferon alfa-2a 
(Pegasys®), peginterferon alfa-2b (PegIntron®), pegfilgrastim (Neulasta®), 
pegaptanib (Macugen®), pegaspargase (Oncaspar®), pegademase (Adagen®), peg-
epoetin beta (Mircera®), pegvisomant (Somavert®) certolizumab pegol (Cimzia®), 
naloxegol (Movantik®), peginesatide (Omontys®), pegaptanib (Macugen®) and 
doxorubicin liposome (Doxil®); 


Study: SEL-212/201 
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3. Medications which are known CYP3A4 inhibitors or inducers MAY be 
exclusionary. Patients taking medications that are known CYP3A4 inhibitors or 
inducers including natural products such as St. John’s Wort or grapefruit juice may 
be included ONLY if they discontinue the medication 14 days before dosing and are 
able to remain off the medication for the duration of the study. 
4. Drugs known to interact with Rapamune such as cyclosporine, diltiazem, 
erythromycin, ketoconazole (and other antifungals), nicardipine (and other calcium 
channel blockers), rifampin, verapamil unless they are stopped 2 weeks prior to 
starting the trial and will not be used during the trial. 
5. Women of child bearing potential, defined as:  
• <6 weeks after surgical bilateral salpingooperhectony with or without 
hysterectomy 
• Pre or perimenopausal ( < less than 24 months of natural amenorrhea) 
6. Initiation or change in dose of hormone-replacement therapy for menopausal women 
less than 1 month prior to the Screening Visit or during the Screening Phase would 
be exclusionary.  If after being on a stable dose of hormone-replacement therapy for 
one month the patient may be considered for the study if she continues to meet all 
other inclusion and exclusion criteria 
7. Uncontrolled diabetes with baseline HbA1c ≥8%; 
8. Fasting screening glucose greater than 240 mg/dL 
9. Fasting triglyceride greater than 300 mg/dl; 
10. Fasting LDL cholesterol greater than 200 mg/dl; 
11. Glucose-6-phosphate dehydrogenase deficiency;  
12. Uncontrolled hypertension: Blood pressure >170/100 at screening and 1 week prior 
to dosing 
13. Individual laboratory values which may be exclusionary 
• White blood cell count less than 3.5 x109 /L 
• Serum aspartate aminotransferase (AST)  or alanine amino transferase  
greater than 3x upper limit of normal (ULN) in the absence of known active 
liver disease 
• Glomerular filtration rate less than 40 ml/min/1.73 m2 
• Hemoglobin less than 9 gm/dL 
• Serum phosphate less than 2.0 mg/dL 
14. Ongoing treatment for arrhythmia, including placement of an implantable 
defibrillator; 


Study: SEL-212/201 
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15. History of coronary artery disease, including myocardial infarction; 
16. Congestive heart failure, New York Heart Association Class III or IV; 
17. ECG with evidence of prior myocardial infarction, clinically significant arrhythmia, 
or other abnormalities that, in the opinion of the investigator, are consistent with 
significant underlying cardiac disease; 
18. History of hematological or autoimmune disorders, is immunosuppressed or 
immunocompromised;  
19. Subject is currently taking dabigatran (Pradaxa®), rivaroxaban (Xarelto®), edoxaban 
(Savaysa®), warfarin (Coumadin®) and apixaban (Eliquis®). 
20. Prior exposure to any experimental or marketed uricase (e.g., rasburicase (Elitek, 
Fasturtec), pegloticase (Krystexxa®), pegsiticase (SEL-037) 
21. History of malignancy within the last 5 years other than basal skin cancer; 
22.  Subjects who, in the opinion of the investigator, present with a condition that would 
compromise their safety or that would make study completion unlikely. 


Study: SEL-212/201 
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Effective Date  
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Investigational product, dosage and mode of administration:  
SEL-037 is supplied as a lyophilized powder in a 2 ml stoppered vial with 6 mg SEL-037 per 
vial.  SEL-037 is reconstituted with 1.1 mL of sterile water for injection, USP.  A sufficient 
volume of reconstituted SEL-037 at 0.2 mg/kg or 0.4 mg/kg will be diluted in 100 mL of 
0.9% sodium chloride for injection, USP and dosed as a single intravenous infusion with an 
infusion pump over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety. If a subject is 
assigned to Cohorts 1 or 2 then the subject will receive a single IV infusion of normal saline 
(20 mL) with a syringe infusion pump over a period of 55 minutes starting concurrently with 
a 60 minute infusion of 125 mL of normal saline.  This will be followed by the infusion 
delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) 
delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be extended in 
order to ensure the infusion of the study medication in entirety. 
SEL-110 will be supplied frozen in 10 ml glass vials. After thawing at room temperature for 
2 hours, the appropriate amount of SEL-110 on a mg/kg basis will be drawn into a syringe or 
syringes and administered as an IV infusion with a syringe infusion pump. If a subject is part 
of Cohorts 3-8, 10, 11, or 12, then SEL-110 is to be administered prior to SEL-037. In 
cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be infused at a single steady 
rate sufficient to deliver the dose volume over a period of 55 minutes concurrently with a 60 
minute infusion of 125 mL of normal saline. In cohorts receiving SEL-110 ≥0.10 mg/kg, the 
rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be 
changed to a steady rate sufficient to deliver the remainder of the dose volume for the 
additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. 
For all cohorts receiving SEL-110, the infusion of SEL-037 (0.2 mg/kg for Cohorts 3, 5, 7, 
and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12), as described above, will be started at the 
60 minute mark. 
For Cohorts 13, 15, and 17, SEL-110 will be administered prior to SEL-037. The rate of 
SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be changed to a 
steady rate sufficient to deliver the remainder of the dose volume for the additional 25 
minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. The infusion of 
0.2 mg/kg SEL-037 will delivered by infusion pump delivered over 60 minutes (+/- 2 
minutes). If necessary, the infusion time may be extended in order to ensure the infusion of 
the study medication in entirety. 
 
Distribution of Subjects 
All enrolled subjects will be randomized initially to Cohorts 1, 2, 3 and 4 such that upon 
reaching 12 subjects total for all 4 cohorts, each cohort will contain 3 subjects. The 
experience of these 12 subjects will guide the further conduct of the study.  Adverse events, 
safety labs and the rate of infusion reactions in individual cohorts will dictate the continuance 
of a specific cohort. After the completion of at least one treatment cycle the subject 
experience will be evaluated before enrollment is opened to all cohorts.  The future 
enrollment will be randomized between all open cohorts.   


Study: SEL-212/201 
Version: 7.1 
Effective Date  
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11 
 
 
  
 
At this time Cohorts 1-10 have been closed to enrollment. Randomization into the remaining 
open cohorts will continue until the cohorts are closed due to enrollment reaching 6-20 
subjects per cohort or due to the stopping rules for individual cohorts. Cohorts that have 
closed due to enrollment levels may be re-opened to increase the enrollment to the maximum 
total number of subjects permitted. 
 
 
Premedication for Study Drug Treatments 
All subjects will receive 180 mg fexofenadine orally the night before receiving study drug 
(12 h ± 2h) and again 2 ± 1 hours before receiving study drug (ie. prior to SEL-037 for 
Cohorts 1 and 2 or SEL-110 for Cohorts 3-8, 10, 11, and 12).  In addition, they will also 
receive methylprednisolone 40 mg (or equivalent drug, for example prednisone 50 mg IV or 
dexamethasone 8 mg IV) intravenously 1 ± 0.5 hour before receiving study drug (ie. prior 
SEL-037 for Cohorts 1 and 2 or SEL-110 for Cohorts 3-8, 10, 11, 12, 13, 15, and 17).  This 
will occur for every dose of study drug in Treatment Periods 1-5. These medications will be 
supplied by the clinic. 
 
 
Premedication for Gout Flare 
All subjects that meet all inclusion and exclusion criteria will be given premedication for 
gout flare prevention.  The regimen will begin 1 week prior to the first dosing of study drug 
and continue for as long as the subject is enrolled in the clinical study.  Subjects will be given 
colchicine 1.2 mg as a single loading dose.  Then they will continue with colchicine 0.6 mg 
QD for the remainder of their participation in the trial. If there is a contraindication to 
colchicine, the subject will receive ibuprofen 600 mg TID or equivalent dose of a NSAID.  If 
there is a contraindication to colchicine and to NSAIDs the subject will receive no 
premedication for gout flare.  The gout flare prevention medication should continue as long 
as the subject is enrolled in the clinical study. Subjects who began receiving a NSAID as gout 
flare prevention medication due to a contraindication to colchicine or under a previous 
version of this protocol should continue to receive the NSAID as long as the subject is 
enrolled in the study. These medications will be supplied by the clinic. 
 
Duration of treatment for Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 mg/kg 
SEL-037 alone) – BOTH COHORTS 1 and 2 CLOSED 
Part A - Treatment period 1  
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when to 
start their premedication (date and medication, Day -7) for the prevention of gout flares.  On 
the evening of Day -1 the subject will self-administer their premedication of fexofenadine 180 
mg orally.  The day of initial dosing of study drug will be designated Day 0.  On the morning 
(Day 0) subjects will report to the clinic for dosing of study drug. 2 hours prior to the dosing 


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of study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to 
the dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects who have been assigned to Cohort 1 or 2 
will receive a single IV infusion of normal saline (20 mL) with a syringe infusion pump over 
a period of 55 minutes starting concurrently with a 60 minute infusion of 125 mL of normal 
saline. This will be followed (± 1 minute) by an infusion delivered by infusion pump of SEL-
037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline 
delivered over 60 minutes. Subjects will remain in the clinic for 9 hours after the start of the 
saline infusion for safety evaluations and PK blood draws (see Schedule of Events below).  
Subjects will return to the clinic for PK and PD blood draws on Treatment Period 1, Days 1, 
7, 14 and 21 and Antibody blood draws on Treatment Period 1, Days 7, 14 and 21 and safety 
blood draws on Treatment Period 1, Day 14.  
Part A - Treatment period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally.  On the morning of Treatment Period 2, Day 0, 
subjects will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of 
study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the 
dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent 
drug) intravenously. Subjects will receive a single IV infusion of normal saline (20 mL) with 
a syringe infusion pump over a period of 55 minutes starting concurrently with a 60 minute 
infusion of 125 mL of normal saline. This will be followed (± 1 minute) by an infusion 
delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) 
diluted into 100 mL of normal saline delivered over 60 minutes.  Subjects will remain in the 
clinic for 9 hours after the start of the saline infusion for safety evaluations and PK blood 
draws (see Schedule of Events below).  Subjects will return to the clinic for PK and PD blood 
draws on Treatment Period 2, Days 1, 7, 14 and 21 and Antibody blood draws on Treatment 
Period 2, Days 7, 14 and 21 and safety blood draws on Treatment Period 2, Day 14.    
Part A - Treatment period 3  
On the evening of Treatment Period 3, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally.  On the morning of Treatment Period 3, Day 0, 
subjects will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of 
study drug SEL-037, subjects will receive fexofenadine 180 mg orally 1 hour prior to the 
dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent 
drug) intravenously. Subjects will receive a single IV infusion of normal saline (20 mL) with 
a syringe infusion pump over a period of 55 minutes starting concurrently with a 60 minute 
infusion of 125 mL of normal saline. This will be followed (± 1 minute) by an infusion 
delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) 
diluted into 100 mL of normal saline delivered over 60 minutes.  Subjects will remain in the 
clinic for 9 hours after the start of the saline infusion for safety evaluations and PK blood 
draws (see Schedule of Events below).  Subjects will return to the clinic for PK and PD blood 
draws on Treatment Period 3, Days 1, 7, 14 and 21 and Antibody blood draws on Treatment 
Period 3, Days 7, 14 and 21 and safety blood draws on Treatment Period 3, Day 14. 
 


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Part B - Treatment period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally.  On the morning of Treatment Period 4, Day 0 
subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of 
study drug SEL-037, subjects will receive fexofenadine 180 mg orally 1 hour prior to the 
dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent 
drug) intravenously.  Eligible subjects will receive a single IV infusion of SEL-037 (0.2 
mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline over 60 
minutes by infusion pump. Subjects will remain in the clinic for 9 hours after the start of the 
saline infusion for safety evaluations and PK blood draws (see Schedule of Events below).  
Subjects will return to the clinic for PK and PD blood draws on Treatment Period 4, Days 1, 
7, 14 and 21 and Antibody blood draws on Treatment Period 4, Days 7, 14 and 21 and safety 
blood draws on Treatment Period 4, Day 14. 
Part B - Treatment period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally.  On the morning of Treatment Period 5, Day 0 
subjects will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of 
study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the 
dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent 
drug) intravenously. Eligible subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg 
for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline over 60 minutes 
by infusion pump. Subjects will remain in the clinic for 9 hours after the start of the saline 
infusion for safety evaluations and PK blood draws (see Schedule of Events below).  Subjects 
will return to the clinic for PK and PD blood draws on Treatment Period 5, Days 1, 7, 14 
and 21 and Antibody blood draws on Treatment Period 5, Days 7, 14 and 21 and safety 
blood draws on Treatment Period 5, Day 14. 
An End of Study visit will be performed on Treatment Period 5, Day 30 ± 1 day. Subjects who 
terminate participation early should have an End of Study visit assessments completed. 
 
Duration of treatment for Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 
4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 0.2 
mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 (0.1 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg SEL-
037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 mg/kg 
SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 mg/kg SEL-
037)  
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort 
numbering convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 
dose. 
Part A – Treatment period 1 
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when to start 


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their premedication (date and medication, Day -7) for the prevention of gout flares. On the 
evening of Day -1 the subject will take their premedication of fexofenadine 180 mg orally.  
The day of initial dosing of study drug will be designated Day 0.  On the morning of Day 0 
subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of 
study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to 
the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects who have been assigned to Cohorts 3-8, 10, 
11, and 12 will receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) 
administered with a syringe infusion pump. In cohorts receiving SEL-110 doses <0.10 
mg/kg, SEL-110 will be infused at a single steady rate sufficient to deliver the dose volume 
over a period of 55 minutes concurrently with a 60 minute infusion of 125 mL of normal 
saline. In cohorts receiving SEL-110 ≥0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 
mL/hour for the first 30 minutes and, then, will be changed to a steady rate sufficient to 
deliver the remainder of the dose volume for the additional 25 minutes, concurrently with a 
60 minute infusion of 125 mL of normal saline.  This will be followed (± 3 minutes) by an 
infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohorts 3, 5, 7, and 11; 0.4 
mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL of normal saline delivered over 60 
minutes (+/- 2 minutes). If necessary the infusion time may be extended in order to ensure 
the infusion of the study medication in entirety.  Subjects will remain in the clinic for 9 hours 
after the start of the infusion of SEL-110 for safety evaluations and PK blood draws (see 
Schedule of Events below).  Subjects will return for PK and PD blood draws on Treatment 
Period 1, Days 1, 7, 14, 21 and safety and Antibody blood draws on Treatment Period 1, 
Days 7, 14, 21.  
  
Part A – Treatment period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 2, Day 0, 
subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of 
study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to 
the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects who have been assigned to Cohorts 3-8, 10, 
11, and 12 will receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) 
administered with a syringe infusion pump. In cohorts receiving SEL-110 doses <0.10 
mg/kg, SEL-110 will be infused at a single steady rate sufficient to deliver the dose volume 
over a period of 55 minutes concurrently with a 60 minute infusion of 125 mL of normal 
saline. In cohorts receiving SEL-110 ≥0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 
mL/hour for the first 30 minutes and, then, will be changed to a steady rate sufficient to 
deliver the remainder of the dose volume for the additional 25 minutes, concurrently with a 
60 minute infusion of 125 mL of normal saline. This will be followed (± 3 minutes) by an 
infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohorts 3, 5, 7, and 11; 0.4 
mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL of normal saline delivered over 60 
minutes (+/- 2 minutes). If necessary the infusion time may be extended in order to ensure 
the infusion of the study medication in entirety. Subjects will remain in the clinic for 9 hours 


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after the start of the infusion of SEL-110 for safety evaluations and PK blood draws (see 
Schedule of Events below).  Subjects will return for PK and PD on Treatment Period 2, Days 
1, 7, 14 and 21 and safety and Antibody blood draws on Treatment Period 2, Days 7, 14 and 
21. 
   
Part A – Treatment period 3 
On the evening of Treatment Period 3, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally the night before dosing.  On the morning of 
Treatment Period 3, Day 0 subjects will report to the clinic for the dosing of study drug. 2 
hours prior to the dosing of study drug SEL-110, subjects will receive fexofenadine 180 mg 
orally and 1 hour prior to the dosing of study drug SEL-110, subjects will receive 
methylprednisolone 40 mg intravenously (or equivalent drug). Eligible subjects who have 
been assigned to Cohorts 3-8, 10, 11, and 12 will receive a single IV infusion of SEL-110 
(dose based on a mg/kg basis) administered with a syringe infusion pump. In cohorts 
receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be infused at a single steady rate 
sufficient to deliver the dose volume over a period of 55 minutes concurrently with a 60 
minute infusion of 125 mL of normal saline. In cohorts receiving SEL-110 ≥0.10 mg/kg, the 
rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be 
changed to a steady rate sufficient to deliver the remainder of the dose volume for the 
additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. 
This will be followed (± 3 minutes) by an infusion delivered by infusion pump of SEL-037 
(0.2 mg/kg for Cohorts 3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 
100 mL of normal saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion 
time may be extended in order to ensure the infusion of the study medication in entirety.  
Subjects will remain in the clinic for 9 hours after the start of the infusion of SEL-110 for 
safety evaluations and PK blood draws (see Schedule of Events below).  Subjects will return 
for PK and PD blood draws on Treatment Period 3, Days 1, 7, 14 and 21 and safety and 
Antibody blood draws on Treatment Period 3, Days 7, 14 and 21. 
Part B – Treatment period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg.  On the morning of Treatment Period 4, Day 0 subjects 
will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg for Cohorts 
3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL of normal 
saline over 60 minutes (+/- 2 minutes) by infusion pump. If necessary the infusion time may 
be extended in order to ensure the infusion of the study medication in entirety.  Subjects will 
remain in the clinic for 9 hours after the start of the infusion of SEL-037 for safety 
evaluations and PK blood draws (see Schedule of Events below).  Subjects will return for PK 
and PD blood draws on Treatment Period 4, Days 1, 7, 14 and 21 and safety and Antibody 
blood draws on Treatment Period 4, Days 7, 14 and 21.   


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Part B – Treatment period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects will 
self-administer fexofenadine 180 mg orally.  On the morning of Treatment Period 5, Day 0 
subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of 
study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the 
dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Subjects will receive a single IV infusion of SEL-037 (0.2 
mg/kg for Cohorts 3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 
mL of normal saline over 60 minutes (+/- 2 minutes) by infusion pump. If necessary the 
infusion time may be extended in order to ensure the infusion of the study medication in 
entirety.  Subjects will remain in the clinic for 9 hours after the start of the infusion of SEL-
037 for safety evaluations and PK blood draws (see Schedule of Events below).  Subjects 
will return for PK and PD blood draws on Treatment Period 5, Days 1, 7, 14 and 21 and 
safety and Antibody blood draws on Treatment Period 5, Days 7, 14 and 21.   
 
 
Duration of treatment for Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (induction dose of 0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037 THEN 
0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-110 + 
0.2 mg/kg SEL 037)  
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the 
cohort numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-
037 dose. 
Part C – Treatment period 1 
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when to start 
their premedication (date and medication, Day -7) for the prevention of gout flares. On the 
evening of Day -1 the subject will take their premedication of fexofenadine 180 mg orally.  
The day of initial dosing of study drug will be designated Day 0.  On the morning of Day 0 
subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of 
study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to 
the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects assigned to Cohort 13, 15, and 17 will 
receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered with a 
syringe infusion pump. The rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 
minutes and, then, will be changed to a steady rate sufficient to deliver the remainder of the 
dose volume for the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL 
of normal saline.  This will be followed (± 3 minutes) by an infusion delivered by infusion 
pump of 0.2 mg/kg SEL-037 diluted into 100 mL of normal saline delivered over 60 minutes 
(+/- 2 minutes). If necessary the infusion time may be extended in order to ensure the 
infusion of the study medication in entirety.  Subjects will remain in the clinic for 9 hours 
after the start of the infusion of SEL-110 for safety evaluations and PK blood draws (see 


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Schedule of Events below).  Subjects will return for PK and PD blood draws on Treatment 
Period 1, Days 1, 7, 14, 21 and safety and Antibody blood draws on Treatment Period 1, 
Days 7, 14, 21.  
 
Part C – Treatment periods 2, 3, 4, and 5 
On the evening of each of Treatment Periods 2-5, Day -1 (27 ± 1 days from prior dosing) 
subjects will self-administer fexofenadine 180 mg orally. On the morning of Treatment 
Period 2, Day 0, subjects will report to the clinic for the dosing of study drug.  2 hours prior 
to the dosing of study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 
1 hour prior to the dosing of study drug SEL-110, subjects will receive methylprednisolone 
40 mg (or equivalent drug) intravenously. Eligible subjects who have been assigned to 
Cohorts 13, 15, and 17 will receive a single IV infusion of SEL-110 (dose based on a mg/kg 
basis) administered with a syringe infusion pump. The rate of SEL-110 infusion will be 5.5 
mL/hour for the first 30 minutes and, then, will be changed to a steady rate sufficient to 
deliver the remainder of the dose volume for the additional 25 minutes, concurrently with a 
60 minute infusion of 125 mL of normal saline. This will be followed (± 3 minutes) by an 
infusion delivered by infusion pump of 0.2 mg/kg SEL-037 diluted into 100 mL of normal 
saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety. Subjects will 
remain in the clinic for 9 hours after the start of the infusion of SEL-110 for safety 
evaluations and PK blood draws (see Schedule of Events below).  Subjects will return for PK 
and PD on Days 1, 7, 14 and 21 of each treatment period and will return for safety and 
Antibody blood draws on Days 7, 14 and 21 of each treatment period. 
 
An End of Study visit will be performed on Treatment Period 5, Day 30± 1 days. Subjects 
who terminate participation early should have an End of Study visit assessments completed. 
 
 
Stopping Rules in an Individual Subject or in a Cohort 
 
For this clinical trial a treatment period is defined as the period of time from the beginning of 
dosing of saline placebo which is followed by SEL-037 (as in the case of Cohorts 1 and 2) or 
SEL-212 (as in the case of Cohorts 3-8, 10, 11, and 12) to the beginning of the next 
scheduled dose of study drug. 
 
For Part C (Cohorts 13, 15, and 17), a treatment period is defined as the period of time from 
the beginning of dosing of SEL-212 to the beginning of the next scheduled dose of study 
drug. 
 
 
 
 


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Individual 
 
For subjects in Cohorts 1 and 2, any subject who has a weekly serum uric acid value ≥6 
mg/dl or >50% of their baseline (where baseline value refers to the pre-dose serum uric acid 
level from visit 4, Day 0, treatment period 1) at Day 21 of their current treatment cycle will 
not be eligible for the next dosing of SEL-037.  The subject will be followed for 30 days post 
the last dose of study drug at which time they will have an End of Study assessment and their 
participation in the study will be terminated.  
 
In Cohorts 3-8, 10-13, 15, and 17 only subjects whose ambient blood samples indicate a serum 
uric acid (sUA) value less than or equal to 1.0 mg/dL at any of the Day 21 visits will be 
eligible for the next dosing of SEL-212 (or SEL-037).  All other subjects will be followed for 
30 ± 2 days post the last dose of study drug at which time all of the End of Study assessments 
will be completed and their participation in the study will be terminated.  
 
Cohort 
 
If 5 subjects in any of Cohorts 1-5 or 7, or if 10 subjects in any of Cohorts 6, 8, 10, 11, or 12 
have met the requirements for individual stopping of their participation in the trial as 
described above or have been stopped based on Section 6.4 then that cohort will no longer 
have any additional subjects enrolled in it.  Those subjects who have been enrolled will 
continue until they fulfill the requirements for individual stopping or complete the clinical 
trial treatment periods. If they continue to meet the requirements for continued participation 
they may continue in the Part B of the clinical trial. 
 
In Part C, if 10 subjects in any of Cohorts 13, 15, or 17 have met the requirements for 
individual stopping of their participation in the trial as described above or have been stopped 
based on Section 6.4 then the cohort will no longer have any additional subjects enrolled in 
it.  Those subjects who have been enrolled will continue until they fulfill the requirements for 
individual stopping or complete the clinical trial treatment periods. If they continue to meet 
the requirements for continued participation they may continue in the clinical trial. 
 


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Criteria for evaluation: 
Pharmacokinetics: 
Blood samples for measuring serum SEL-037 levels and serum uricase activity levels and 
whole blood levels of rapamycin (API in SEL-110) in their respective cohorts will be 
collected as shown in the Schedule of Events, with time zero being the start of the SEL-110 
or saline IV infusion: Pharmacokinetic (PK) parameters will be calculated including the 
maximum observed serum concentration (Cmax), the time at which Cmax occurred (Tmax), area 
under the serum concentration-time curve from time 0 to the time of last quantifiable 
concentration (AUClast), area under the serum concentration-time curve from time 0 to 
infinity (AUCinf), the terminal elimination rate constant (Kel), terminal half-life (t1/2), serum 
clearance of drug (CL), and apparent volume of distribution at equilibrium (Vss).  
Pharmacodynamics: 
Blood samples will be collected as indicated in the schedule of events for evaluation of 
circulating serum uric acid levels. The blood samples will be processed for a determination of 
serum uric acid levels according to the procedures in the study laboratory manual. 
 
Blood samples will be collected as indicated in the schedule of events for evaluation of 
antibodies to pegsiticase, uricase, and PEG. Procedures for processing samples will be 
included in the study laboratory manual. 
Safety (Part A and Part B): 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort 
numbering convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 
dose. 
• Physical exam at the Screening Visit and Treatment Period 5, Day 30/early termination.   
• Part A - Treatment period 1 - Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) 
 Vitals at the Screening Visit, (Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (saline placebo) at 30, 60, 90, 120, and 180 minutes, then at 
6, 9 hours; and then at Day 1, 7, 14, 21 and early termination.  Vitals will be assessed 
at the designated times ± 2.5 minutes for all treatment periods and cohorts. 
 ECG exam at the Screening Visit, (Day 0) predose, 6 hours after completion of 
dosing, and early termination. 
• Part A - Treatment period 1 - Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 
mg/kg SEL-037) 


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 Vitals at the Screening Visit, (Day 0) predose (T-0), intradose (after the start of study 
drug IV syringe infusion SEL-110) 15, 30, 45, 60, 90, 120 and 180 minutes, then at 6, 
9 hours; and then at Day 1, 7, 14, 21 and early termination. 
 ECG exam at the Screening Visit, (Day 0) predose, 6 hours after completion of 
dosing and early termination. 
• Part A - Treatment period 2 - Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) 
 Vitals at (Treatment Period 2, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (saline placebo) at 30, 60, 90, 120 and 180 minutes, then at 
6, 9 hours; and then at Treatment Period 2, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 2, Day 0) predose and early termination. 
• Part A - Treatment period 2 - Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037, Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 
mg/kg SEL-037) 
 Vitals at (Treatment Period 2, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (SEL-110) at 15, 30, 45, 60, 90, 120, 180 minutes, then at 6, 
9 hours; and then at Treatment Period 2, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 2, Day 0) predose and early termination. 
• Part A - Treatment period 3 - Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) 
 Vitals at (Treatment Period 3, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (saline placebo) at 30, 60, 90, 120, 180 minutes, then at 6, 9 
hours; and then at Treatment Period 3, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 3, Day 0) predose and early termination. 
• Part A - Treatment period 3 - Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037)  


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
21 
 
 
  
 
 Vitals at (Treatment Period 3, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (SEL-110) at 15, 30, 45, 60, 90, 120, 180 minutes, then at 6, 
9 hours; and then at Treatment Period 3, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 3, Day 0) predose and early termination. 
• Part B - Treatment period 4 - Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) 
 Vitals at (Treatment Period 4, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120, and 180 minutes, then at 6 
hours; and then at Treatment Period 4, Day 1, 7, 14, 21 and early termination 
 ECG exam at (Treatment Period 4, Day 0) predose and early termination. 
• Part B - Treatment period 4 - Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037)  
 Vitals at (Treatment Period 4, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120, and 180 minutes, then at 6 
hours; and then at Treatment Period 4, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 4, Day 0) predose and early termination. 
• Part B - Treatment period 5 - Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) 
 Vitals at (Treatment Period 5, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120, and 180 minutes, then at 6 
hours; and then at Treatment Period 5, Day 1, 7, 14, 21 and 30 or early termination 
  ECG exam at (Treatment Period 5, Day 0) predose and End of Study Treatment 
Period 5, Day 30 or early termination. 
• Part B - Treatment period 5 - Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037)      


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
22 
 
 
  
 
 Vitals at (Treatment Period 5, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120 and 180 minutes, then at 6 
hours; and then at Day 1, 7, 14, 21 and 30 or early termination. 
 ECG exam at (Treatment Period 5, Day 0) predose and End of Study Treatment 
Period 5, Day 30 or early termination. 
• Adverse events (AE) and serious adverse events (SAE) starting at dosing. AEs will be 
graded according to Rheumatology Common Toxicity Criteria, version 2.0.  If a severe 
infusion reaction occurs, a determination of anaphylaxis (Grade 4 reaction) will be based 
on the National Institute of Allergy and Infectious Diseases (NIAID)/ Food Allergy & 
Anaphylaxis Network (FAAN) Anaphylaxis Criteria. 
• Concomitant medication usage will be recorded throughout the trial. 
• Clinical laboratory tests (blood chemistry, hematology including clotting parameters, and 
urinalysis) per the Time and Events Schedule. 
• Immunogenicity samples for anti-PEG antibodies at the Screening Visit and for anti-
pegsiticase, anti-uricase, and anti-PEG antibodies at baseline (predose for Treatment 
Periods 1, 2, 3, 4 and 5), Day 7, 14, and 21 post each treatment for Treatment Periods 1, 
2, 3, 4, and 5, and EOS / early termination (Treatment Period 5, Day 30). 
 
Safety (Part C, Cohorts 13, 15, and 17): 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the 
cohort numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-
037 dose. 
• Physical exam at the Screening Visit and Treatment Period 5, Day 30/early termination.   
• Part C - Treatment Period 1 – Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (induction dose of 0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 
(0.10 mg/kg SEL-110 + 0.2 mg/kg SEL 037) 
 Vitals at the Screening Visit, (Day 0) predose (T-0), intradose (after the start of study 
drug IV syringe infusion SEL-110) 15, 30, 45, 60, 90, 120 and 180 minutes, then at 6, 
9 hours; and then at Day 1, 7, 14, 21 and early termination. 
 ECG exam at the Screening Visit, (Day 0) predose, 6 hours after completion of 
dosing and early termination. 
• Part C - Treatment Period 2 – Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-
110 + 0.2 mg/kg SEL 037) 
 Vitals at (Treatment Period 2, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (SEL-110) at 15, 30, 45, 60, 90, 120, 180 minutes, then at 6, 
9 hours; and then at Treatment Period 2, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 2, Day 0) predose and early termination. 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
23 
 
 
  
 
• Part C - Treatment Period 3 – Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-
110 + 0.2 mg/kg SEL 037) 
 Vitals at (Treatment Period 3, Day 0) predose (T-0), intradose after the start of study 
drug IV syringe infusion (SEL-110) at 15, 30, 45, 60, 90, 120, 180 minutes, then at 6, 
9 hours; and then at Treatment Period 3, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 3, Day 0) predose and early termination. 
• Part C - Treatment Period 4 – Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-
110 + 0.2 mg/kg SEL 037) 
 Vitals at (Treatment Period 4, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120, and 180 minutes, then at 6 
hours; and then at Treatment Period 4, Day 1, 7, 14, 21 and early termination. 
 ECG exam at (Treatment Period 4, Day 0) predose and early termination. 
• Part C - Treatment Period 5 – Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 15 (0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-
110 + 0.2 mg/kg SEL 037) 
 Vitals at (Treatment Period 5, Day 0) predose (T-0), intradose after the start of study 
drug IV infusion (SEL-037) at 15, 30, 45, 60, 90, 120 and 180 minutes, then at 6 
hours; and then at Day 1, 7, 14, 21 and 30 or early termination. 
 ECG exam at (Treatment Period 5, Day 0) predose and End of Study Treatment 
Period 5, Day 30 or early termination. 
Statistical methods: 
Data will be listed and summarized as appropriate.  Descriptive statistics at each dose level 
(number of subjects, arithmetic mean, standard deviation, geometric mean, coefficient of 
variation, median, minimum and maximum, as appropriate) will be used to summarize the 
PK and safety results by dose groups.  The PK and PD relationship will be explored.  
 
 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
24 
 
 
  
 
1.1. 
Schedule of Events 
Table 1: 
Schedule of Events, Cohorts 1 & 2, Part A - Treatment Periods 1-3 
 
 
   


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
25 
 
 
  
 
Table 2: 
Schedule of Events, Cohorts 1 & 2, Part B - Treatment Periods 4-5 
 
 
 
 
V21
V23
V24
V25
V26
P4
D-1
P4
D1
P4
D7
P4
D14
P4
D21
V27
V29
V30
V31
V32
P5
D-1
P5
D1
P5
D7
P5
D14
P5
D21
Hour (h)
Pre-
dose
0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Informed Consent
Dual Energy CT Scan
X
X
Inflammatory Markers
X
X
T-Cell Recall 
X11
Demographics
Inclusion/exclusion
Medical History1
Safety Examinations
Predose 0h 0.25h 0.5h 0.75h
1h
1.5
2h
3h
6h
9h
Physical Examination
X
Concomitant medications
Vital signs2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG3
X
X
Adverse Events - Rheumatology CTC
Safety Labs
Predose 0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Safety Labs - As indicated in individual schedules4
X
X
X
Immunogenicity
Anti-Pegsiticase
X
X
X
X
X
Anti-Uricase
X
X
X
X
X
Anti-PEG
X
X
X
X
X
PK/PD Assessments
SEL-110 PK
SEL-037 PK
X
X
X
X
X
X
Uricase Activity
X
X
X
X
X
X
X
X
X
X
X
X
Uric Acid
X
X
X
X
X
X
X
X
X
X
X
X
Study Treatment
Predose 0h 0.25h 0.5h 
0.75h 1h
1.5h
2h
3h
6h
9h
Study drug IV (SEL-037) : 0-60min
Premedicate against Gout Flare5
Premedicate against infusion reaction6
X(-12h)
X (-2h)
Premedicate against infusion reaction7
X (-1h)
1 - Confirm no active vaccinations
2 - Blood pressure after sitting 5 minutes, heart rate, oral temperature, respiratory rate
3 - If a conflict occurs due to multiple assessments occurring at the same time point, the ECG may be performed +/- 30 minutes from the designated time
5 - Premedicate with colchicine 0.6 mg QD beginning at D-7 for duration of study
6 - Premedicate with fexofenadine at -12h ± 2h and -2h ± 1h prior to dose
7 - Additionally premedicate with IV methylprednisolone at -1h ± 0.5h
8 - Window for visit is +/- 1 day
9 - Blood work as subset of listed points per schedules in Appendices by cohort
10 - DECT and Inflammatory markers at EOS unless done at previous P5 visit
11 - T-Cell recall sample ONLY for Treatment Period 5 (Visit 30) only
4 - All Safety Labs indicated in individual schedule by cohort
X
X
←――――――――――――――――――――――   continuous   ―――――――――――――――――――――→
←―――――――――――――――――――   continuous  ―――――――――――――――――→
IV SEL-037
Early 
Term
V22
In Clinic
Outpatient Follow-up Visits
PK at ±2h 
from D0 
0h9 
PK blood draws should
 occur at same time
each visit ± 8 h from D0 0 hour9 
P4
D08 (28 days after P3 D0)
P5 
D21 
to 
D30
Early 
Term / 
EOS P5 
D308,10
P5
D08 (28 days after P4 D0)
V28
Infusion 
(time after dosing started)
Post-infusion 
(time after dosing started)
Cohorts 1 & 2    Phases: 
Treatment Period #4; Visit (V); Day (D); Period (P) 
Out 
patient
Treatment Period #5; Visit (V); Day (D); Period (P) 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
26 
 
 
  
 
Table 3: Schedule of Events, Cohorts 3-8, 10, 11, and 12, Part A - Treatment Periods 1-3 
 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering convention of 
associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
 
V1 
V211
V3
V5
V6
V7
V8
 D-45 
to -1
P1
D-7
P1
D-1
P1
D1
P1
D7
P1
D14
P1
D21
V9
V11
V12
V13
V14
P2
D-1
P2
D1
P2
D7
P2
D14
P2
D21
V15
V17
V18
V19
V20
Treatment Period #3; Visit (V); Day (D); Period (P) 
P3
D-1
P3
D1
P3
D7
P3
D14
P3
D21
Hour (h)
Pre-
dose
0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Informed Consent
X
Dual Energy CT Scan
X
X15
X
Inflammatory Markers
X12
X
T-Cell Recall
X12
X13
X
Demographics
X
Inclusion/exclusion
X
Medical History1
X
Safety Examinations
Predose 0h 0.25h 0.5h 0.75h
1h
1.5
2h
3h
6h
9h
Physical Examination
X
X
Concomitant medications
Vital signs2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
ECG3
X
X
X10
X
Adverse Events - Rheumatology CTC
Safety Labs
Predose 0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Safety Labs - As indicated in individual schedules4
X
X
X
X
X
X
Immunogenicity
Anti-Pegsiticase
X
X
X
X
X
Anti-Uricase
X
X
X
X
X
Anti-PEG
X
X
X
X
X
X
PK/PD Assessments
SEL-110 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SEL-037 PK
X
X
X
X
X
X
Uricase Activity
X
X
X
X
X
X
X
X
X
X
X
X
Uric Acid
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Treatment
Predose 0h 0.25h 0.5h 
0.75h 1h
1.5h
2h
3h
6h
9h
Study drug IV (SEL-110) : 0-55min14
Study drug IV (SEL-037) : 60-120 min
Premedicate against Gout Flare5
X
Premedicate against infusion reaction6
X(-12h)
X (-2h)
Premedicate against infusion reaction7
X (-1h)
1 - Confirm no active vaccinations
2 - Blood pressure after sitting 5 minutes, heart rate, oral temperature, respiratory rate
3 - If a conflict occurs due to multiple assessments occurring at the same time point, the ECG may be performed +/- 30 minutes from the designated time
5 - Premedicate with colchicine 0.6 mg QD beginning at D-7 for duration of study
6 - Premedicate with fexofenadine at -12h ± 2h and -2h ± 1h prior to dose
7 - Additionally premedicate with IV methylprednisolone at -1h ± 0.5h
8 - Window for visit is +/- 1 day
9 - Blood work as subset of listed points per schedules in Appendices by cohort
10 - ECG at 6 hr ONLY for Treatment Period 1, not for Treatment Periods 2 nor 3
11 - Gout flare premedication can be started during screening interval and does not require an on-site visit
12 - T-Cell recall sample and Inflammatory marker sample ONLY for Treatment Period 1 (Visit 4) only
13 - T-Cell recall sample ONLY for Treatment Period 3 (Visit 18) only
15 - DECT is permitted to be performed at any time between Days 21-28 (inclusive) of Treatment Period 3.
14 - In cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be infused at a single steady rate sufficient to deliver the dose volume over a period of 55 minutes concurrently with a 60 minute 
infusion of 125 mL of normal saline. In cohorts receiving ≥0.10 mg/kg SEL-110, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be changed to a steady rate 
sufficient to deliver the remainder of the dose volume for the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline.
P3
D08 (28 days after P2 D0)
P1
D0
PK blood draws should
 occur at same time
each visit ± 8 h from D0 0 
hour9 
PK at 
±2h 
from 
D0 0h9 
Post-infusion 
(time after dosing started)
Infusion 
(time after dosing started)
4 - All Safety Labs indicated in individual schedule by cohort
X
X
――――――――――――――――――――――――――   continuous   ―――――――――――――――――――――――――
←―――――――――――――――――――   continuous  ―――――――――――――――――→
IV SEL-110
IV SEL-037
Treatment Period #1; Visit (V); Day (D); Period (P) 
Early 
Term
Cohorts 3 - 8, 10, 11, & 12       Phases:
Screen
In Clinic
Treatment Period #2; Visit (V); Day (D); Period (P) 
V16
Early 
Term
Early 
Term
P2
D08 (28 days after P1 D0)
Outpatient Follow-up Visits
Outpatient Visits
V4
V10


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
27 
 
 
  
 
Table 4: Schedule of Events, Cohorts 3-8, 10, 11, and 12, Part B - Treatment Periods 4-5 
 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering convention of 
associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
V21
V23
V24
V25
V26
P4
D-1
P4
D1
P4
D7
P4
D14
P4
D21
V27
V29
V30
V31
V32
P5
D-1
P5
D1
P5
D7
P5
D14
P5
D21
Hour (h)
Pre-
dose
0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Informed Consent
T-Cell Recall
X12
X
Dual Energy CT Scan
X
X
Inflammatory Markers
X
X
Demographics
Inclusion/exclusion
Medical History1
Safety Examinations
Predose 0h 0.25h 0.5h 0.75h
1h
1.5
2h
3h
6h
9h
Physical Examination
X
Concomitant medications
Vital signs2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
ECG3
X
X
Adverse Events - Rheumatology CTC
Safety Labs
Predose 0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Safety Labs - As indicated in individual schedules4
X
X
X
X
X
Immunogenicity
Anti-Pegsiticase
X
X
X
X
X
Anti-Uricase
X
X
X
X
X
Anti-PEG
X
X
X
X
X
PK/PD Assessments
SEL-110 PK
X11
X
SEL-037 PK
X
X
X
X
X
X
Uricase Activity
X
X
X
X
X
X
X
X
X
X
X
X
Uric Acid
X
X
X
X
X
X
X
X
X
X
X
X
Study Treatment
Predose 0h 0.25h 0.5h 
0.75h 1h
1.5h
2h
3h
6h
9h
Study drug IV (SEL-037) : 0-60min
Premedicate against Gout Flare5
Premedicate against infusion reaction6
X(-12h)
X (-2h)
Premedicate against infusion reaction7
X (-1h)
1 - Confirm no active vaccinations
2 - Blood pressure after sitting 5 minutes, heart rate, oral temperature, respiratory rate
3 - If a conflict occurs due to multiple assessments occurring at the same time point, the ECG may be performed +/- 30 minutes from the designated time
5 - Premedicate with colchicine 0.6 mg QD beginning at D-7 for duration of study
6 - Premedicate with fexofenadine at -12h ± 2h and -2h ± 1h prior to dose
7 - Additionally premedicate with IV methylprednisolone at -1h ± 0.5h
8 - Window for visit is +/- 1 day
9 - Blood work as subset of listed points per schedules in Appendices by cohort
10 - DECT and Inflammatory markers at EOS unless done at previous P5 visit
11 -  Predose sample collected on Treatment Period 4 only
12 - T-Cell recall sample ONLY for Treatment Period 5 (Visit 30) only
13 - Additional observational visit at Treatment Period 5, Day 60 may be required as per section 10.1.1
Treatment #5; Visit (V); Day (D)
P5 
D21 
to 
D30
Early 
Term / 
EOS P5 
D308,10,13
Cohorts 3 - 8, 10, 11, & 12       Phases:
Treatment #4; Visit (V); Day (D)
Early 
Term
P4
D08 (28 days after P3 D0)
V28
Out 
patient
In Clinic
Outpatient Follow-up Visits
V22
P5
D08 (28 days after P4 D0)
Infusion 
(time after dosing started)
Post-infusion 
(time after dosing started)
PK blood draws should
 occur at same time
each visit ± 8 h from D0 0 hour9 
PK at 
±2h from 
D0 0h9 
4 - All Safety Labs indicated in individual schedule by cohort
X
X
←――――――――――――――――――――――   continuous   ―――――――――――――――――――――→
←―――――――――――――――――――   continuous  ―――――――――――――――――→
IV SEL-037


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
28 
 
 
  
 
Table 5: 
Schedule of Events, Cohorts 13, 15, and 17 Part C - Treatment Periods 1-5 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the cohort numbering 
convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose. 
V1 
V211 V3
V5
V6
V7
V8
 D-45 
to -1
P1
D-7
P1
D-1
P1
D1
P1
D7
P1
D14
P1
D21
V9
V11
V12
V13
V14
P2
D-1
P2
D1
P2
D7
P2
D14
P2
D21
V15
V17
V18
V19
V20
P3
D-1
P3
D1
P3
D7
P3
D14
P3
D21
V21
V23
V24
V25
V26
P4
D-1
P4
D1
P4
D7
P4
D14
P4
D21
V27
V29
V30
V31
V32
P5
D-1
P5
D1
P5
D7
P5
D14
P5
D21
Hour (h)
Pre-
dose
0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Informed Consent
X
T-Cell Recall
X
X12
X13
X
Dual Energy CT Scan
X
X14
X
X
Inflammatory Markers
X
X
X
X
Demographics
X
Inclusion/exclusion
X
Medical History1
X
Safety Examinations
Predose 0h 0.25h 0.5h 0.75h
1h
1.5
2h
3h
6h
9h
Physical Examination
X
X
Concomitant medications
Vital signs2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
ECG3
X
X
X10
X
Adverse Events - Rheumatology CTC
Safety Labs
Predose 0h 0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
9h
Safety Labs - As indicated in individual schedules4
X
X
X
X
X
X
Immunogenicity
Anti-Pegsiticase
X
X
X
X
X
Anti-Uricase
X
X
X
X
X
Anti-PEG
X
X
X
X
X
X
PK/PD Assessments
SEL-110 PK
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SEL-037 PK
X
X
X
X
X
X
Uricase Activity
X
X
X
X
X
X
X
X
X
X
X
X
Uric Acid18
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Treatment
Predose 0h 0.25h 0.5h 
0.75h 1h
1.5h
2h
3h
6h
9h
Study drug IV (SEL-110) : 0-55min14
Study drug IV (SEL-037) : 60-120 min
Premedicate against Gout Flare5
X
Premedicate against infusion reaction6
X(-12h)
X (-2h)
Premedicate against infusion reaction7
X (-1h)
1 - Confirm no active vaccinations
2 - Blood pressure after sitting 5 minutes, heart rate, oral temperature, respiratory rate
3 - If a conflict occurs due to multiple assessments occurring at the same time point, the ECG may be performed +/- 30 minutes from the designated time
5 - Premedicate with colchicine 0.6 mg QD beginning at D-7 for duration of study
6 - Premedicate with fexofenadine at -12h ± 2h and -2h ± 1h prior to dose
7 - Additionally premedicate with IV methylprednisolone at -1h ± 0.5h
8 - Window for visit is +/- 1 day
9 - Blood work as subset of listed points per schedules in Appendices by cohort
10 - ECG at 6 hr ONLY for Treatment Period 1, not for Treatment Periods 2, 3, 4 nor 5
11 - Gout flare premedication can be started during screening interval and does not require an on-site visit
12 - T-Cell recall sample ONLY for Treatment Period 1 (Visit 4) only
13 - T-Cell recall sample ONLY for for Treatment Period 3 (Visit 18)  and Treatment Period 5 (Visit 30) only
15 - Only 1 Inflammatory marker and 1 DECT sample to be collected for the end of Treatment Period 5 - may be done at V32, between V32 and EOS or at EOS Visit or at ET Visit
16 - Additional observational visit at Treatment Period 5, Day 60 may be required as per section 10.1.1
In Clinic
Outpatient Follow-up Visits
Treatment Period #4; Visit (V); Day (D); Period (P) 
V22
Early 
Term
P4
D08 (28 days after P3 D0)
V10
Screen
Early 
Term
Early 
Term
Outpatient 
Visits
Treatment Period #1; Visit (V); Day (D); Period (P) 
Treatment Period #2; Visit (V); Day (D); Period (P) 
Treatment Period #5; Visit (V); Day (D); Period (P) 
Cohorts 13, 15, & 17              Phases: 
17 - In cohorts receiving ≥0.10 mg/kg SEL-110, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be changed to a steady rate sufficient to deliver the remainder of the dose 
volume for the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline.
4 - All Safety Labs indicated in individual schedule by cohort
V4
P1
D0
X
X
←―――――――――――――――――――   continuous  ―――――――――――――――――→
IV SEL-110
IV SEL-037
V28
P5 
D21 
to 
D30
Early 
Term / 
EOS P5 
D308,15,16
P5
D08 (28 days after P4 D0)
P2
D08 (28 days after P1 D0)
Infusion 
(time after dosing started)
Post-infusion 
(time after dosing started)
PK at ±2h 
from D0 
0h9 
PK blood draws should
 occur at same time
each visit ± 8 h from D0 0 hour9 
Early 
Term
18 - Collect 2 blood samples at each timepoint for sUA measurement. Store and ship 1 sample at ambient temperature and 1 sample under frozen conditions. Refer to the Laboratory Manual for details about 
sample handling.
14 - DECT ONLY for Treatment Period 3 and is permitted to be performed at any time between Days 21-28 (inclusive) of Treatment Period 3.
←―――――――――――――――--―――――----――   continuous   ―----------――――――――――――――――――――→
V16
P3
D08 (28 days after P2 D0)
Treatment Period #3; Visit (V); Day (D); Period (P) 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
1.1. 
Schedule of Events .....................................................................................................24 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............29 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................37 
4. 
INTRODUCTION ......................................................................................................39 
4.1. 
Investigational product ...............................................................................................39 
4.2. 
Background .................................................................................................................40 
4.2.1. 
Hyperuricemia ............................................................................................................40 
4.2.2. 
Use of Uricases to Treat Hyperuricemia and Gout .....................................................40 
4.2.3. 
Other Pegylated Proteins ............................................................................................40 
4.3. 
Summary of Previous Findings of SEL-037 and SEL-110 ........................................41 
4.3.1. 
Nonclinical Animal Studies ........................................................................................41 
4.3.1.1. 
SEL-037 ......................................................................................................................41 
4.3.1.2. 
SEL-110 ......................................................................................................................42 
4.3.1.3. 
SEL-212 ......................................................................................................................44 
4.3.2. 
Previous Human Experience SEL-212, SEL-037 alone and SEL-110 alone .............45 
4.3.2.1. 
SEL-037 ......................................................................................................................45 
4.3.2.2. 
SEL-110 ......................................................................................................................46 
4.3.2.3. 
SEL-212 ......................................................................................................................47 
4.4. 
Potential Risks and Benefits .......................................................................................52 
4.4.1. 
SEL-037 ......................................................................................................................52 
4.4.2. 
SEL-110 ......................................................................................................................53 
4.4.3. 
SEL-212 ......................................................................................................................55 
4.5. 
Rationale for SEL-212 Doses Selected .......................................................................55 
4.5.1. 
Rationale for Dose Selected (Part C) ..........................................................................56 
4.6. 
Study Population .........................................................................................................57 
4.7. 
Study Rationale ...........................................................................................................57 


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5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................57 
5.1. 
Primary Objective .......................................................................................................57 
5.2. 
Secondary Objectives .................................................................................................57 
5.3. 
Exploratory objective ..................................................................................................58 
6. 
INVESTIGATIONAL PLAN .....................................................................................58 
6.1. 
Overall Study Design ..................................................................................................58 
6.2. 
Number of Subjects ....................................................................................................66 
6.3. 
Treatment Assignment ................................................................................................67 
6.3.1. 
Stopping Rules in an Individual Subject or in a Cohort .............................................67 
6.3.2. 
Safety committee ........................................................................................................68 
6.4. 
Criteria for Study Termination ...................................................................................68 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................69 
7.1. 
Subject Inclusion Criteria ...........................................................................................69 
7.2. 
Subject Exclusion Criteria ..........................................................................................69 
7.3. 
Subject Restrictions and Requirements ......................................................................71 
7.3.1. 
Medication and Therapy Restrictions .........................................................................71 
7.3.2. 
Contraception ..............................................................................................................71 
7.3.3. 
Subject Confinement ..................................................................................................71 
7.3.4. 
Blood and Sperm Donations .......................................................................................71 
7.3.5. 
Foods, Meals, Beverages and Fluid Intake .................................................................72 
7.4. 
Subject Completion and Withdrawal ..........................................................................72 
7.4.1. 
Screen Failures ............................................................................................................72 
7.4.2. 
Subject Completion ....................................................................................................72 
7.4.3. 
Enrolled Subject Withdrawal and Discontinuations ...................................................72 
7.4.3.1. 
Withdrawal Procedures ...............................................................................................72 
7.4.3.2. 
Subjects Lost To Follow-Up .......................................................................................73 
7.4.4. 
Replacement of Subjects .............................................................................................73 
8. 
TREATMENT OF SUBJECTS ..................................................................................73 
8.1. 
Description of Study Drug ..........................................................................................73 
8.2. 
Concomitant Medications and Therapies ...................................................................74 
8.2.1. 
Premedication with Antihistamines and Steroids .......................................................75 


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8.2.2. 
Management and Treatment of Infusion Reactions ....................................................75 
8.2.3. 
Gout Flares (Prevention and Treatment) ....................................................................76 
8.3. 
Treatment Compliance ................................................................................................77 
8.4. 
Randomization ............................................................................................................77 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................77 
9.1. 
Study Drug ..................................................................................................................77 
9.2. 
Study Drug Packaging and Labeling ..........................................................................77 
9.3. 
Study Drug Storage .....................................................................................................77 
9.4. 
Study Drug Preparation ..............................................................................................77 
9.4.1. 
SEL-037 Preparation ..................................................................................................78 
9.4.2. 
SEL-110 Preparation ..................................................................................................78 
9.5. 
Administration ............................................................................................................78 
9.6. 
Study Drug Accountability .........................................................................................79 
9.7. 
Study Drug Disposal ...................................................................................................79 
10. 
PHARMACOKINETIC, PHARMACODYNAMIC AND RADIOLOGIC 
ASSESSMENTS.........................................................................................................79 
10.1. 
Sample Collection .......................................................................................................79 
10.1.1. 
Additional Observational Visit ...................................................................................80 
10.2. 
Analytical Procedures .................................................................................................80 
10.3. 
Pharmacokinetic Assessments ....................................................................................80 
10.4. 
Radiologic Assessments .............................................................................................81 
10.5. 
Inflammatory Marker Assessments ............................................................................81 
10.6. 
T-cell recall Assessments ...........................................................................................81 
11. 
ASSESSMENT OF SAFETY .....................................................................................82 
11.1. 
Safety Parameters .......................................................................................................82 
11.1.1. 
Demographic/Medical History ...................................................................................82 
11.1.2. 
Vital Signs ..................................................................................................................82 
11.1.3. 
Weight and Height ......................................................................................................82 
11.1.4. 
Physical Examination .................................................................................................82 
11.1.5. 
Electrocardiogram (ECG) ...........................................................................................82 
11.1.6. 
Laboratory Assessments .............................................................................................82 


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11.1.7. 
Immunogenicity ..........................................................................................................83 
11.2. 
Adverse and Serious Adverse Events .........................................................................83 
11.2.1. 
Definitions ..................................................................................................................83 
11.2.1.1. 
Adverse Event .............................................................................................................83 
11.2.1.2. 
Unexpected Adverse Events and Unexpected Suspected Drug Reaction ..................83 
11.2.1.3. 
Serious Adverse Event ................................................................................................83 
11.2.2. 
Recording Adverse Events .........................................................................................84 
11.2.2.1. 
Adverse Event Term/Name/Description .....................................................................84 
11.2.2.2. 
Relationship to Study Drug ........................................................................................84 
11.2.2.3. 
Adverse Event Intensity/Severity Grading .................................................................85 
11.2.2.4. 
Assessment of Outcome .............................................................................................86 
11.2.2.5. 
Action taken with study drug ......................................................................................86 
11.2.2.6. 
Laboratory and Diagnostic Abnormalities as Adverse Events ...................................86 
11.2.2.7. 
Pregnancy ...................................................................................................................86 
11.3. 
Reporting Adverse Events ..........................................................................................87 
11.3.1. 
Adverse Event Reporting Period ................................................................................87 
11.3.2. 
SAE Reporting Procedures .........................................................................................87 
11.3.3. 
Regulatory Reporting Requirements for SAEs ...........................................................88 
11.3.4. 
Reporting Safety Information to the IRB ...................................................................88 
11.4. 
Follow-up of Adverse Events .....................................................................................88 
12. 
STATISTICS ..............................................................................................................89 
12.1. 
Sample Size Determination ........................................................................................89 
12.2. 
Safety Analysis Set .....................................................................................................89 
12.3. 
PK Analysis Set ..........................................................................................................89 
12.4. 
PK Analyses ................................................................................................................89 
12.5. 
Pharmacodynamic Analyses .......................................................................................90 
12.6. 
Radiologic Analysis ....................................................................................................90 
12.7. 
Inflammatory Markers Analysis .................................................................................90 
12.8. 
Safety Analyses ..........................................................................................................90 
12.8.1. 
Demographic and Baseline Characteristics ................................................................90 
12.8.2. 
Adverse Events ...........................................................................................................90 


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12.8.3. 
Clinical Laboratory Tests ...........................................................................................91 
12.8.4. 
Cardiovascular Safety .................................................................................................91 
12.8.5. 
Vital Signs ..................................................................................................................91 
12.8.6. 
Physical Examination .................................................................................................91 
12.8.7. 
Immunogenicity ..........................................................................................................92 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................92 
13.1. 
Study Monitoring ........................................................................................................92 
13.2. 
Audits and Inspections ................................................................................................92 
13.3. 
Institutional Review Board (IRB) ...............................................................................92 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................93 
14.1. 
Regulatory Authority Approval ..................................................................................93 
14.2. 
Protocol Modifications ...............................................................................................93 
15. 
ETHICS ......................................................................................................................93 
15.1. 
Ethics Review .............................................................................................................93 
15.2. 
Ethical Conduct of the Study ......................................................................................94 
15.3. 
Written Informed Consent ..........................................................................................94 
16. 
DATA HANDLING AND RECORDKEEPING .......................................................95 
16.1. 
Case Report Form Completion and Source Documentation .......................................95 
16.2. 
Data Management .......................................................................................................95 
16.3. 
Study Site Close-Out ..................................................................................................95 
16.4. 
Retention of Study Documents and Records ..............................................................95 
16.5. 
Inspection of Records .................................................................................................96 
17. 
PUBLICATION POLICY ..........................................................................................96 
17.1. 
Ownership ...................................................................................................................96 
17.2. 
Confidentiality ............................................................................................................96 
17.3. 
Publication ..................................................................................................................97 
18. 
LIST OF REFERENCE ..............................................................................................98 
19. 
APPENDICES ..........................................................................................................102 
19.1. 
Common Toxicity Criteria for Rheumatology, version 2.0 ......................................102 
19.1.1. 
Clinical Signs and Symptoms ...................................................................................102 
19.1.2. 
Laboratory Data ........................................................................................................107 


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19.2. 
NIAID/FAAN Clinical Criteria for Anaphylaxis .....................................................109 
19.3. 
Reconstitution and Dilution for Infusion Instructions ..............................................110 
19.3.1. 
SEL-037 Instructions ................................................................................................110 
19.3.2. 
SEL-110 Instructions ................................................................................................112 
19.4. 
Laboratory Schedules by Cohort ..............................................................................114 
19.5. 
New York Heart Association Functional Classification ...........................................117 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events, Cohorts 1 & 2, Part A - Treatment Periods 1-3 .........................24 
Table 2: 
Schedule of Events, Cohorts 1 & 2, Part B - Treatment Periods 4-5 .........................25 
Table 3: 
Schedule of Events, Cohorts 3-8, 10, 11, and 12, Part A - Treatment Periods 
1-3 ...............................................................................................................................26 
Table 4: 
Schedule of Events, Cohorts 3-8, 10, 11, and 12, Part B - Treatment Periods 
4-5 ...............................................................................................................................27 
Table 5: 
Schedule of Events, Cohorts 13, 15, and 17 Part C - Treatment Periods 1-5 .............28 
Table 6: 
Abbreviations and Specialist Terms ...........................................................................37 
Table 7.  
Summary of SEL-110 Whole Blood PK Parameters ..................................................49 
Table 8: 
Investigational Product ...............................................................................................74 
Table 9: 
Laboratory Schedule - Cohorts 1 & 2 (SEL-037) .....................................................114 
Table 10: Laboratory Schedule - Cohorts 3-8, 10, 11, and 12 (SEL-212) ................................115 
Table 11 
Laboratory Schedule – Part C: Cohorts 13, 15, and 17 (SEL-212) ..........................116 
Table 12.  Laboratory Schedule for Suspected Infusion Reaction, All Cohorts ........................117 
 


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LIST OF FIGURES 
Figure 1: 
Pharmacodynamic Activity of SEL-212 and Components (SEL-037 and 
SEL-110) .....................................................................................................................48 
Figure 2. 
Dose Proportionality of SEL-110 AUC ......................................................................51 
Figure 3. 
Effect of SEL-037 on SEL-110 Systemic Exposure (AUC0-inf) (ANOVA) ...............52 
Figure 4: 
Overall scheme of trial (Part A and Part B) ................................................................59 
Figure 5: 
Overall scheme of trial (Part C) ..................................................................................60 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 6: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUCinf 
Serum concentration-time curve from time 0 to infinity 
AUClast 
Serum concentration-time curve from time 0 to the time of last 
quantifiable concentration 
CBC 
Complete blood count 
CL 
Serum clearance of drug 
Cmax 
Maximum observed serum concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Computed tomography 
D 
Day, Study day 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
FAAN 
Food Allergy & Anaphylaxis Network 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
H 
Hour 
HED 
Human equivalent dose 
HIV  
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 


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Abbreviation or Specialist Term 
Explanation 
Kel 
Terminal elimination rate constant 
Kg 
Kilograms 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligrams 
Ml 
Milliliters 
MTD 
Maximum tolerated dose 
NIAID 
National Institute of Allergy and Infectious Diseases 
PD 
Pharmacodynamic 
PEG 
Polyethylene glycol 
PK 
Pharmacokinetic 
PTT 
Partial thromboplastin time 
SAE 
Serious adverse event 
SEM 
Standard error of the mean 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse events 
Tmax 
Time at which Cmax occurred 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia  
V 
Visit 
Vss 
Apparent volume of distribution at equilibrium 
 


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4. 
INTRODUCTION 
4.1. 
Investigational product 
SEL-212 is a combination product containing SEL-037 (pegsiticase, Recombinant Pegylated 
Candida Urate Oxidase) and SEL-110 a drug product consisting of a biodegradable polymeric 
nanoparticle consisting of PLA (poly(D,L-lactide)) and PLA-PEG (poly(D,L-lactide)-block-
poly-(thylene-glycol)) encapsulating rapamycin. 
 
SEL-037 (pegsiticase; Recombinant Pegylated Candida Urate Oxidase) is a lyophilized 
recombinant uricase (urate oxidase) conjugated to multiple 20 kDa molecular weight 
polyethylene glycol (PEG) molecules.  The uricase component of SEL-037 is cloned from the 
yeast Candida utilis (Koyama, 1996) and expressed in Escherichia coli for production 
(Bomalaski, 2002).  The uricase component catalyzes the conversion of uric acid to the more 
soluble compound allantoin that is then readily excreted and is being developed to reduce 
hyperuricemia in chronic gout patients refractory to conventional therapy. SEL-037 has been 
given to humans in a single ascending dose escalation Phase 1 clinical study SEL-037/101 and 
was given in a single fixed dose of 0.4 mg/kg with or without SEL-110 in a Phase 1b clinical 
study SEL-212/101.  
SEL-110, (PLA, PLA-PEG nanoparticle encapsulating rapamycin) is designed to inhibit the 
formation of anti-drug antibodies (ADAs) when concomitantly administered with a biologic drug 
during the first few doses of the biologic. When SEL-110 is dosed in this manner it induces 
durable, antigen-specific immune tolerance to the biologic therapeutic in animal models.  SEL-
110 has demonstrated the ability to induce antigen specific immune tolerance to pegylated 
uricase (SEL-037) in wild type mice, uricase deficient (knock-out) mice, rats and cynomolgus 
monkeys. SEL-110 was tested in man for the first time in a single ascending dose clinical study 
SEL-212/101. All of the proposed SEL-110 alone doses (0.03 mg/kg, 0.1mg/kg, 0.3mg/kg and 
0.5mg/kg) have been completed.  We believe we have identified a MTD in this clinical study for 
SEL-110 of 0.3 mg/kg as discussed further in Section 4.3.2.2.  
SEL-212 is the combination (i.e. sequentially administered) of SEL-110 and SEL-037 in order to 
prevent the formation of anti-drug antibodies (ADAs) and induce immune tolerance to SEL-037 
such that subsequent doses of SEL-037 will remain effective at lowering uric acid levels in 
patients. SEL-212 was evaluated in a single dose clinical study (SEL-212/101).  The highest dose 
cohort of SEL-212 proposed was not enrolled as the SEL-110 component dose exceeded what 
we believe was the MTD for SEL-110. 
The current multiple dose study of SEL-212 evaluates the safety, pharmacokinetics, 
immunogenicity, and the ability of SEL-212 to reduce blood uric acid levels, reduce/prevent the 
development of anti-uricase and anti-pegsiticase antibodies in patients with symptomatic gout 
and elevated uric acid levels.  


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4.2. 
Background 
4.2.1. 
Hyperuricemia 
Uric acid is a poorly soluble end product of purine nucleotide metabolism.  Humans do not have 
uricases to metabolize uric acid and renal clearance is the sole method of elimination of uric acid 
(Wu, 1989; Wu, 1992; Oda, 2002).  Hyperuricemia can occur when excess circulating uric acid 
overwhelms renal excretion capacity or when renal clearance is impaired.  As uric acid 
concentrations rise and reach saturation or super-saturation levels, urate crystals can precipitate 
in tissues.  This can lead to gout, a painful joint inflammation, due to the precipitation of urate 
crystals in joints.  This can also lead to tophus formation, destructive arthritis and renal calculi.  
The American College of Rheumatology guidelines recommend lowering uric acid levels to at 
least below 6 mg/dL (Khanna, 2012a; Khanna, 2012b).   
There are 5 lines of therapy for the reduction of uric acid levels and gout treatment: 1) 
nonpharmacological therapy through diet, lifestyle and comorbidity management, 2) 
symptomatic treatment with NSAIDS, colchicine, or corticosteroids, 3) xanthine oxidase 
inhibitors that inhibit uric acid production like allopurinol, 4) uricosuric agents that improve uric 
acid renal clearance such as probenecid and febuxostat, and 5) uricase therapy with pegloticase 
(Krystexxa®) in patients with severe gout who are refractory to other treatments. 
4.2.2. 
Use of Uricases to Treat Hyperuricemia and Gout 
Uricases metabolize uric acid to allantoin, which is readily soluble and excreted.  Uricase 
therapies infused into humans have been shown to reduce blood uric acid levels and improve 
gout symptoms.  Rasburicase (Elitek®), an unpegylated recombinant uricase cloned from 
Aspergillus flavus (Oldfield, 2006; Cammalleri, 2007), is approved for management of uric acid 
levels in patients with tumor lysis syndrome (Elitek®).  Krystexxa® (pegloticase) is a 
recombinant uricase (primarily porcine with a carboxyl-terminus sequence from baboon) bound 
by multiple 10 kDa PEG molecules approved for the treatment of refractory gout (Biggers, 2008; 
Sherman, 2008).  The conjugation of uricase with PEG is thought to decrease the 
immunogenicity and increase the half-life of the uricase molecules (Zalipsky, 1992; Mehvar, 
2000; Fishburn, 2008; Veronese, 2008).  The clinical experience with Krystexxa®  has shown that 
a significant number of patients will develop anti-drug antibodies which limit the long term 
efficacy of the drug (Lipsky, 2014). 
4.2.3. 
Other Pegylated Proteins 
Pegylated proteins are also approved for use in other indications such as pegylated E. coli 
asparginase (Oncaspar) as a component of chemotherapy for the treatment of acute 
lymphoblastic leukemia and bovine pegademase (pegylated adenosine deaminase) as a 
replacement therapy for adenosine deaminase deficiency in infants and children. 


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4.3. 
Summary of Previous Findings of SEL-037 and SEL-110 
4.3.1. 
Nonclinical Animal Studies 
4.3.1.1. 
SEL-037 
SEL-037 in rodent models reduces serum uric acid concentrations in a dose related manner at 
doses tested up to 1.2 mg/kg.  
Nonclinical drug metabolism and pharmacokinetic studies of SEL-037 showed dose-dependent 
increases in exposure in both the rat and monkey, though terminal half-life was considerably 
longer in the monkey.  The distribution study in rat indicated accumulation in the lungs, kidneys 
and bladder at all time points relative to the concentration found in plasma and other tissues.  
Renal excretion is the primary route of elimination of SEL-037 in rats. 
The nonclinical toxicology program consists of single intravenous dose toxicity studies 
conducted in rats and monkeys at doses up to 58.2 mg/kg and 28 day general toxicity studies in 
rats and monkeys in doses up to 10 mg/kg and 5 mg/kg, respectively, a reproductive and early 
embryonic developmental toxicology study conducted in rats up to a dose of 10 mg/kg, an 
immunotoxicology study conducted in guinea pigs, an immunogenicity study conducted in 
monkeys, an in-vitro hemolysis test conducted in blood obtain from New Zealand White rabbits, 
and a 28-day injection site evaluation study conducted in monkeys.  
SEL-037 was well tolerated and there were no clinically significant findings observed in any of 
the above studies with the exception of immunotoxicity noted in the guinea pig and a decrease in 
complement in the monkey.  Following sensitization in the guinea pig, a strong anaphylactic 
reaction leading to death in all dosing groups was observed.  In monkeys, following weekly 
intravenous administration, SEL-037 produced a low titer of non-neutralizing antibodies to SEL-
037 and uricase at all dosing levels.  Antibodies were noted within 14 days of the initiation of 
dosing.  In general, antibodies to PEG were not observed.  A decrease in complement was also 
noted in monkeys at 5 mg/kg which appears to return to near normal values following a 4 week 
recovery period.  These changes noted in complement may be secondary to consumption of 
formed immune complexes. 
In addition, SEL-037 was further evaluated in multidose intravenous toxicity studies of five 
monthly repeated doses of SEL-037 with a one month recovery in rats and cynomolgus 
monkeys.   
In the GLP repeated dose study of SEL-037 in rats (Study 1933-008), reversible test article-
related clinical pathology findings included mild transient prolongation in APTT and mild to 
moderate transient decreases in absolute reticulocyte counts that resolved despite continued 
dosing. Test article-related slight increased incidence of minimal to mild mononuclear cell 
infiltration and/or fibrosis of the heart in both males and females remaining slightly increased 
over that of controls following the recovery phase. Based on the reversibility and/or minimal 
severity of the findings, 8.0 mg/kg/dose, the highest dose level tested, was identified as the 
NOAEL for repeated doses of SEL-037 in rats.   


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In the GLP repeated dose study of SEL-037 in cynomolgus monkeys (Study 1933-009), there 
were no adverse findings noted. Test article-related effects were limited to watery feces which 
were observed in males in all treated groups periodically throughout the treatment phase, but not 
observed during the recovery period and were not considered to be adverse due to the sporadic 
and minimal nature of the finding. Based on these data, the NOAEL for this study was 4.0 mg/kg 
SEL-037, the highest dose level tested. 
4.3.1.2. 
SEL-110   
Consistent with ICH guidance, SEL-110 has been evaluated in nonclinical studies to support 
clinical study in humans, including safety pharmacology studies in rats and monkeys, as well as 
single and multiple dose toxicology studies in rats and monkeys.  Immunotoxicology and local 
injection site reactions also were evaluated as a component of a repeat dose study in monkeys 
(Study 1933-004).  Initial nonGLP dose finding studies of SEL-110 toxicity were completed in 
Sprague Dawley rats (Study 14-04312-N1) and cynomolgus monkeys (Study 14-04311-N1) in 8-
week studies (given biweekly five times by IV bolus).   
In the GLP repeated dose study of SEL-110 in rats (Study 1933-005), 1, 3 and 6 mg/kg were 
given as an intravenous slow bolus 3 times separated by 28 days. SEL-110 produced dose-
dependent decreases in body weight and food consumption over the course of the study, 
primarily in the male animals that persisted for both sexes in the 6 mg/kg dose group through the 
end of the recovery period.  Observation of reduced sizes of reproductive organs including testes 
and ovaries, as well as microscopic correlates, were observed at the 3 and 6 mg/kg dose levels. 
These changes are consistent with the known effect of rapamycin on the gonadotropin axis (Roa, 
2009).  Microscopic changes were observed in the heart (mild cardiomyopathy) in males at the 
high dose 6.0 mg/kg group.  At recovery, bilateral incipient cataracts were present in all male 
animals in the 6.0 mg/kg/dose group.  Cataracts are a known toxicity of rapamycin in male rats, 
which is thought to be related to the development of hyperglycemia (Rapamune NDA 21-083). 
Based on the adverse findings observed at 3 and 6 mg/kg/dose including effects on the male 
reproductive system, 1 mg/kg/dose was identified as the No-Observed-Adverse-Effect-Level 
(NOAEL) for SEL-110 (rapamycin containing nanoparticle) when administered as a bolus 
intravenous injection on three occasions (Days 1, 29, and 57) in rats. 
While adverse effects of rapamycin in the male rat reproductive system are not unexpected (e.g., 
Chen et al., 2013), they have been shown to be reversible (Rovira et al., 2012).  Because the 
major impact of SEL-110 was on the seminiferous epithelium, which produces the spermatozoa, 
it is important for the recovery period to span at least one spermatogenic cycle.  In rats, 
spermatogenesis is approximately 53 days (Gray et al., 2004) and is followed by approximately 
8-10 days during which the sperm enter and mature in the epididymis.  Because there were 
findings of nearly empty epididymal lumens (which account for the reduced epididymal 
weights), it is important to allow the recovery period to span at least 63 days before looking for 
signs of potential recovery.  In the completed toxicology studies the recovery period was 30 
days. 
In response to the findings involving the reproductive organs of rats in Study 1933-005, the 
Sponsor conducted Study 1933-013, an 8-week toxicity study in rats with a recovery period of up 


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to 36 weeks. This study examined the effects produced when both male and female rats were 
treated with the high dose of SEL-110 (6 mg/kg) administered as IV bolus injections on study 
days 1, 29, and 57.  A total of 195 animals (75 males and 120 females) were randomly assigned 
by weight to control or treatment groups for the dosing period of the study. Animals were 
euthanized at 61 days (4 days after the last administration) and at times during the recovery 
period correlating with successive spermatogenic cycles in male rats.  Histopathologic 
examination of the organs in the reproductive systems of both males and females was performed. 
In males, recovery appeared to begin as soon as Day 124, when active degeneration of germ cells 
was no longer identified and early spermatocytes were regularly observed suggesting that 
spermatogonial mitotic activity continued and spermatogenesis was starting to resume. Absence 
of spermatids and pachytene spermatocytes was likely the result of degeneration of those cell 
types at Day 61 and depletion may have contributed to the lower mean testis weight at this time 
point. By Day 187, 20% of animals showed testes within normal limits and in many animals, 
tubules displayed normal spermatogenesis. By Day 250, the amount of sperm present in all 
animals was within normal limits, suggesting full recovery. The testes of 40% of animals were 
within normal limits. At Days 187, 250, and 313, varying degrees of tubular atrophy were 
present in over half of the animals. Most cases were minimal to mild and the majority of the 
tubules displayed normal spermatogenesis. In females, differences in follicular cyst formation 
and decreased corpora lutea were observed between rats at the 6.0 mg/kg dose and in controls at 
Days 61 and 89. However, differences were minor and may have represented a spectrum of 
normal age-related changes. Notably, at Day 118 there were no microscopic differences between 
control animals and those at 6.0 mg/kg/dose.  In females, the partial reversibility of ovarian 
findings seen previously in the rat was shown to be completely reversible during extended 
recovery. The return of spermatogenesis and normal levels of sperm in many male rats suggest 
recovery from the original testicular effects. In some rats the presence of atrophic tubules at the 
end of the recovery period may represent partial recovery or may have been related to normal 
senescence. In either case, in both male and female rats, there was nonetheless strong evidence of 
reversibility of the toxic effects of high dose (6 mg/kg) SEL-110 on reproductive organs in both 
female and male rats. 
In the multi-dose study of SEL-110 in cynomolgus monkeys (Study 1933-006), 0.3, 1.0 and 3.0 
mg/kg were given as an intravenous slow bolus 3 times separated by 28 days. SEL-110 was well 
tolerated at all doses, although there were observations of inappetence, vomitus and watery feces 
in males and females at the 1.0 and 3.0 mg/kg doses. It should be noted that reproductive organ 
toxicity was not observed in Cynomolgus monkeys and no adverse findings were observed in the 
reproductive tracts of either sex at any time or at any dose level. Additionally, consistent with the 
immunosuppressive action of rapamycin, test article related microscopic findings of minimal 
follicular lymphoid depletion in the spleen in males and females at all dose levels and lymph 
nodes (mandibular and mesenteric) in males and females at 1.0 and 3.0 mg/kg were observed, 
but were not severe enough to be considered adverse.  The no-observed-adverse-effect level 
(NOAEL) for this study was 3.0 mg/kg for males and females, the highest dose level tested. 
In order to provide more comprehensive PK data, the Sponsor also undertook an additional GLP 
rat PK study (1933-014) that examined dose levels of 0.5, 1.5, and 3 mg/kg of SEL-110.  In this 
study whole blood samples containing SEL-110/rapamycin were analyzed using a new validated 


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GLP assay.  At the 0.5 mg/kg dose level of SEL-110 reported in study 1933-014, AUC0-720 was 
determined to be 43,300 ng*hr/mL for SEL-110 administered alone and 57,700 ng*hr/mL for 
SEL-110 administered in combination with 0.4 mg/kg of SEL-037.  At the 1.5 mg/kg dose level 
of SEL-110, AUC0-720 was 289,000 ng*hr/mL for SEL-110 administered alone and 243,000 
ng*hr/mL for SEL-110 administered in combination with 0.4 mg/kg of SEL-037.  These 
exposures are significantly higher than the AUC0-672 of 5,100 ng*hr/mL previously reported in 
the 1933-005 study, which used a non-validated bioanalytical method. This difference was due to 
using a validated assay in the 1933-014 study that overcame the extraction limitations 
experienced previously when attempting to measure high concentrations of SEL-110/rapamycin 
in rat whole blood at the early PK time points for study 1933-005. Based on these results, the 
AUC corresponding to the 1 mg/kg NOAEL (study 1933-005) is conservatively estimated to be 
86,600 ng*hr/mL and therefore, using the recommended AUCNOAELrat/2, the data support clinical 
doses with 4-week AUC values of 43,400 ng*hr/mL. 
4.3.1.3. 
SEL-212 
Consistent with ICH guidance, SEL-212 has been evaluated in nonclinical studies to support 
clinical study in humans, including safety pharmacology studies in monkeys, as well as a single 
dose toxicology study in rats, a two dose toxicology study in Cynomolgus monkeys and a 
repeated dose toxicology study in Cynomolgus monkeys. 
Consistent with the 3 R’s principle, a modified acute toxicology study of SEL-212 in 
Cynomolgus monkeys was conducted (Study 1933-011). Animals received a slow bolus 
intravenous injection on Day 1 and Day 14 with animals sacrificed 24 hours after the second 
injection. The groups were SEL-110 alone at 0.3, 1 and 3 mg/kg, SEL-037 at 2.0 mg/kg with 
SEL-110 at 0.3, 1.0, and 3.0 mg/kg, SEL-037 at 5.0 mg/kg with SEL-110 at 0.3, 1.0 and 3.0 
mg/kg as well as 3 control groups of saline, empty nanoparticle (same composition of SEL-110 
but without the rapamycin) and SEL-037 at 5.0 mg/kg.  SEL-110 (alone or in combination with 
SEL-037) administered by intravenous injection 14 days apart for a total of 2 doses did not result 
in adverse findings.  Evidence of an inflammatory effect was noted in groups receiving 1.0 or 
3.0 mg/kg SEL-110 (rapamycin) as indicated by minimal to mild increases in fibrinogen and 
microscopic changes consisting of granulomatous inflammation, decreased hematopoietic 
cellularity, and abscess of the femoral bone marrow. There were no adverse effects of SEL-037 
or SEL-110 given alone or in combination and no evidence of exacerbation of effects of either 
component on the other one.  Based on all of the data, the NOAEL for the combination (SEL-
212) was 3.0 mg/kg SEL-110 and 5.0 mg/kg SEL-037.      
In rats, a single dose, slow bolus intravenous study of SEL-212 was conducted with the main 
group sacrificed 24 hours after dosing and the recovery group sacrificed 14 days after dosing 
(Study 1933-010). The groups included SEL-110 alone at 1, 3 and 6 mg/kg, SEL-037 at 4.0 
mg/kg with SEL-110 at 1, 3, and 6 mg/kg, SEL-037 at 10 mg/kg with SEL-110 at 1, 3 and 6 
mg/kg as well as 3 control groups of saline, empty nanoparticle (same composition of SEL-110 
but without the rapamycin) and SEL-037 at 10 mg/kg. A single intravenous dose of SEL-110 
(alone or in combination with SEL-037) administered to rats resulted in adverse mean body 
weight decreases compared to control in males (at 3 and 6 mg/kg) and microscopic findings (at 


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1, 3, and 6 mg/kg) that were noted in the heart and correlated to hematology findings consistent 
with inflammation (increased circulating neutrophils and/or monocytes and increased 
fibrinogen).  The microscopic finding in the heart was considered to be adverse due to the trend 
towards increased incidence and severity over the course of the recovery phase.  
In the multi-dose study of SEL-212 in Cynomolgus monkeys (study 1933-007), the toxicity of 
repeated doses of SEL-037 alone, SEL-110 alone, and the combination product SEL-212 was 
assessed over 16 weeks with a one month recovery.  Once monthly IV administration of SEL-
110 for a total of 3 doses (alone or in combination with SEL-037) plus two additional doses of 
SEL-037 alone did not result in adverse findings. Microscopic findings related to SEL-110 
consisted of follicular lymphoid depletion in the spleen and lymph nodes (mandibular and 
mesenteric). Microscopic finding related to SEL-037 consisted of minimal follicular lymphoid 
hyperplasia in the spleen and/or lymph nodes (mesenteric, mandibular) of some animals. SEL-
110-related clinical pathology changes consisted of infrequent minor increases in lymphocytes, 
monocytes, fibrinogen and/or eosinophils. Clinical signs related to SEL-110 consisted of watery 
feces and periocular erythema and/or swelling in individual males and females. Based on these 
data, the NOAEL for the study was 3.0 mg/kg SEL-110 when administered alone or in 
combination with SEL-037 and was 4.0 mg/kg SEL-037 when administered alone or in 
combination with SEL-110. 
Local irritation was evaluated in a nonGLP repeated dose study of SEL-212 in Cynomolgus 
monkeys to assess anti-drug antibodies (Study 1933-004). There was no evidence of dermal 
irritation with repeated dosing of SEL-212.   
4.3.2. 
Previous Human Experience SEL-212, SEL-037 alone and SEL-110 
alone 
4.3.2.1. 
SEL-037 
To date there has been one completed clinical study (Phase I Study SEL-037/101) in humans for 
SEL-037 under IND 126034.  Doses of 0.1, 0.2, 0.4, 0.8 and 1.2 mg/kg SEL-037 administered as 
single IV infusions to otherwise healthy patients with screening serum uric acid > 6 mg/dL 
demonstrated no evidence of safety signals as no SAEs or clinically significant treatment-
emergent adverse events (TEAEs). SEL-037 demonstrated potent dose-dependent reductions in 
serum uric acid levels that were below quantification limits from Study Day 2 for all subjects 
(N=22). The duration of the PD effect was durable to Day 7 for all except 1 subject and to Day 
30 in 1 subject. Duration appeared to be subject-dependent, not dose-dependent. The presence of 
ADA generally correlated with enhanced clearance of SEL-037 and diminished 
pharmacodynamic activity of SEL-037 at Study Day 14 in 3 subjects (0.1 mg/kg), 2 subjects (0.2 
mg/kg), 3 subjects (0.4 mg/kg), and 2 subjects (0.8 mg/kg). At Study Day 30, two subjects with 
very low anti-uricase antibodies had serum uric acid concentrations below 1 mg/kg. The clinical 
study report was submitted to IND 126034.  
A second Phase I clinical study (SEL-212/101) in humans for SEL-212 (the combination of SEL-
110 and SEL-037) under IND 124184 is complete. SEL-212 in this clinical study was tested as a 
single dose where increasing amounts of SEL-110 were combined with SEL-037 at a fixed dose 


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level. In this study there were 4 cohorts of SEL-110 alone, 6 cohorts of the combination SEL-212 
(SEL-110 with SEL-037), and one cohort of SEL-037 alone.  In the cohort of subjects who 
received SEL-037 alone (0.4 mg/kg), one serious adverse event (SAE) of non-study drug-related 
atrial fibrillation was reported.  In addition, among the 5 subjects who received 0.4 mg/kg SEL-
037, the pharmacodynamic activity of SEL-037 was demonstrated by rapid reduction in serum 
uric acid levels (Figure 1). Data for this clinical study has been submitted to the FDA under IND 
124184.  
Additionally a similar product, designated Uricase-PEG 20 and manufactured by EnzymeRx 
(Paramus, NJ) was evaluated in two Phase 1 clinical studies under IND 009800. The first study 
(NCT01038947) examined the safety, pharmacokinetics and pharmacodynamics of Uricase-PEG 
20 after intramuscular administration and the second study (NCT1021241) examined the safety, 
pharmacokinetics and pharmacodynamics of Uricase-PEG 20 after intravenous administration. In 
both studies, Uricase-PEG 20 was found to be well tolerated and effective in reducing serum uric 
acid levels. 
4.3.2.2. 
SEL-110 
SEL-110 was investigated in the completed Phase I study (SEL-212/101) in a total of 28 subjects 
with elevated uric acid levels (excluding the potential need for replacement subjects) who were 
dosed in four cohorts in a stepwise ascending manner. Within each cohort, five subjects received 
active drug substance and two subjects received placebo (saline). The doses of SEL-110 
evaluated were 0.03, 0.1, 0.3, and 0.5 mg/kg. In that study, overall, SEL-110 was well tolerated, 
at doses < 0.5 mg/kg, and the majority of TEAEs were mild or moderate in severity. Treatment-
emergent AEs (all causality) that occurred in ≥ 2 subjects who received SEL-110 alone (N=20) 
were headache (7 subjects, 35%), infusion related reaction (4 subjects, 20%), dizziness (2 
subjects, 10%), paresthesia (2 subjects, 10%), rash maculopapular (2 subjects, 10%), and 
stomatitis (2 subjects, 10%).  Two subjects each experienced SAEs of stomatitis at the highest 
dose of SEL-110 (0.5 mg/kg). The events were assessed as severe and related to study drug, and 
the subjects recovered from the events. As a result of these events, the Sponsor did not 
investigate planned doses of the combination drug (SEL-212) that had the 0.5 mg/kg SEL-110 
dose level as a component. Stomatitis is a known adverse event associated with rapamycin, the 
active ingredient in SEL-110. Data for this trial has been submitted to IND 124184.  
Additionally, the components of SEL-110 have been in previous clinical trials. The nanoparticles 
primarily consist of the class of biodegradable lactide polymers, part of the family of 
poly(lactide-co-glycolide) (PLGA) biodegradable polymers such as those found in the Food and 
Drug Administration (FDA) approved absorbable sutures Vicryl® and Dexon® and FDA 
approved products Zoladex®, Risperdal® Consta®, and Vivitrol®. Rapamycin (sirolimus) is the 
active ingredient in Rapamune, an FDA approved product for the prevention of organ rejection 
in kidney transplant patients.   
SEL-110 at any of the dose levels tested alone has not demonstrated any effect on serum uric 
acid levels. 


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4.3.2.3. 
SEL-212 
In the completed Phase I study of SEL-212, six cohorts received a combination of SEL-037 at a 
dose of 0.4 mg/kg and increasing doses of SEL-110 (0.03, 0.1, 0.15, and 0.3 mg/kg).  Adult male 
and female subjects (N= 36) were enrolled on a dose level (cohort) basis with 5 subjects per 
cohort, with each cohort administered study drug in an ascending, stepwise manner. In addition, 
the order of administration was reversed and the time of administration between the components 
of SEL-212 was separated by 48 hours rather than sequentially and immediately. Safety and 
tolerability, pharmacodynamic activity, and pharmacokinetics of SEL-212 were assessed. 
Overall, SEL-212 was well tolerated, and the majority of TEAEs were mild or moderate in 
severity. Treatment-emergent AEs that occurred in ≥ 2 subjects who received SEL-212 (N=31) 
were headache (4 subjects, 13%), rash (4 subjects, 13%), dizziness (3 subjects, 9.7%), dyspnea 
(3 subjects, 9.7%), nausea (3 subjects, 9.7%), aphthous ulcer (2 subjects, 6.5%), arthralgia (2 
subjects, 6.5%), flushing (2 subjects, 6.5%), gout (2 subjects, 6.5%), pneumonia (2 subjects, 
6.5%), and rash pruritic (2 subjects, 6.5%). Two subjects who received SEL-212 (0.1 mg/kg 
SEL-110 + 0.4 mg/kg SEL-037) were reported with SAEs that were moderate in intensity and 
assessed by the investigator as related to study drug. One subject experienced drug 
hypersensitivity, and the other subject experienced acute kidney injury and pneumonia (assessed 
by the Sponsor as not likely related to study drug). Both subjects recovered from the events. A 
third subject who received SEL-212 (0.15 mg/kg SEL-110 + 0.4 mg/kg SEL-037) had SAEs of 
upper gastrointestinal hemorrhage, small bowel obstruction, and intestinal mass that were 
assessed as not related to study drug. The subject recovered from these events. 
SEL-212 demonstrated pharmacodynamic activity in reducing serum uric acid levels rapidly at 
the SEL-037 dose tested (0.4 mg/kg) and reducing or preventing the formation of anti-uricase 
antibodies in a dose dependent fashion.  The uric acid level of all subjects treated with SEL-212 
dropped to below 0.1 mg/dL within 24 hours after infusion. SEL-110 appeared to inhibit the 
formation of anti-uricase antibodies in a dose-dependent manner correlating with more sustained 
control of uric acid levels (Figure 1).  Evaluation of anti-uricase, anti-PEG, and anti-pegsiticase 
antibodies showed that anti-uricase antibodies were the most sensitive measure of ADAs in the 
Phase 1 study, corresponding with decreased pharmacodynamic activity of SEL-037 as 
evidenced by increased serum uric acid levels. 


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Figure 1: 
Pharmacodynamic Activity of SEL-212 and Components (SEL-037 and 
SEL-110) 
 
Pharmacokinetic assessments of concentrations of SEL-110 in whole blood were performed on 
samples collected from cohorts who received SEL-110 alone and in combination with SEL-037. 
Results are summarized in Table 7 for cohorts of patients who received SEL-110 doses above 
≥0.1 mg/kg (ie, suggested minimum therapeutic dose) and showed dose-dependent responses to 
SEL-110 with potential influence by co-administration with SEL-037. Importantly, the mean and 
median values for systemic exposure (AUC) of SEL-110 at doses of 0.1 mg/kg and 0.3 mg/kg 
(Table 7) examined in conjunction with the results of analyses depicted in Figure 2 and Figure 3 
suggest that a dose of 0.15 mg/kg SEL-110 will result in systemic exposure substantially below 
the exposure determined by the recent nonclinical analyses for the NOAEL in rats (Section 
4.3.1.2). 


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Table 7.  
Summary of SEL-110 Whole Blood PK Parameters 
Parameter 
Statistic 
Cohort 3 
Cohort 4 
Cohort 5 
Cohort 6 
Cohort 7 
0.1 mg/kg 
SEL-110 
(alone) 
0.1 mg/kg  
SEL-110 +  
0.4 mg/kg 
SEL-037 
0.3 mg/kg 
SEL-110 
(alone) 
0.3 mg/kg 
SEL-110 + 
0.4 mg/kg  
SEL-037 
0.5 mg/kg 
SEL-110 
(alone) 
Cmax 
N 
4 
5 
5 
5 
4 
(ng/mL) 
Mean (SD) 
558.5 
(181.92) 
631.0 
(177.87) 
1173.8 
(326.81) 
2434.4 
(428.80) 
2464.3 
(463.91) 
 
Median 
621.5 
582.3 
1076.4 
2319.6 
2292.8 
 
Min, Max 
291, 700 
495, 942 
854, 1640 
1942, 3096 
2142, 3130 
Tmax 
N 
4 
5 
5 
5 
4 
(h) 
Median 
1.0 
1.0 
1.0 
1.0 
1.0 
 
Min, Max 
1, 2 
1, 1 
1, 1 
1, 2 
1, 1 
AUC0-last 
(h*ng/mL) 
N 
4 
5 
5 
5 
4 
Mean (SD) 
6671.4 
(2006.87) 
10332.1 
(4912.06) 
18043.4 
(7908.47) 
37015.0 
(7920.00) 
37537.9 
(4543.67) 
 
Median 
6811.0 
8177.8 
19620.0 
36847.8 
39221.7 
 
Min, Max 
4187, 8877 
6223, 18548 
7056, 28308 
25217, 46916 
30827, 40881 
AUC0-inf 
(h*ng/mL) 
N 
3 
3 
4 
5 
4 
Mean (SD) 
6596.2 
(1747.06) 
7817.6 
(901.59) 
23241.2 
(6277.67) 
37950.3 
(7590.15) 
39812.8 
(5077.75) 
 
Median 
6565.9 
8126.3 
22759.2 
37635.8 
41569.2 
 
Min, Max 
4865, 8358 
6802, 8524 
16065, 31381 
26629, 47451 
32363, 43749 
t½z 
N 
3 
3 
5 
5 
4 
(h) 
Mean (SD) 
280.2 
(18.36) 
299.7 
(60.73) 
214.7 
(131.67) 
284.4 
(54.46) 
207.6 
(23.68) 
 
Median 
287.7 
322.4 
290.6 
278.5 
212.1 
 
Min, Max 
259, 294 
231, 346 
25, 333 
235, 375 
177, 229 
CL 
N 
3 
3 
4 
5 
4 
(L/h) 
Mean (SD) 
1.415 
(0.16299) 
1.139 
(0.14129) 
1.159 
(0.22069) 
0.9555 
(0.36861) 
1.217 
(0.15249) 
 
Median 
1.372 
1.219 
1.144 
0.9661 
1.161 
 
Min, Max 
1.28, 1.6 
0.976, 1.22 
0.905, 1.44 
0.569, 1.46 
1.1, 1.44 
Vd 
N 
3 
3 
4 
5 
4 
(L) 
Mean (SD) 
574.4 
(99.00) 
489.8 
(105.15) 
433.6 
(159.46) 
380.1 
(114.56) 
360.9 
(18.04) 
 
Median 
569.5 
407 
454.8 
396.5 
362.8 
 
Min, Max 
478, 676 
453.9, 608 
220, 604 
204, 495 
338, 380 
Abbreviations: AUC0-inf = area under the plasma concentration-time curve from time 0 to infinity; AUC0-last = area 
under the plasma concentration-time curve from time 0 to the time t of the last quantifiable concentration; CL = total 
plasma clearance; Cmax = maximum observed plasma concentration; max = maximum; min = minimum; NA = not 
applicable; PK = pharmacokinetics; SD = standard deviation; t½z = apparent terminal elimination half-life; Tmax = 
time of maximum observed plasma concentration; Vd = distribution volume in the terminal elimination phase; n = 
number of actual reliable observations, may be lower for elimination parameters due to exclusion of unreliable PK 
parameters based on PK acceptance criteria as described in SAP. 


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The relationship between SEL-110 exposure (Cmax, AUC0-last, AUC0-inf) and dose level was 
explored using two statistical approaches. The first approach applied the Hummel power analysis 
performed using Linear Mixed Effects model to determine the slope of the linear regression 
between log-transformed PK parameters. The second approach applied ANOVA comparisons of 
PK parameters for cohorts at the same dose level. Under both approaches, cohorts that received 
SEL-110 alone and co-administered with SEL-037 were analyzed.  
Dose proportionality was confirmed for SEL-110 administered alone (slope of approximately 1) 
and SEL-110 co-administered with SEL-037 (slope of approximately 1.2) (Figure 2).  Further, 
ANOVA confirmed that SEL-037 increased systemic exposure of SEL-110 (Figure 3). 
 


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Figure 2. 
Dose Proportionality of SEL-110 AUC  
Cohorts 1, 3, 5, 7 – (SEL-110 administered alone) 
Cohorts 2, 4, 6, 12, 14 (SEL-212) 
AUC0-last – total dose 
 
 
 
AUC0-inf – total dose 
 


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Figure 3. 
Effect of SEL-037 on SEL-110 Systemic Exposure (AUC0-inf) (ANOVA) 
 
Note: The horizontal solid line inside the box represents arithmetic mean value, dashed line – median value, box represents 1st 
and 3rd quartile (25th and 75th percentile), whisker bars represent fences of 1.5x IQR (interquartile range) or min/max range if 
smaller than 1.5xIQR , markers represent outlier points (outside fences). 
Data for this clinical study has been submitted to the FDA under IND 124184. 
 
4.4. 
Potential Risks and Benefits 
4.4.1. 
SEL-037 
Some subjects may have uric acid levels lowered for a brief or a longer period depending upon 
the subject’s response to multiple doses of pegisiticase alone. 
Potential risks include those that have been identified in preclinical studies and clinical studies of 
SEL-037 and SEL-212 as well as similar marketed products.  These include 1) infusion reactions 
including anaphylaxis, 2) gout flares and 3) methemoglobinemia and hemolysis.   
The use of biological therapeutics utilizing a protein of non-human origin is associated with the 
risk of immunogenicity that could result in infusion reactions including anaphylaxis.  The 
formation of antibodies to SEL-037 was found in the animal toxicology studies.  Previous human 
use of pegylated and unpegylated uricases have been associated with infusion reactions and 
anaphylaxis (Sundy, 2007; Cortes, 2010; Sundy, 2011).  These adverse events would appear to 
be more prevalent in multiple dosing regimens but have been reported associated with the first 
dose presumably due to cross-reactivity or preexisting immunogenicity to the various 
components of the drug product or non-IgE related reactions. The current study excludes subjects 
with previous exposure to uricases and with preexisting immunoreactivity to PEG. 


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Gout flares are a potential risk in subjects with gout as therapies that reduce uric acid 
concentrations can produce flares.  Premedication for flare will be given to subjects. 
One of the byproducts of the degradation of uric acid by SEL-037 is hydrogen peroxide.  
Excessive oxidative stress can be detrimental to red blood cells.  Serious hemolytic reactions and 
methemoglobinemia were reported in less than 1% of the oncology patients with tumor lysis 
syndrome in clinical studies with Elitek®.  Similar events of severe hemolytic reactions have 
been reported with Krystexxa®.    Subjects that are catalase or glucose-6-phosphate 
dehydrogenase deficient have a reduced ability to deal with oxidative stress and these subjects 
will be excluded. 
4.4.2. 
SEL-110  
Some subjects who receive SEL-110 as part of a SEL-212 arm may have uric acid levels lowered 
for a brief or a longer period depending upon the subject’s anti-drug antibody response and the 
effect of SEL-212 to mitigate the formation of anti-drug antibodies over multiple doses and may 
have the development of antibodies to both uricase and pegsiticase prevented. 
Potential risks include those that have been identified in preclinical and clinical studies of SEL-
110 and SEL-212 as well as similar marketed products.  These include 1) infusion reactions 
including anaphylaxis, 2) leukopenia and opportunistic infection, 3) metabolic disturbances 
(hyperglycemia, hypertriglyceridemia and hypercholesterolemia), 4) hypophosphatemia, 5) 
stomatitis, 6) oligo/azoospermia and 7) potential fetal development effects as seen in preclinical 
studies. 
Rare cases of anaphylaxis were reported in the Phase 3 trials of Sirolimus (Rapamune®) during 
its development.  Identification of the reason for these reactions has not been made whether it be 
the rapamycin or other ingredients in the oral formulation.  Subjects with a history of 
anaphylaxis, angioedema or previous infusion reactions will be excluded from the trial.  
Additionally only sites with immediate capability to handle a reaction of this severity will be 
allowed to participate in the trial to reduce the risk to any subject. 
Leukopenia has been reported in patients taking oral rapamycin. Whether the cause of the 
leukopenia is a direct relation to the rapamycin exposure, precedes or is due to the development 
of an opportunistic infection is unknown. Resolution of the leukopenia occurred in cases without 
subsequent infection with the stoppage of Sirolimus (Rapamycin) exposure.  The current study 
will exclude subjects with any evidence of infection or developing infection by evaluating their 
WBC count and differential.  Additionally all subjects will told to avoid anyone who has an 
active infection either bacterial or viral. Subjects will also have a WBC performed on day 7, 14, 
21 and 28 post exposure of each treatment cycle. In our single clinical study SEL-212/101 we 
have not seen this effect. (Data on file) 
Metabolic disruptions (hyperglycemia, insulin resistance, hypertriglyceridemia and 
hypercholesterolemia) have been reported in post-transplant patients who have been exposed to 
rapamycin (Johnston, 2008; Ghisdal, 2012). The occurrence of post-transplant diabetes mellitus 
(PTDM) has been recognized for many years as a consequence of solid organ transplant 


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immunosuppression (Shivaswamy, 2013). Dyslipidemia is a well-recognized side effect of 
rapamycin therapy (Hakeam, 2008). In our single ascending dose clinical study SEL-212/101 we 
have not seen this effect. (Data on file) 
The exact mechanisms of rapamycin induced hyperglycemia, insulin resistance and its lipid 
effects are unclear at this time.  It has been shown that rapamycin can diminish β-cell 
proliferation in hyperglycemic states thereby inhibiting the natural cellular response of 
neogenesis, proliferation, hypertrophy and a reduction in aptosis (Barlow, 2013). Additionally, 
rapamycin has been shown to inhibit phosphorylation of IRS-1 and IRS-2 in human adipocytes 
mimicking changes seen in type 2 diabetes and in human peripheral blood monocytes associated 
with insulin resistance (Pereira, 2012). Rapamycin has also been shown to increase basal 
lipolysis and reduce lipid storage (Pereira, 2012).  Due to these, subjects who participate will 
have these specific laboratories (fasting glucose, triglyceride and cholesterol levels) monitored 
closely for significant changes during their participation.  Subjects will be monitored on days 7, 
14, 21 and 28 of each treatment cycle as is directed in the schedule of events.  
The mechanism of hypophosphatemia is not known, but it has been seen in patients that have 
received mTOR inhibitors such as rapamycin (Soefje, 2011). And so subjects will be monitored 
on days 7, 14, 21 and 28 of each treatment cycle as is directed in the schedule of events. 
The mechanism of stomatitis is not known, but it has been seen in patients that have received 
mTOR inhibitors such as rapamycin as early as 7 days after treatment and responds to locally 
applied Clobetasol cream (Soefje, 2011).  And so subjects will be monitored on days 7, 14, 21 
and 28 of each treatment cycle as is directed in the schedule of events. 
Oligo/azoospermia has been seen in some male renal transplant patients taking an oral form of 
SEL-110 (rapamycin) administered chronically on a daily or three times weekly basis for the 
prevention of transplant rejection when treated for a period greater than six months.  The 
mechanism for this effect is not known. In those patients where oligo/azoospermia has been seen 
partial to full reversibility of sperm production following cessation of treatment with the oral 
form of rapamycin has been demonstrated (e.g., Deutsch et al., 2007; Skrzypek, 2007; Zuber et 
al., 2008). Male patients should be informed that their fertility may be affected temporarily or 
permanently after being given SEL-110.    
In preclinical animal studies performed with an oral form of the drug to be administered in this 
study, SEL-110 (a component of SEL-212) showed adverse effects when given to pregnant rats.  
These effects included fetal death, reduced fetal weights, and delays in the formation of bones. It 
is not known whether these effects would also occur humans, a similar risk should be considered 
possible until such studies are performed. Because of these potential adverse effects, all females 
who directly participate in this clinical study must be of no childbearing potential and all males 
with female partners with childbearing potential must agree to use effective contraception and 
agree to continue doing so for four months after study drug dosing.  Childbearing potential is 
defined as: a) less than 6 weeks after surgical removal of ovaries, tubes with or without removal 
of the womb or (b) pre or perimenopausal (less than 24 months of being without a period 
naturally). 


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4.4.3. 
SEL-212 
Some subjects may have uric acid levels lowered for a brief or a longer period depending upon 
the subject’s anti-drug antibody response and the effect of SEL-212 to mitigate the formation of 
anti-drug antibodies over multiple doses and may have the development of antibodies to both 
uricase and pegsiticase prevented. 
No additional risks have been identified at this time to the combination of SEL-037 and SEL-110 
when presented as SEL-212. 
4.5. 
Rationale for SEL-212 Doses Selected 
Dosing in this Phase II study (SEL-212/201) of up to 0.15 mg/kg SEL-110 in combination with 
either 0.2 mg/kg or 0.4 mg/kg SEL-037 (ie, SEL-212) is supported by the nonclinical and clinical 
data presented in Section 4.3.1 and Section 4.3.2, respectively.   
Doses of 0.2 mg/kg and 0.4 mg/kg SEL-037 were selected for the Phase II study based on 
preclinical evaluation in rodent, rat, and monkey (Section 4.3.1.1) and clinical evaluation in two 
completed Phase I studies. In the Phase I clinical study SEL-037/101 (IND 126034) doses of 0.1, 
0.2, 0.4, 0.8 and 1.2 mg/kg SEL-037 demonstrated potent and dose-dependent reductions in 
serum uric acid levels and no evidence of safety signals as no SAEs or clinically significant 
treatment-emergent adverse events (TEAEs) were reported. Further clinical evidence supporting 
the Phase II doses of SEL-037 come from the completed Phase I Study SEL-212/101. 
Preliminary analyses of the study data show that one serious adverse event (SAE) of non-study 
drug-related atrial fibrillation was reported in 1 subject who received 0.4 mg/kg SEL-037 alone. 
Among the 5 subjects who received 0.4 mg/kg SEL-037, the pharmacodynamic activity of SEL-
037 was demonstrated by rapid reduction in serum uric acid levels (Figure 1).  
Doses of SEL-110 in the Phase II Study of SEL-212 (SEL-212/201) are based on the nonclinical 
toxicological data (Section 4.3.1.2) and the dose range tested in the Phase I single ascending dose 
clinical trial SEL-212/101.  Preliminary analyses of safety data in the Phase I study suggest that 
doses of SEL-110 up to 0.3 mg/kg were well-tolerated (Section 4.3.2.2). In nonclinical studies, 
the concern regarding the irreversibility of testis toxicity (the effect on the gonadotropin axis) in 
the rat was addressed by strong evidence of reversibility established in the nonclinical Study 
1933-013 with an extended recovery period covering multiple spermatogenic cycles (Section 
4.3.1.2). Importantly, a rat GLP PK study performed with a validated PK assay shows that the 
SEL-110 exposure based on AUC at the NOAEL dose of 1 mg/kg provides a greater than 4-fold 
safety margin at the proposed dose level of 0.15 mg/kg in humans (Section 4.3.1.2). In addition, 
the calculation of the clinical doses of SEL-110 are predicted based upon the NOAEL of 3 mg/kg 
in Cynomolgus monkeys which is an appropriate species for these estimates.  Therefore, the 
clinical dose of 0.15 mg/kg SEL-110 represents a 6.5-fold safety factor over the 3 mg/kg 
NOAEL in the non-human primate study based on body surface area (Section 4.3.1.2) and a 6.5-
fold safety factor over the 6 mg/kg dosed to rats in Study 1933-013 based on body surface area 
(Section 4.3.1.2).  


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Finally, doses of SEL-212 (ie, combination of SEL-037 and SEL-110) in the Phase II study are 
supported by the preliminary analyses of safety, pharmacodynamic, and pharmacokinetic data in 
the completed Phase I study (SEL-212/101). SEL-212 appears to be well-tolerated at doses of 
0.03-0.3 mg/kg SEL-110 in combination with 0.4 mg/kg SEL-037. SEL-212 reduces serum uric 
acid levels rapidly and demonstrates dose-dependent inhibition of ADAs with increasing doses 
of SEL-110 (Section 4.3.2.3).  Importantly, the mean and median values for systemic exposure 
(AUC) of SEL-110 at doses of 0.1 mg/kg and 0.3 mg/kg (Table 7) examined in conjunction with 
the results of analyses depicted in Figure 2 and Figure 3 suggest that a dose of 0.15 mg/kg SEL-
110 will result in systemic exposure substantially below the exposure determined by the recent 
nonclinical analyses for the NOAEL in rats (Section 4.3.1.2). 
The dose-dependent inhibition of the formation of anti-uricase antibodies correlated with more 
sustained control of uric acid levels and is an important consideration for higher doses of SEL-
110 in light of the potential risk of infusion related reactions with repeat dosing with SEL-037. It 
is expected that the risk of anaphylaxis will decrease with increasing doses of SEL-110 due to 
inhibition of ADA formation. 
4.5.1. 
Rationale for Dose Selected (Part C) 
Dosing in the Part C of this Phase II study (SEL-212/201) of up to 0.15 mg/kg SEL-110 in 
combination with 0.2 mg/kg SEL-037 (ie, SEL-212) is similarly supported by the nonclinical and 
clinical data presented in Section 4.3.1 and Section 4.3.2, respectively.  From our review of 
interim serum uric acid and antibody data from Part A and B cohorts, we believe that 5 doses of 
the combination may be allow enhanced reduction of antibodies and serum uric acid for the 
duration of the therapy.  Similar to Parts A & B, doses of 0.2 mg/kg SEL-037 were selected for 
Part C based on preclinical evaluation in rodent, rat, and monkey (Section 4.3.1.1) and clinical 
evaluation in two completed Phase I studies.  Support for 3 doses of SEL-110 in combination 
with SEL-037 is described above for Part A and B.  We have continued to extend our toxicology 
program to include additional doses of SEL-110 alone and in combination with SEL-037.  We 
will submit toxicology data that demonstrates the safety of delivering 5 doses at up to 0.15 
mg/kg SEL-110 prior to any patients receiving the 4th dose of SEL-212 in Part C.  Should a delay 
occur such that the toxicology data to support the safety of the 4th and 5th doses of the 
combination of SEL-212 at the proposed doses is not available at the scheduled time of the 4th 
dose for a subject, that subject will be converted from the planned regimen of 5 doses of SEL-
212 to a receive only SEL-037 at 0.2 mg/kg at the 4th and 5th dose and hence converted to a 
regimen of 3 doses of SEL-212 followed by 2 doses of SEL-037.  This regimen is similar to the 
regimen of previous cohorts in Part A and B. 
To investigate dose ranging in the 5 combination dosing regimen, Cohort 17 will have 5 doses of 
SEL-110 at a lower dose of 0.1 mg/kg at all 5 treatment periods and Cohort 15 will have 4 doses 
of SEL-110 at a lower dose of 0.1 mg/kg at treatment periods 2-5.  Preliminary analyses of data 
in the Phase I study (SEL-212/101) and cohorts in Part A and Part B suggest that the first 
treatment period may be a critical time period for preventing antibody development to SEL-037; 
thus increased doses of SEL-110 in the first treatment period may help achieve a higher rate of 
patients who do not develop antibodies to SEL-037.  As such, the first dose of SEL-110 in 


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treatment period 1 will be at a higher dose of 0.15 mg/kg in Cohort 15 to allow for comparison of 
efficacy and safety with other regimens in Part C.  
       
4.6. 
Study Population 
Approximately 140 subjects with symptomatic gout and elevated uric acid levels ≥ 6 mg/dL. 
4.7. 
Study Rationale 
When blood levels of urate exceed the physiologic limit of solubility, it may crystallize in the 
tissues and cause gout.  Gout is an intermittent inflammatory arthritis caused by the formation of 
urate crystals in joint fluid, which can cause an intensely painful joint inflammation.  Chronic 
hyperuricemia can lead to further deposition of uric acid in soft tissues, resulting in destructive 
arthritis and formation of tophi and renal calculi (Choi, 2006; So, 2008; Wortmann, 2008).  
The incidence of gout increases as circulating uric acid levels increase (Campion, 1987) and 
lowering circulating urate levels is a primary means of managing gout.  The American College of 
Rheumatology recommends lowering urate levels to a target of less than 6 mg/dL at minimum 
(Khanna, 2012a) to improve the signs and symptoms of gout.  
Intravenous uricase therapies have been shown to reduce uric acid levels (Goldman, 2001; 
Cortes, 2010; Sundy, 2011).  They have also been shown to lose efficacy due to the formation of 
anti-drug antibodies (Lipsky, 2014).  SEL-212 is an intravenous uricase therapy consisting of a 
combination SEL-037 and of SEL-110, a synthetic biodegradable polymeric nanoparticle 
encapsulating rapamycin an immune modulator. This therapy differs from other uricase therapies 
in the source of the uricase, product formulation and the type of pegylation which may improve 
tolerability and efficacy, and the addition of the immune modulator to reduce/prevent anti-
uricase antibody formation.  The current study evaluates the safety, tolerability, 
pharmacokinetics, pharmacodynamics (uric acid lowering ability) and the ability to mitigate the 
formation of anti-drug antibodies of SEL-212 after multiple IV infusion administration in 
subjects with symptomatic gout and circulating uric acid levels greater than or equal to 6 mg/dL. 
5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
To assess the safety and tolerability of multiple intravenous infusions of SEL-212.  
5.2. 
Secondary Objectives 
To assess the pharmacokinetics (PK), pharmacodynamics (PD) (ability to reduce circulating uric 
acid) and immunogenicity (anti-uricase, anti-PEG and anti-pegsiticase antibodies) of SEL-037 after 
multiple IV infusions of SEL-037 with or without multiple doses of SEL-110. 


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To assess the pharmacokinetics (PK) of rapamycin after multiple IV infusions of SEL-110 with 
multiple IV infusions of SEL-037. 
5.3. 
Exploratory objective 
To assess the effect on uric acid deposits and/or total body uric acid deposited as measured by 
Dual Energy Computed Tomography scan of multiple doses of SEL-037 alone or multiple doses 
of SEL-212 plus additional doses of SEL-037 
6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This is a Phase 2 (Part A) open label multiple dose clinical study of a combination drug (SEL-
212) combined with an open label multiple dose clinical study of one drug (SEL-037) followed 
by (Part B) an open label study of a single drug (SEL-037) to assess the safety, tolerability, PK, PD 
of SEL-212 (the combination of SEL-110 (Rapamycin) and SEL-037 (pegsiticase)).  Part C will 
involve patients naïve to SEL-212 who are treated with multiple doses of the combination drug 
(SEL-212). 
The safety, tolerability, PK and PD of multiple doses of SEL-037 will be assessed.  Additionally 
to assess the ability of SEL-212 to reduce serum uric acid and prevent anti-drug antibodies to 
uricase and pegsiticase.  
All enrolled subjects will be randomized initially to Cohorts 1, 2, 3 and 4 such that upon 
reaching 12 subjects total for all 4 cohorts, each cohort will contain 3 subjects. The experience of 
these 12 subjects will guide the further conduct of the study.  Adverse events, safety labs and the 
rate of infusion reactions in individual cohorts will dictate the continuance of a specific cohort. 
After the completion of at least one treatment cycle the subject experience will be evaluated 
before enrollment is opened to all cohorts.  The future enrollment will be randomized between all 
open cohorts.  
At this time Cohorts 1-10 are closed to enrollment. Randomization into the remaining open 
cohorts will continue until the cohorts are closed due to enrollment reaching 6-20 subjects per 
cohort or due to the stopping rules for individual cohorts. Cohorts that have closed due to 
enrollment levels may be re-opened to increase the enrollment to the maximum total number of 
subjects permitted. 
Treatment and events are by the cohort to which each subject is assigned. 


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Figure 4: 
Overall scheme of trial (Part A and Part B) 
 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering convention of 
associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
 
 
SEL-037 (0.2 mg/kg)
Cohort 1 Part A
SEL-037 (0.4 mg/kg)
Cohort 2 Part A
SEL-212 (0.05 + 0.2 mg/kg)
Cohort 3 Part A
SEL-212 (0.05 + 0.4 mg/kg)
Cohort 4 Part A
SEL-037 (0.2 mg/kg)
Cohort 1 Part B
SEL-037 (0.4 mg/kg)
Cohort 2 Part B
SEL-037 (0.2 mg/kg)
Cohort 3 Part B
SEL-037 (0.4 mg/kg)
Cohort 4 Part B
SEL-212 (0.08 + 0.2 mg/kg)
Cohort 5 Part A
SEL-212 (0.08 + 0.4 mg/kg)
Cohort 6 Part A
SEL-037 (0.2 mg/kg)
Cohort 5 Part B
SEL-037 (0.4 mg/kg)
Cohort 6 Part B
SEL-212 (0.1 + 0.2 mg/kg)
Cohort 7 Part A
SEL-212 (0.1 + 0.4 mg/kg)
Cohort 8 Part A
SEL-037 (0.2 mg/kg)
Cohort 7 Part B
SEL-037 (0.4 mg/kg)
Cohort 8 Part B
SEL-212 (0.125 + 0.4 mg/kg)
Cohort 10 Part A
SEL-037 (0.4 mg/kg)
Cohort 10 Part B
SEL-212 (0.15 + 0.4 mg/kg)
Cohort 12 Part A
SEL-037 (0.4 mg/kg)
Cohort 12 Part B
Cohort
SEL-110
SEL-037
1 (Closed)
NA
0.2 mg/kg
2 (Closed)
NA
0.4 mg/kg
3 (Closed)
0.05 mg/kg
0.2 mg/kg
4 (Closed)
0.05 mg/kg
0.4 mg/kg
5 (Closed)
0.08 mg/kg
0.2 mg/kg
6 (Closed)
0.08 mg/kg
0.4 mg/kg
7 (Closed)
0.1 mg/kg
0.2 mg/kg
8 (Closed)
0.1 mg/kg
0.4 mg/kg
10 (Closed)
0.125 mg/kg
0.4 mg/kg
11
0.15 mg/kg
0.2 mg/kg
12
0.15 mg/kg
0.4 mg/kg
SEL-212 (0.15 + 0.2 mg/kg)
Cohort 11 Part A
SEL-037 (0.2 mg/kg)
Cohort 11 Part B


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Figure 5: 
Overall scheme of trial (Part C) 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the cohort numbering 
convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose. 
 
Screening procedures will begin after a subject voluntarily agrees to participate in the clinical 
trial and signs the ICF.  After the informed consent process, subjects will have a physical 
examination and ECG performed, and vitals and clinical laboratory specimens collected.   
 
Duration of treatment for Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 mg/kg SEL-
037 alone) – BOTH COHORTS 1 and 2 CLOSED 
Part A - Treatment period 1  
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion criteria 
and all assessments are considered acceptable they will be instructed on when to start their 
premedication (date and medication, Day -7) for the prevention of gout flares.  On the evening of 
Day -1 the subject will self-administer their premedication of fexofenadine 180 mg orally.  The 
day of initial dosing of study drug will be designated Day 0.  On the morning (Day 0) subjects 
will report to the clinic for dosing of study drug. 2 hours prior to the dosing of study drug SEL-
037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of study 
drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Eligible subjects who have been assigned to Cohort 1 or 2 will receive a single IV 
infusion of normal saline (20 mL) with a syringe infusion pump over a period of 55 minutes 
starting concurrently with a 60 minute infusion of 125 mL of normal saline. This will be followed 
(± 1 minute) by an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 1 or 
0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline delivered over 60 minutes. Subjects 
will remain in the clinic for 9 hours after the start of the saline infusion for safety evaluations 
and PK blood draws (see Schedule of Events [Section 1.1]).  Subjects will return to the clinic for 
PK and PD blood draws on Treatment Period 1, Days 1, 7, 14 and 21 and Antibody blood draws 
on Treatment Period 1, Days 7, 14 and 21 and safety blood draws on Treatment Period 1, Day 
14.  
 
 
SEL-212 
(0.1 + 0.2 mg/kg)
Cohort 15 Part C
Cohort
SEL-110
SEL-037
13
0.15 mg/kg
0.2 mg/kg
15 
(first/induction dose)
0.15 mg/kg
0.2 mg/kg
15
(4 subsequent doses)
0.1 mg/kg
0.2 mg/kg
17
0.1 mg/kg
0.2 mg/kg
SEL-212
(0.15 + 0.2 mg/kg)
Cohort 13 Part C
SEL-212 
(0.15 + 0.2 mg/kg)
Cohort 15 Part C
SEL-212
(0.1 + 0.2 mg/kg)
Cohort 17 Part C


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Part A - Treatment period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally.  On the morning of Treatment Period 2, Day 0, subjects 
will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Subjects will receive a single IV infusion of normal saline (20 mL) with a syringe 
infusion pump over a period of 55 minutes starting concurrently with a 60 minute infusion of 125 
mL of normal saline. This will be followed (± 1 minute) by an infusion delivered by infusion 
pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of 
normal saline delivered over 60 minutes.  Subjects will remain in the clinic for 9 hours after the 
start of the saline infusion for safety evaluations and PK blood draws (see Schedule of Events 
[Section 1.1]).  Subjects will return to the clinic for PK and PD blood draws on Treatment 
Period 2, Days 1, 7, 14 and 21 and Antibody blood draws on Treatment Period 2, Days 7, 14 and 
21 and safety blood draws on Treatment Period 2, Day 14.    
Part A - Treatment period 3  
On the evening of Treatment Period 3, Day -1(27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally.  On the morning of Treatment Period 3, Day 0, subjects 
will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Subjects will receive a single IV infusion of normal saline (20 mL) with a syringe 
infusion pump over a period of 55 minutes starting concurrently with a 60 minute infusion of 125 
mL of normal saline. This will be followed (± 1 minute) by an infusion delivered by infusion 
pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of 
normal saline delivered over 60 minutes.  Subjects will remain in the clinic for 9 hours after the 
start of the saline infusion for safety evaluations and PK blood draws (see Schedule of Events 
[Section 1.1]).  Subjects will return to the clinic for PK and PD blood draws on Treatment 
Period 3, Days 1, 7, 14 and 21 and Antibody blood draws on Treatment Period 3, Days 7, 14 and 
21 and safety blood draws on Treatment Period 3, Day 14. 
 
Part B - Treatment period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally.  On the morning of Treatment Period 4, Day 0 subjects 
will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously.  Eligible subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg for 
Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline over 60 minutes by 
infusion pump. Subjects will remain in the clinic for 9 hours after the start of the saline infusion 
for safety evaluations and PK blood draws (see Schedule of Events [Section 1.1]).  Subjects will 
return to the clinic for PK and PD blood draws on Treatment Period 4, Days 1, 7, 14 and 21 and 


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Antibody blood draws on Treatment Period 4, Days 7, 14 and 21 and safety blood draws on 
Treatment Period 4, Day 14. 
Part B - Treatment period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally.  On the morning of Treatment Period 5, Day 0 subjects 
will report to the clinic for the dosing of study drug. 2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Eligible subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg for 
Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline over 60 minutes by 
infusion pump. Subjects will remain in the clinic for 9 hours after the start of the saline infusion 
for safety evaluations and PK blood draws (see Schedule of Events [Section 1.1]).  Subjects will 
return to the clinic for PK and PD blood draws on Treatment Period 5, Days 1, 7, 14 and 21 and 
Antibody blood draws on Treatment Period 5, Days 7, 14 and 21 and safety blood draws on 
Treatment Period 5, Day 14. 
An End of Study visit will be performed on Treatment Period 5, Day 30 ± 1 day. Subjects who 
terminate participation early should have an End of Study visit assessments completed. 
 
Duration of treatment for Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 4 (0.05 
mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 (0.1 mg/kg SEL-110 + 0.2 
mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 10 (0.125 mg/kg 
SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), and 
Cohort 12 (0.15 mg/kg SEL-110 + 0.4 mg/kg SEL-037)   
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort 
numbering convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
Part A - Treatment period 1 
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion criteria 
and all assessments are considered acceptable they will be instructed on when to start their 
premedication (date and medication, Day -7) for the prevention of gout flares. On the evening of 
Day -1 the subject will take their premedication of fexofenadine 180 mg orally.  The day of 
initial dosing of study drug will be designated Day 0.  On the morning of Day 0 subjects will 
report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug SEL-
110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of study 
drug SEL-110, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Eligible subjects who have been assigned to Cohorts 3-8, 10, 11, and 12 will 
receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered with a 
syringe infusion pump. In cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be 
infused at a single steady rate sufficient to deliver the dose volume over a period of 55 minutes 
concurrently with a 60 minute infusion of 125 mL of normal saline. In cohorts receiving SEL-
110 ≥0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, 


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then, will be changed to a steady rate sufficient to deliver the remainder of the dose volume for 
the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. 
This will be followed (± 3 minutes) by an infusion delivered by infusion pump of SEL-037 (0.2 
mg/kg for Cohorts 3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL 
of normal saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety.  Subjects will remain 
in the clinic for 9 hours after the start of the infusion of SEL-110 for safety evaluations and PK 
blood draws (see Schedule of Events [Section 1.1]).  Subjects will return for PK and PD blood 
draws on Treatment Period 1, Days 1, 7, 14, 21 and safety and Antibody blood draws on 
Treatment Period 1, Days 7, 14, 21.  
Part A - Treatment period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally. On the morning of Treatment Period 2, Day 0, subjects 
will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug 
SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-110, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Eligible subjects who have been assigned to Cohorts 3-8, 10, 11, and 12 will 
receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered with a 
syringe infusion pump. In cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be 
infused at a single steady rate sufficient to deliver the dose volume over a period of 55 minutes 
concurrently with a 60 minute infusion of 125 mL of normal saline. In cohorts receiving SEL-
110 ≥0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, 
then, will be changed to a steady rate sufficient to deliver the remainder of the dose volume for 
the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. 
This will be followed (± 3 minutes) by an infusion delivered by infusion pump of SEL-037 (0.2 
mg/kg for Cohorts 3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL 
of normal saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety. Subjects will remain 
in the clinic for 9 hours after the start of the infusion of SEL-110 for safety evaluations and PK 
blood draws (see Schedule of Events [Section 1.1]).  Subjects will return for PK and PD on 
Treatment Period 2, Days 1, 7, 14 and 21 and safety and Antibody blood draws on Treatment 
Period 2, Days 7, 14 and 21. 
Part A - Treatment period 3 
On the evening of Treatment Period 3, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally the night before dosing.  On the morning of Treatment 
Period 3, Day 0 subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-110, subjects will receive fexofenadine 180 mg orally and 1 hour prior 
to the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects who have been assigned to Cohorts 3-8, 10, 11, 
and 12 will receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered 
with a syringe infusion pump. In cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be 
infused at a single steady rate sufficient to deliver the dose volume over a period of 55 minutes 


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concurrently with a 60 minute infusion of 125 mL of normal saline. In cohorts receiving SEL-
110 ≥0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, 
then, will be changed to a steady rate sufficient to deliver the remainder of the dose volume for 
the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. 
This will be followed (± 3 minutes) by an infusion delivered by infusion pump of SEL-037 (0.2 
mg/kg for Cohorts 3, 5, 7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL 
of normal saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety. Subjects will remain 
in the clinic for 9 hours after the start of the infusion of SEL-110 for safety evaluations and PK 
blood draws (see Schedule of Events [Section 1.1]).  Subjects will return for PK and PD blood 
draws on Treatment Period 3, Days 1, 7, 14 and 21 and safety and Antibody blood draws on 
Treatment Period 3, Days 7, 14 and 21. 
Part B - Treatment period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg.  On the morning of Treatment Period 4, Day 0 subjects will 
report to the clinic for the dosing of study drug.   2 hours prior to the dosing of study drug SEL-
037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of study 
drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg for Cohorts 3, 5, 
7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL of normal saline over 
60 minutes (+/- 2 minutes) by infusion pump. If necessary the infusion time may be extended in 
order to ensure the infusion of the study medication in entirety.  Subjects will remain in the clinic 
for 9 hours after the start of the infusion of SEL-037 for safety evaluations and PK blood draws 
(see Schedule of Events [Section 1.1]).  Subjects will return for PK and PD blood draws on 
Treatment Period 4, Days 1, 7, 14 and 21 and safety and Antibody blood draws on Treatment 
Period 4, Days 7, 14 and 21.   
Part B - Treatment period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects will self-
administer fexofenadine 180 mg orally.  On the morning of Treatment Period 5, Day 0 subjects 
will report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug 
SEL-037, subjects will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-037, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Subjects will receive a single IV infusion of SEL-037 (0.2 mg/kg for Cohorts 3, 5, 
7, and 11; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100 mL of normal saline over 
60 minutes (+/- 2 minutes) by infusion pump.  If necessary the infusion time may be extended in 
order to ensure the infusion of the study medication in entirety.  Subjects will remain in the clinic 
for 9 hours after the start of the infusion of SEL-037 for safety evaluations and PK blood draws 
(see Schedule of Events [Section 1.1]).  Subjects will return for PK and PD blood draws on 
Treatment Period 5, Days 1, 7, 14 and 21 and safety and Antibody blood draws on Treatment 
Period 5, Days 7, 14 and 21.   
 
 
 


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Duration of treatment for Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 
15 (induction dose of 0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037 THEN 0.1 mg/kg SEL-110 
+ 0.2 mg/kg SEL-037), and Cohort 17 (0.10 mg/kg SEL-110 + 0.2 mg/kg SEL 037) 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the 
cohort numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 
dose. 
Part C – Treatment period 1 
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion criteria 
and all assessments are considered acceptable they will be instructed on when to start their 
premedication (date and medication, Day -7) for the prevention of gout flares. On the evening of 
Day -1 the subject will take their premedication of fexofenadine 180 mg orally.  The day of 
initial dosing of study drug will be designated Day 0.  On the morning of Day 0 subjects will 
report to the clinic for the dosing of study drug.  2 hours prior to the dosing of study drug 
SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to the dosing of 
study drug SEL-110, subjects will receive methylprednisolone 40 mg (or equivalent drug) 
intravenously. Eligible subjects assigned to Cohorts 13, 15, and 17 will receive a single IV 
infusion of SEL-110 (dose based on a mg/kg basis) administered with a syringe infusion pump. 
The rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be 
changed to a steady rate sufficient to deliver the remainder of the dose volume for the additional 
25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline.  This will be 
followed (± 3 minutes) by an infusion delivered by infusion pump of 0.2 mg/kg SEL-037 diluted 
into 100 mL of normal saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion 
time may be extended in order to ensure the infusion of the study medication in entirety.  
Subjects will remain in the clinic for 9 hours after the start of the infusion of SEL-110 for safety 
evaluations and PK blood draws (see Schedule of Events below).  Subjects will return for PK 
and PD blood draws on Treatment Period 1, Days 1, 7, 14, 21 and safety and Antibody blood 
draws on Treatment Period 1, Days 7, 14, 21.  
 
Part C – Treatment periods 2, 3, 4, and 5 
On the evening of each of Treatment Periods 2-5, Day -1 (27 ± 1 days from prior dosing) 
subjects will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 2, 
Day 0, subjects will report to the clinic for the dosing of study drug.  2 hours prior to the dosing 
of study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour prior to 
the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Eligible subjects who have been assigned to Cohorts 13, 15, and 
17 will receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered with 
a syringe infusion pump. The rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 
minutes and, then, will be changed to a steady rate sufficient to deliver the remainder of the dose 
volume for the additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of 
normal saline. This will be followed (± 3 minutes) by an infusion delivered by infusion pump of 
0.2 mg/kg SEL-037 diluted into 100 mL of normal saline delivered over 60 minutes (+/- 2 
minutes). If necessary the infusion time may be extended in order to ensure the infusion of the 


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study medication in entirety. Subjects will remain in the clinic for 9 hours after the start of the 
infusion of SEL-110 for safety evaluations and PK blood draws (see Schedule of Events below).  
Subjects will return for PK and PD on Days 1, 7, 14 and 21 of each treatment period and will 
return for safety and Antibody blood draws on Days 7, 14 and 21 of each treatment period. 
 
An End of Study visit will be performed on Treatment Period 5, Day 30 ± 1 days. Subjects who 
terminate participation early should have all End of Study visit assessments completed. 
 
6.2. 
Number of Subjects 
Number of patients (planned): In Part A and Part B, approximately 100 subjects will be 
divided into 11 dosing cohorts, each consisting of 6-20 subjects.  Cohorts 1-10 are closed to 
enrollment but are permitted to be re-opened to increase the enrollment to the maximum total 
number of subjects permitted. Cohorts 11 and 12 will continue enrolling up to 20 subjects per 
cohort. Cohort 1 will receive SEL-037 (pegsiticase alone, 0.2 mg/kg), Cohort 2 will receive SEL-
037 (pegsiticase alone, 0.4 mg/kg), Cohort 3 will receive SEL-212 (with 0.05 mg/kg of SEL-110 
+ 0.2 mg/kg pegsiticase), Cohort 4 will receive SEL-212 (with 0.05 mg/kg of SEL-110 + 0.4 
mg/kg pegsiticase), Cohort 5 will receive SEL-212 (with 0.08 mg/kg of SEL-110 + 0.2 mg/kg 
pegsiticase), Cohort 6 will receive SEL-212 (with 0.08 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase), Cohort 7 will receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.2 mg/kg 
pegsiticase), Cohort 8 will receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase), Cohort 10 will receive SEL-212 (with 0.125 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase), Cohort 11 will receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.2 mg/kg 
pegsiticase), and Cohort 12 will receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.4 mg/kg 
pegsiticase). Note that Cohort 9 is intentionally omitted from this protocol in order to maintain 
the cohort numbering convention of associating even numbered cohorts with the 0.4 mg/kg SEL-
037 dose. 
 
In Part C, up to 40 patients naïve to SEL-212 will be enrolled. Patients enrolled in Cohort 13 will 
receive SEL-212 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037). Patients enrolled in Cohort 15 
will receive an initial induction dose of SEL-212 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037) 
and, then, four subsequent doses of SEL-212 (0.10 mg/kg SEL-110 + 0.2 mg/kg SEL-037). 
Patients enrolled in Cohort 17 will receive SEL-212 (0.10 mg/kg SEL-110 + 0.2 mg/kg SEL 
037). (Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain 
the cohort numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-
037 dose.) 
 
Subjects who withdraw early or have significant protocol deviations or compliance issues may 
be replaced at the discretion of the Sponsor to assure completion of the objectives of the clinical 
study and to maintain the integrity of the data set.  


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6.3. 
Treatment Assignment 
All enrolled subjects will be randomized initially to Cohorts 1, 2, 3 and 4 such that upon 
reaching 12 subjects total for all 4 cohorts, each cohort will contain 3 subjects. The experience of 
these 12 subjects has guided the further conduct of the study.  Adverse events, safety labs and the 
rate of infusion reactions in individual cohorts will dictate the continuance of a specific cohort. 
After the completion of at least one treatment cycle the subject experience will be evaluated 
before enrollment is opened to all cohorts.  The future enrollment will be randomized between all 
open cohorts.   
At this time Cohorts 1-10 are closed to enrollment. Randomization into the remaining open 
cohorts will continue until the cohorts are closed due to enrollment reaching 6-20 subjects per 
cohort or due to the stopping rules for individual cohorts. Cohorts that have closed due to 
enrollment levels may be re-opened to increase the enrollment to the maximum total number of 
subjects permitted. 
6.3.1. 
Stopping Rules in an Individual Subject or in a Cohort 
For this clinical trial a treatment period is defined as period of time from the beginning of dosing 
of the first study drug on a given dosing day (ie, Either saline placebo or SEL-110 during Part A 
of the study and SEL-037 during Part B of the study) to the beginning of the next scheduled dose 
of study drug, and has a typical duration of 28 days. 
 
For Part C (Cohorts 13, 15, and 17), a treatment period is defined as the period of time from the 
beginning of dosing of SEL-212 to the beginning of the next scheduled dose of study drug. 
 
Individual 
 
For subjects in Cohorts 1 and 2, any subject who has a weekly serum uric acid value ≥6 mg/dl or 
>50% of their baseline (where baseline value refers to the pre-dose serum uric acid level from visit 
4, Day 0, treatment period 1) at Day 21 of their current treatment cycle will not be eligible for the 
next dosing of SEL-037.   The subject will be followed for 30 days post the last dose of study drug at 
which time they will have an End of Study assessment and their participation in the study will be 
terminated. 
  
In Cohorts 3-8, 10-13, 15, and 17 only subjects whose ambient blood samples indicate a serum uric 
acid (sUA) value less than or equal to 1.0 mg/dL at any of the Day 21 visits will be eligible for the 
next dosing of SEL-212 (or SEL-037).  All other subjects will be followed for 30 ± 2 days post the 
last dose of study drug at which time all of the End of Study assessments will be completed and their 
participation in the study will be terminated.  
 
Cohort 
 
If 5 subjects in any of Cohorts 1-5 or 7, or if 10 subjects in any of Cohorts 6, 8, 10, 11, or 12 have 
met the requirements for individual stopping of their participation in the trial as described above or 
have been stopped based on Section 6.4 then that cohort will no longer have any additional subjects 
enrolled in it.  Those subjects who have been enrolled will continue until they fulfill the requirements 


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for individual stopping or complete the clinical trial treatment periods.  If they continue to meet the 
requirements for continued participation they may continue in Part B of the study. 
 
In Part C, if 10 subjects in either of Cohorts 13, 15, or 17 have met the requirements for 
individual stopping of their participation in the trial as described above or have been stopped 
based on Section 6.4 then the cohort will no longer have any additional subjects enrolled in it.  
Those subjects who have been enrolled will continue until they fulfill the requirements for 
individual stopping or complete the clinical trial treatment periods. If they continue to meet the 
requirements for continued participation they may continue in the clinical trial. 
 
The medical monitor, Investigator, IRB, or regulatory agency may also stop additional dosing or 
dose escalation based on any condition that warrants termination such as the discovery of an 
unexpected, serious or unacceptable risk to subjects or an unacceptable incidence of an expected 
event (e.g., unacceptable incidence or severity of infusion reactions) which suggests additional 
dosing is not warranted.   
6.3.2. 
Safety committee 
Safety data will be monitored on an ongoing basis by the Investigators and medical monitor.  If 
two or more subjects in a single cohort experience SAEs that are assessed as related or possibly 
related to study drug, then the safety committee will review all relevant safety information for all 
subjects in that cohort. The data will include the accumulated data through the time of the 
scheduled meeting.  At minimum, this committee will include the Investigators, or their 
representatives, who have had subjects dosed at their site in the cohort of interest, the medical 
monitor and a sponsor representative.  
6.4. 
Criteria for Study Termination 
The study will be terminated when the subjects have completed follow-up assessments as per 
Section 1.1 or the medical monitor, Sponsor, Investigators, safety committee, IRB or regulatory 
agencies have determined there is an unacceptable risk to subjects or additional dosing or 
procedures are  not warranted or necessary.   
The study may be terminated at a particular investigational site under the following conditions: 
• The Investigator fails to enroll subjects at an acceptable rate; 
• The Investigator fails to comply with pertinent regulations; 
• There is insufficient adherence to the protocol; 
• Knowingly false information is submitted to the IRB, Sponsor or designee, or regulatory 
authorities; 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
1. Has provided written informed consent prior to the conduct of any study specific 
procedures and continues to provide consent; 
2. Understands and is willing and able to comply with study requirements, including the 
schedule of follow-up visits, and has demonstrated compliance with study requirements 
during Screening; 
3. At the Screening Visit male age 21 - 75, inclusive or female age 21-75 of non-child 
bearing potential; 
4. Has at the Screening Visit a serum uric acid ≥ 6 mg/dL, with established or symptomatic 
gout which is defined as having at least ONE of any of the 3 following factors: 
a. ≥ 1 tophus 
b. 1 gout flare within the last 6 months 
c. Chronic gouty arthropathy 
5. The use of allopurinol, febuxostat (Uloric®), or probenecid as uric acid-lowering therapy 
is permissible if dosing has been stable for at least the month prior to the Screening Visit 
and remains stable during the Screening Phase (i.e., no initiation, change in dose or 
discontinuation 1 month prior to screening and during screening).    
6. Is negative for anti-PEG antibodies at the Screening Visit; 
7. Has not participated in a clinical trial within 30 days of the Screening Visit and agrees to 
not participate in a clinical trial for the duration of the study; 
8. Negative serology for HIV-1/-2 and negative antibodies to hepatitis C; 
9. Has adequate venous access and able to receive IV therapy; 
10. If applicable, has fully recovered from any prior surgery; 
11. Is not presently receiving any vaccination scheme or have received a live virus vaccine in 
the previous 6 months. 
7.2. 
Subject Exclusion Criteria 
1. History of anaphylaxis or severe allergic reactions; 
2. History of any allergy to pegylated products, including peginterferon alfa-2a (Pegasys®), 
peginterferon alfa-2b (PegIntron®), pegfilgrastim (Neulasta®), pegaptanib (Macugen®), 
pegaspargase (Oncaspar®), pegademase (Adagen®), peg-epoetin beta (Mircera®), 
pegvisomant (Somavert®) certolizumab pegol (Cimzia®), naloxegol (Movantik®), 
peginesatide (Omontys®), pegaptanib (Macugen®) and doxorubicin liposome (Doxil®); 


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3. Medications which are known CYP3A4 inhibitors or inducers MAY be exclusionary. 
Patients taking medications that are known CYP3A4 inhibitors or inducers including 
natural products such as St. John’s Wort or grapefruit juice may be included ONLY if 
they discontinue the medication 14 days before dosing and are able to remain off the 
medication for the duration of the study. 
4. Drugs known to interact with Rapamune such as cyclosporine, diltiazem, erythromycin, 
ketoconazole (and other antifungals), nicardipine (and other calcium channel blockers), 
rifampin, verapamil unless they are stopped 2 weeks prior to starting the trial and will 
not be used during the trial. 
5. Women of child bearing potential, Defined as:  
• <6 weeks after surgical bilateral salpingooperhectony with or without 
hysterectomy 
• Pre or perimenopausal (< less than 24 months of natural amenorrhea) 
6. Initiation or change in dose of hormone-replacement therapy for menopausal women 
less than 1 month prior to the Screening Visit or during the Screening Phase would be 
exclusionary.  If after being on a stable dose of hormone-replacement therapy for one 
month the patient may be considered for the study if she continues to meet all other 
inclusion and exclusion criteria 
7. Uncontrolled diabetes with baseline HbA1c ≥8%; 
8. Fasting screening glucose greater than 240 mg/dL 
9. Fasting triglyceride greater than 300 mg/dl; 
10. Fasting LDL cholesterol greater than 200 mg/dl; 
11. Glucose-6-phosphate dehydrogenase deficiency;  
12. Uncontrolled hypertension: Blood pressure >170/100 at screening and 1 week prior to 
dosing 
13. Individual laboratory values which may be exclusionary 
• White blood cell count less than 3.5 x109 /L 
• Serum aspartate aminotransferase (AST) or alanine amino transferase  greater 
than 3x upper limit of normal (ULN) in the absence of known active liver disease 
• Glomerular filtration rate less than 40 ml/min/1.73 m2 
• Hemoglobin less than 9 gm/dL 
• Serum phosphate less than 2.0 mg/dL 
14. Ongoing treatment for arrhythmia, including placement of an implantable defibrillator; 
15. History of coronary artery disease, including myocardial infarction; 


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16. Congestive heart failure, New York Heart Association Class III or IV; 
17. ECG with evidence of prior myocardial infarction, clinically significant arrhythmia, or 
other abnormalities that, in the opinion of the investigator, are consistent with significant 
underlying cardiac disease; 
18. History of hematological or autoimmune disorders, is immunosuppressed or 
immunocompromised;  
19. Subject is currently taking dabigatran (Pradaxa®), rivaroxaban (Xarelto®), edoxaban 
(Savaysa®), warfarin (Coumadin®) and apixaban (Eliquis®). 
20. Prior exposure to any experimental or marketed uricase (e.g., rasburicase (Elitek, 
Fasturtec), pegloticase (Krystexxa®), pegsiticase (SEL-037) 
21. History of malignancy within the last 5 years other than basal skin cancer; 
22.  Subjects who, in the opinion of the investigator, present with a condition that would 
compromise their safety or that would make study completion unlikely. 
7.3. 
Subject Restrictions and Requirements 
7.3.1. 
Medication and Therapy Restrictions 
See Section 8.2. 
7.3.2. 
Contraception 
Females must be of non-childbearing potential, where childbearing potential is defined as being:  
(a) <6 weeks after surgical bilateral salpingooperhectony with or without hysterectomy or (b) pre 
or perimenopausal ( < less than 24 months of natural amenorrhea). 
All males with female partners with childbearing potential agree to use effective contraception 
and agree to continue doing so for four months after study drug dosing.  Effective contraception 
is defined (for male subjects with a female partner with childbearing potential) as (a) two 
separate forms of contraception simultaneously, one of which must be a male condom with 
spermicide; or (b) be non-heterosexually active. 
7.3.3. 
Subject Confinement 
Subjects will undergo multiple blood draws and safety assessments as dictated by the schedule of 
events.  There will be no overnight clinic stays.  Subjects will need to remain in the clinic for a 
minimum of 9 hours after the start of dosing of study drug infusion.   
7.3.4. 
Blood and Sperm Donations 
Subjects will be advised that they should not donate blood and males should not donate sperm 
until after completion of this study. 


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7.3.5. 
Foods, Meals, Beverages and Fluid Intake 
Subjects will be given a standardized low-purine diet during the In-Clinic Phase (dosing of study 
drug).  There are no other food, meal, and beverage or fluid intake restrictions.  Subjects should 
maintain a normal routine and diet as much as possible. 
7.4. 
Subject Completion and Withdrawal 
7.4.1. 
Screen Failures 
An evaluation of the subject’s eligibility occurs from consent through the predose assessments 
and a subject will not be considered enrolled in the study until dosed with study drug.  Any 
subject that is screened but not dosed will be considered a screen failure and the reason for 
failure will be documented.  
7.4.2. 
Subject Completion 
A subject will be considered to have completed the study when the subject has completed the 
Treatment Period 5, Day 30 visit.  Enrolled subjects who prematurely discontinue for any reason 
before completion of the study will be treated as outlined in the following section. 
7.4.3. 
Enrolled Subject Withdrawal and Discontinuations 
7.4.3.1. 
Withdrawal Procedures 
Early terminations are when an enrolled subject withdraws consent or the Investigator terminates 
a subject.  The reason for withdrawal will be evaluated and recorded in the case report form 
(CRF) and source documents.  Subjects that withdraw may be replaced (see Replacement of 
Subjects, Section 7.4.4). 
Subjects may withdraw consent at any time.  A documented effort must be made to determine 
why a subject withdraws consent, fails to return for the necessary visits, or is dropped from the 
study.  All subjects that withdraw early upon termination should have the Early Termination visit 
assessments completed (i.e., End of Study assessments), if the assessments pose no risk to the 
subject and the subject allows such assessments.   
The Investigator should consult with the Sponsor/medical monitor prior to withdrawing any 
subject.  Since this is a multiple dose safety study, once dosed, subjects generally should not be 
terminated by the Investigator and should be followed through 30 days after last dose of study 
drug unless the subject withdraws consent or is lost to follow-up.  In situations where continued 
participation in certain aspects of the study pose a risk to the subject, with consultation with the 
medical monitor, the Investigator should discontinue those procedures that pose a risk and should 
continue to collect data and conduct those assessments that do not put the subject at risk through 
30 days after last study drug (e.g., End of Study).  Subjects with compliance issues or major 
deviations that effect data quality will also continue to be followed through 30 days after last 
study drug collecting as much data on the subject as possible, unless otherwise indicated by the 
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7.4.3.2. 
Subjects Lost To Follow-Up 
For subjects to be considered as lost to follow-up, at least three contact attempts must be 
documented, of which the last must be a letter sent by a service that requires a delivery signature 
record (e.g. US Postal Service certified letter or Federal Express/UPS letter that requires 
signature of delivery).  If the letter is undeliverable or no response is received within 7 days the 
subject will be considered terminated due to lost to follow-up.   
7.4.4. 
Replacement of Subjects 
An excessive rate of withdrawal of subjects and missing data within a cohort can have a negative 
impact on this study given the small cohort size.  Subjects may be replaced at the discretion of 
the Sponsor based on a review of withdrawal rates within a cohort, the impact of missing or 
unusable data, out of window blood draws and protocol deviations or other unanticipated events.  
No additional subjects will be replaced or dosed if the reason for withdrawal was the fulfilment 
of the stopping rules for individuals or cohorts.  
8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
The investigational products are listed in Table 8. The first one is lyophilized SEL-037 supplied 
as 6 mg SEL-037, with phosphate buffer and mannitol as excipients, in a 2 ml borosilicate glass 
vial with a bromobutyl rubber stopper and an aluminum-plastic combination cap. The second 
product is SEL-110, a frozen suspension of synthetic biodegradable polymeric nanoparticles 
encapsulating rapamycin in PBS, supplied at a 2 mg/mL rapamycin concentration in a 10 mL 
borosilicate glass vial filled to provide a deliverable dose of 5mL with a coated butyl rubber 
stopper and aluminum-plastic combination cap.  


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Table 8: 
Investigational Product 
 
Investigational Product 
Investigational Product 
Product Name: 
SEL-037 
SEL-110 
Dosage Form: 
Lyophilized product 
 Frozen nanoparticle 
suspension 
Unit Dose 
6 mg SEL-037 per vial diluted to 
final dose in normal saline 
10 mg / 5 ml in the thawed  
state 
Route of 
Administration 
Intravenous infusion 
IV infusion 
Physical Description 
2 ml borosilicate glass vial with 
rubber stopper and aluminum-plastic 
combination cap 
10 mL borosilicate glass vial 
with rubber stopper and 
aluminum-plastic 
combination cap      
Manufacturer 
Manufactured for Selecta 
Biosciences by 3SBio 
Manufactured for Selecta 
Biosciences by Emergent 
BioSolutions 
 
8.2. 
Concomitant Medications and Therapies 
Concomitant medications are permitted during this study unless otherwise restricted.  
Concomitant medications used in the 3 months prior to screening and during the study will be 
documented.   
Uric acid lowering therapy: 
1. Uric acid lowering therapy of allopurinol, febuxostat (Uloric®), and probenecid is 
allowed if the dose was stable (no clinically significant dose change or therapy started or 
stopped) for at least the month prior to the Visit 1 Screening Visit and remains stable 
throughout the trial.   
2. No new uric acid therapy should be initiated or existing therapy stopped until after the 
study. 
3.  Subjects cannot have any prior exposure to or be presently be taking any experimental 
or marketed uricase therapy (e.g., rasburicase (Elitek®, Fasturtec®), pegloticase 
(Krystexxa®), pegsiticase (SEL-037)).  
 


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Anticoagulants use: 
1. The use of the following anticoagulants are prohibited during the trial  
a. dabigatran (Pradaxa®),  
b. rivaroxaban (Xarelto®)  
c. apixaban (Eliquis®) 
d. edoxaban (Savaysa®) 
e. warfarin (Coumadin®). 
Hormone replacement therapy: 
Hormone replacement therapy in menopausal women should remain stable throughout the study. 
 
Drugs which have an effect on CYP3A4 
The use of CYP3A4 inducers or inhibitors are prohibited during the trial.  
Examples of inducers would be carbamazepine-Tegretol®, phenobarbital, phenytoin-Dilantin®, 
rifampin/rifampicin-Rifadis®, rifabutin-Mycobutin®, St. John’s Wort-Hypericum perforatum. 
Examples of inhibitors would benefazodone-Serazone®, itraconazole-Sporanox®, ketoconazole-
Nizoral®, voricinazole-Vfend®, atraznavir-Reyataz®, indinavir-Crixvan®, nelfinavir-Viracept®, 
ritonavir-Norvir, saquinavir-Invirase®, clarithromycin-Biaxin®,telithomycin-Ketek® and 
grapefruit juice.  
8.2.1. 
Premedication with Antihistamines and Steroids  
All subjects in the study will be pre-medicated with oral 180 mg fexofenadine two times 
(evening before (-12 h ± 2h, self-administered) and -2 h ± 1 hours before receiving study drug) 
and 40 mg methylprednisolone (or equivalent drug, for example prednisone 50 mg IV or 
dexamethasone 8 mg IV) intravenously -1 h ± 0.5 hours before receiving study drug (ie. prior to 
SEL-037 for Cohorts 1 and 2 and Part B of all cohorts or prior to SEL-110 for Cohorts 3-8, 10, 
11, and 12) to reduce infusion reactions.  These medications will be supplied by the clinic. 
In Part C (Cohorts 13, 15, and 17), the premedication schedule described above will apply. 
8.2.2. 
Management and Treatment of Infusion Reactions 
The following steps will be implemented in this protocol to either reduce the risk of infusion 
reactions or manage infusion reactions. 
• Subjects with immunoreactivity to PEG will be ineligible for the study  
• Subjects with prior exposure to uricase therapy will be ineligible  
• Each subject will be observed for infusion reactions after dosing of study drug in the 
clinic for 9 hours from the start of study drug infusion (SEL-110 or saline for Part A or 
SEL-037 for Part B).  Subjects will be instructed on the signs or symptoms of infusion 
reaction and told to notify the PI immediately if they feel they are experiencing one. 


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• SEL-110 will be administered via syringe pump to control the infusion rate of the small 
volume of material  
• SEL-037 will be administered by slow infusion over an hour only in a healthcare setting 
and by healthcare providers sufficiently equipped and prepared to manage infusion 
reactions including anaphylaxis.   
• Subjects will be pre-medicated with 180 mg fexofenadine orally two times before dosing 
and 40 mg methylprednisolone (or equivalent drug) intravenously -1 ± 0.5h before dosing 
in an attempt to reduce infusion reactions in subjects.   
• Subjects with a history of anaphylaxis, angioedema or previous infusion reactions will be 
excluded from the trial. 
• Only sites with immediate capability to appropriately respond to a reaction of this 
severity will be allowed to participate in the trial to reduce the risk to any subject 
If an infusion reaction occurs, Investigators are allowed to use concomitant medications or 
treatments deemed necessary to provide adequate subject care.  Investigators should also utilize 
the infusion reaction lab kit (see Appendices) to collect additional blood specimens.  In the case 
of a Grade 3 or 4 infusion reactions occurring during an infusion, the administration of study 
drug should be immediately discontinued, and the affected subject should be treated according to 
the clinical trial site’s protocol for infusion reactions (e.g., monitoring, administration of 
antihistamines, corticosteroids, fluids and epinephrine, as clinically indicated).   
8.2.3. 
Gout Flares (Prevention and Treatment) 
All subjects that meet all inclusion and exclusion criteria will be given premedication for gout 
flare prevention.  The regimen will begin 1 week prior to the first dosing of study drug and 
continue for as long as the subject is enrolled in the clinical study.  Subjects will be given 
colchicine 1.2 mg as a single loading dose.  Then they will continue with colchicine 0.6 mg QD 
for the remainder of their participation in the trial.  If there is a contraindication to colchicine, the 
subject will receive ibuprofen 600 mg TID or an equivalent NSAID unless the subject has a 
contraindication to NSAID.  If the subject has a contraindication to colchicine and to NSAIDs 
then no premedication will be given.  The gout flare prevention medication should continue as 
long as the subject is enrolled in the clinical study. Subjects who began receiving a NSAID as 
gout flare prevention medication due to a contraindication to colchicine or under a previous 
version of this protocol should continue to receive the NSAID as long as the subject is enrolled 
in the study. These medications will be supplied by the clinic. 
As gout flares are expected to happen despite the subject receiving preventative premedication 
they (the gout flare) are to be recorded as an adverse event and treated at the discretion of the 
investigator to provide adequate patient care. Investigators should consult with the medical 
monitor if a change in the subject’s uric acid lowering medication is needed. 


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8.3. 
Treatment Compliance 
Study drug will be administered in the controlled environment of a clinical research center. 
Direct observation of the administration of the study drug by study staff will ensure compliance.  
The date and time of the start and stop of drug administration and volume infused will be 
recorded. 
8.4. 
Randomization 
This is an open label clinical study.  At this time Cohorts 1-10 are closed to enrollment. 
Randomization into the remaining open cohorts will continue until the cohorts are closed due to 
enrollment reaching 6-20 subjects per cohort or due to the stopping rules for individual cohorts. 
Cohorts that have closed due to enrollment levels may be re-opened to increase the enrollment to 
the maximum total number of subjects permitted. 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
This study has two study drugs, SEL-037 and SEL-110. SEL-037, lyophilized pegylated uricase, 
is supplied in stoppered 2 mL vials. 
SEL-110 is a biodegradable polymeric nanoparticle encapsulating rapamycin which is supplied 
as a frozen suspension in stoppered 10 ml vials. 
9.2. 
Study Drug Packaging and Labeling 
Study drug will be supplied in vials in bulk boxes with boxes and vials unassigned to a subject. 
9.3. 
Study Drug Storage 
Upon receipt of the SEL-037 vials at the clinical site, the vials should be stored in a secured way 
at 2 to 8 °C within the primary or secondary box container in order to protect the SEL-037 from 
long-term light exposure. 
Upon receipt of the SEL-110 vials at the clinical site, the vials should be stored in a secured way 
at -15 to -25 °C within the primary or secondary box container in order to protect the SEL-110 
from long-term light exposure. 
9.4. 
Study Drug Preparation 
Detailed procedures and sample calculations for dosing are found in the appendix (Section 19.3).  
Doses are calculated on a mg/kg basis according to a patient’s weight. For the first treatment 
period dosing day (Visit 4), the weight used for dose preparation should be the subject’s weight 
at screening.  For later dosing, weight used for dose preparation should be the subject’s weight at 
the Day 21 visit from the preceding treatment period.  


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9.4.1. 
SEL-037 Preparation 
Each vial of SEL-037 will be reconstituted with 1.1 ml of sterile water for injection, USP (United 
States Pharmacopeia) which forms a 6 mg/mL concentrated solution and then diluted for 
administration in 100 ml of room temperature 0.9% sodium chloride for injection, USP. The full 
resultant volume of the SEL-037-normal saline solution (100 mL saline + required volume of 
reconstituted SEL-037) will be administered in the allotted time.  Reconstituted SEL-037 is 
stable at room temperature and normal light conditions for 8 hours and the diluted SEL-037-
normal saline solution for infusing should be used (i.e., infusion completed) within 6 hours of 
dilution.   
9.4.2. 
SEL-110 Preparation 
Each vial of SEL-110 will be thawed at room temperature and brought to room temperature over 
a 2 hour period before being drawn into appropriate size syringe/syringes for IV infusion with 
syringe pump. Thawed SEL-110 is stable for 24 hours at room temperature at normal light 
conditions. 
SEL-110 should be administered as soon as possible after thawing; however, overnight thawing 
of SEL-110 at room temperature is permitted as long as the SEL-110 dose is completely 
administered within 24 hours of removal from its frozen storage conditions.  
Doses are calculated on a mg/kg basis according to a patient’s weight as described in Section 
19.3.2. In cohorts receiving SEL-110 doses <0.10 mg/kg, the maximum dose per study visit, 
irrespective of the patient’s weight, is 12 mg (equivalent to 6.0 mL of SEL-110). In cohorts 
receiving SEL-110 doses ≥0.10 mg/kg, there is no maximum dose; however, the rate of SEL-110 
infusion will be restricted as described in Section 9.5, with an initial infusion rate of 5.5 
mL/hour.  
9.5. 
Administration 
The thawed SEL-110 will be withdrawn from the vial and dosed via IV infusion with a syringe 
infusion pump.  In cohorts receiving SEL-110 doses <0.10 mg/kg, SEL-110 will be infused at a 
single steady rate sufficient to deliver the dose volume over a period of 55 minutes concurrently 
with a 60 minute infusion of 125 mL of normal saline. In cohorts receiving SEL-110 ≥0.10 
mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will 
be changed to a steady rate sufficient to deliver the remainder of the dose volume for the 
additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal saline.  
The diluted SEL-037 in 0.9% sodium chloride for injection, USP 100 ml will be infused 
intravenously with an infusion pump over a 60 minute period.   
All study drugs should be administered through the same IV access.  All blood samples should 
be drawn from an alternative venous access. 
Only if medically warranted in response to an AE will the Investigator modify the infusion 
parameters (decrease the rate of infusion, interrupt the infusion, or reduce the dose volume 
infused).  The Investigator will notify the study team of any changes in infusion parameters. 


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9.6. 
Study Drug Accountability 
Study drugs will only be used as directed in the protocol.  Study personnel will account for all vials 
of study drugs received, dispensed and used for each subject, and vials returned.  The date and time 
of reconstitution and dilution will be recorded.  Used vials should be traceable back to the subject.    
The Investigator is responsible for the study drug accountability, reconciliation, and record 
maintenance.   
9.7. 
Study Drug Disposal 
Unused, partially used and empty vials will be stored until the Sponsor or sponsor representative 
instructs the site to return or dispose of the vials.  Unused supplies will be returned or disposed of 
using appropriate documentation according to International Conference on Harmonization-Good 
Clinical Practice (ICH-GCP), local requirements, applicable Occupational Safety and Health 
Administration and Environmental Protection Agency regulations, and applicable study-specific 
procedures. 
10. 
PHARMACOKINETIC, PHARMACODYNAMIC AND 
RADIOLOGIC ASSESSMENTS 
10.1. 
Sample Collection 
Multiple blood samples will be collected from a venous access which is different and on an 
alternative limb than the site where study drug has been administered. The blood samples will be 
processed for a determination of whole blood levels of rapamycin, serum levels of SEL-037, 
uricase activity, serum uric acid levels, antibody (anti-PEG, anti-pegsiticase and anti-uricase) 
levels, inflammatory marker assessments and T-cell recall assessments according to the 
procedures in the study laboratory manual and in Section 1.1 (the schedule of events by cohort). 
For Part C (Cohorts 13, 15, and 17), at each timepoint specified in the schedule of events 
(Section 1.1, Table 5), 2 blood samples will be collected for sUA measurement. One sample will 
be stored and shipped under ambient temperature and one sample will be stored and shipped 
under frozen conditions. Refer to the Laboratory Manual for details about sample handling. 
The target blood collection time for the follow-up visits will be approximately the same time of 
day as the start of study drug dosing.  Blood draws should be collected as close to the times 
specified, as possible.  The acceptable window of collecting samples is: 
• All dosing day (Treatment Periods 1, 2, 3, 4 and 5 Day 0) samples: target collection time ± 5 
minute window 
• Follow-up visit (Treatment Periods 1, 2, 3, 4 and 5 Day 1): the target collection time ± 2 hour 
window from D0 0 hour 
• Follow-up visits (All except Day 1): the target collection time ± 8 hour window from D0 0 
hour 


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• Dosing day (Treatment Periods 2, 3, 4 and 5, Day 0) and EOS visit: target day ± 1 day 
window 
• Infusion reaction labs ± 5 minute window 
The actual date and time that blood samples were drawn will be captured.   
10.1.1. 
Additional Observational Visit 
We have noted in the open label portion of the SEL-212/101 clinical trial and the initial portion 
of this SEL-212/201 clinical trial a persistent and beneficial effect on serum uric acid (sUA) 
when subjects are given SEL-212. This effect had persisted beyond 30 days in 17 of 31 subjects 
as of November 28, 2016.  Based on these results, our goal is to follow subjects in Cohorts 3-8, 
10, 11, and 12 beyond the current protocol Treatment Period 5, Day 30 Visit so that we may 
monitor and characterize the continued effect of SEL-212. Since there is a lag between lab 
results and the visits we would propose to see the subject for an additional visit if the sUA at the 
Treatment Period 5 Day 21 (Visit 32) is below 6 mg/dL. The additional visit would be 60 ± 1 
days after the Treatment Period 5 Day 0 dosing day (Visit 28) at which time we would have the 
value of the sUA for the Day 21 (Visit 32) visit and their end of study visit (EOS P5 Day 30) 
value. The beneficial effect on the sUA is an unexpected, positive event which is beneficial to 
the subject and would likely be beneficial to the projected treatment population in the future. 
 
In Part C (Cohorts 13, 15, and 17), subjects will be followed as described above. 
 
Blood samples will be taken at the observational visits for assessments that will include: serum 
uric acid, and serum samples for anti-pegsiticase, anti-uricase and anti-PEG. 
10.2. 
Analytical Procedures 
Serum samples for SEL-037, for uricase activity and for uric acid determinations and whole 
blood samples for rapamycin determinations will be measured by validated methods.  Serum 
samples for antibody (anti-PEG, anti-uricase, and anti-pegsiticase) determinations will be 
measured by validated methods.  Procedures for processing samples will be included in the 
Study Manual.  
Anti-pegsiticase, anti-uricase and anti-PEG samples will be sampled as per the schedule of 
events.  At minimum, the samples to be analyzed will include the Day 14 and pre-dose samples 
for each treatment period as well as the Day 7, 14, 21 and EOS/Early Termination visit for the 
final treatment period for each subject. 
10.3. 
Pharmacokinetic Assessments 
The following PK parameters will be calculated on SEL-037, uricase activity and SEL-110 and 
assessed: the maximum observed serum concentration (Cmax), the time at which Cmax occurred 
(Tmax), area under the serum concentration-time curve from time 0 to the time of last quantifiable 
concentration (AUClast), area under the serum concentration-time curve from time 0 to infinity 


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(AUCinf), the terminal elimination rate constant (Kel), terminal half-life (t1/2), serum clearance of 
drug (CL), and apparent volume of distribution at equilibrium (Vss). 
10.4. 
Radiologic Assessments 
Dual energy computed tomography (CT) scans will be performed as an exploratory measure for 
at least 2 subjects in Cohorts 10, 11, and 12 during the screening interval, between Days 21-28 of 
Treatment Period 3 (Visit 20-Visit 21), and between Days 21-30 (inclusive) of Treatment Period 
5 (Visit 32) or at Early Termination to investigate changes to uric acid deposits. In addition, in 
any cohorts reopened for enrollment, at least 2 newly enrolled subjects per cohort will undergo 
DECT during the screening interval, between Days 21-28 of Treatment Period 3 (Visit 20-Visit 
21), and between Days 21-30 (inclusive) of Treatment Period 5 (Visit 32) or at Early 
Termination to investigate changes to uric acid deposits. 
In Part C, dual energy CT scans will be performed for Cohorts 13, 15, and 17 as described above. 
Procedures for the dual energy CT scan and analysis can be found in the study procedure 
manual.   
10.5. 
Inflammatory Marker Assessments 
Assessments of inflammatory markers will be performed as an exploratory measure for all 
subjects enrolled in each cohort at the predose visit for Treatment Period 1 (Visit 4/Day 0) and 
one additional inflammatory marker sample is to be collected for Treatment Period 5 – this may 
be collected at Visit 32/Day 21, between Visit 32/Day 21 and the EOS Visit, or at the EOS 
Visit/Day 30, or at Early Termination to investigate changes to inflammatory markers.  No 
inflammatory marker assessments will be performed on subjects who have received their first 
treatment period dose under prior protocol versions not subject to inflammatory marker 
assessments.  Procedures for the assessments and analysis can be found in the study procedure 
laboratory manual. 
In Part C (Cohorts 13, 15, and 17), assessments of inflammatory markers will be performed as an 
exploratory measure for all subjects at the predose visit and day 7 visit for all Treatment Periods 
1-5 and one additional inflammatory marker sample is to be collected near the end of Treatment 
Period 5 – this may be collected at Visit 32/Day 21, between Visit 32/Day 21 and the EOS Visit, 
or at the EOS Visit/Day 30, or at Early Termination to investigate changes to inflammatory 
markers. 
10.6. 
T-cell recall Assessments 
Assessments of T-cell recall responses to pegsiticase will be performed as an exploratory 
measure for all subjects in each cohort to investigate changes to T-cell recall response to 
pegsiticase.  Assessments will be performed for each subject at 3 time points as per the schedules 
of events and at Early Term visit. If a predose T-cell recall specimen is not available this will not 
preclude the drawing of a specimen for T-cell recall at v18, v30 or at Early Term. Procedures for 
the assessments and analysis can be found in the study procedure manual. 


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11. 
ASSESSMENT OF SAFETY 
11.1. 
Safety Parameters 
11.1.1. 
Demographic/Medical History 
Demographic and significant medical history will be documented.  Medical history will be 
recorded up to the time of dosing. 
11.1.2. 
Vital Signs 
Blood pressure, pulse and respiratory rate, temperature will be assessed at times indicated in the 
schedule of events ± 2.5 minutes.  Blood pressure and heart rate will be recorded after at least 5 
minutes of rest in a sitting position.  If a conflict occurs during a visit because of multiple 
assessments needing to occur at the same time point, the ECG may be performed +/- 30 minutes 
from the designated time so that the vital signs and the blood draws may occur within the stated 
parameters. 
11.1.3. 
Weight and Height 
Height and weight will be recorded at the Screening Visit.  Weight will also be recorded at Day 
21 visits for each treatment period, ie. at Visits 8, 14, 20, 26 and 32. 
11.1.4. 
Physical Examination 
Physical examinations will be conducted at visits indicated in the schedule of events.  Breast, 
rectal and urogenital exams are not required unless warranted based on the clinical judgment of 
the subject’s medical history or current medical condition.  The physical exam should be done by 
a physician or physician’s assistant or similarly qualified individual. 
11.1.5. 
Electrocardiogram (ECG) 
ECG will be recorded with the subject in a semi-recumbent position after at least 5 minutes of 
rest and until 4 regular consecutive complexes are available depending on heart rate.  If a conflict 
occurs during a visit because of multiple assessments needing to occur at the same time point, 
the ECG may be performed +/- 30 minutes from the designated time so that the vital signs and 
the blood draws may occur within the stated parameters.  ECGs will be recorded at times 
indicated in the schedule of events. Twelve-lead ECGs will be recorded at paper speed of 25 
mm/sec.  ECG intervals RR, PR, QRS, QT, QTcB and QTcF will be calculated. 
11.1.6. 
Laboratory Assessments 
Fasting blood samples collected as indicated in the schedule of events will include a complete 
blood count (CBC) with differential, clinical chemistry (serum comprehensive metabolic panel 
including electrolytes – sodium, potassium, chloride, bi-carbonate, phosphate and magnesium), 


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lipid panel and coagulation parameters (international normalized ratio (INR), activated partial 
thromboplastin time (aPTT), fibrinogen) and urinalysis.   
Screening tests for glucose-6-phosphate dehydrogenase deficiencies, HbA1c, HIV and hepatitis 
C will be conducted at the Screening Visit.   
The collection date, time, and study day will be documented.  
11.1.7. 
Immunogenicity 
Blood samples will be collected per the schedule of events.  Procedures for processing samples 
will be included in the study laboratory manual. 
11.2. 
Adverse and Serious Adverse Events 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of a non-serious adverse events (AE), serious adverse events (SAE) as provided in this 
protocol.   
11.2.1. 
Definitions 
11.2.1.1. Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug (i.e., study drug) in 
humans, whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug and does not imply any judgment about causality. An AE can 
arise with use of any drug or medicinal product.  
Subjects will be considered enrolled in the study upon dosing of study drug for the first time.  
AEs (and thus SAEs) will be collected from the time the subject is dosed (infusion is started) 
until the end of the End of Study Visit.  During the Screening Phase (from time informed consent 
is signed to immediately before dosing) any clinically significant changes in the subject’s health 
will be recorded in the subject’s medical history. 
11.2.1.2. Unexpected Adverse Events and Unexpected Suspected Drug Reaction 
An AE or suspected adverse reaction (an AE where there is a reasonable possibility that the drug 
caused the event; suspected drug related) is considered "unexpected" if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed. 
11.2.1.3. Serious Adverse Event 
An SAE is any adverse event that occurs irrespective of study treatment assignment, if it satisfies 
any of these criteria:  
• results in death;  
• is life-threatening;  


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• requires inpatient hospitalization or prolongs existing hospitalization;  
• results in persistent or significant disability or incapacity or substantial disruption of the 
ability to conduct normal life functions;  
• is a congenital anomaly or birth defect;   
• is an important medical event that, based upon appropriate medical judgment, may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
11.2.2. 
Recording Adverse Events 
Subjects will be encouraged to spontaneously report any changes in health from the time of 
informed consent signing through completion of the study.  Study staff will also inquire about 
any changes in the subject’s health.   
All AEs will be recorded in the source document and the CRF.  It is the responsibility of the 
Investigator to review all documentation (e.g., hospital progress notes, laboratory, and 
diagnostics reports) for the presence of AEs and for a complete evaluation of known AEs. 
At minimum for each AE, the investigator will evaluate and report the event 
name/term/description, onset (date and time), resolution (date and time), event severity/intensity, 
relationship to study drug, action taken in regards to study drug, whether the event is an SAE, 
and whether or not it caused the patient to discontinue the study.  The event time is only required 
while the subject is in the clinic. 
11.2.2.1. Adverse Event Term/Name/Description 
The Investigator will attempt to establish a diagnosis of each AE based on signs, symptoms, and/or 
other clinical information.  In such cases, the diagnosis will be the AE term used to document the 
AE/SAE and not the individual signs/symptoms.   
11.2.2.2. Relationship to Study Drug 
The Investigator is obligated to assess the relationship between study drug and the occurrence of 
each AE/SAE.  The Investigator will use clinical judgment to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, other 
risk factors, and the temporal relationship of the event to the study drug will be considered and 
investigated. The Investigator will also consult the Investigator’s Brochure and/or Product 
Information for marketed products in the determination of his/her assessment. 
The Investigator will assess causality as to whether the event is related or not related to study 
drug based on the following definitions:  
• Not Related (If no valid reason exists for suggesting a relationship to study drug or the AE 
was more likely explained by causes other than study drug). 


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• Unlikely to be Related: Onset of the event has a reasonable temporal relationship to study 
drug administration and although a causal relationship is unlikely, it is biologically plausible. 
• Possibly Related: Onset of the event has a strong temporal relationship to administration of 
the study drug and a causal relationship is biologically plausible 
• Related (the study drug dosing and AE were closely related in time and the AE may be 
explained by exposure to study product: e.g., known pharmacological effect or recurrence on 
re-challenge).  
There may be situations, particularly when an SAE has occurred, where the Investigator has 
minimal information to make an assessment in an initial SAE report. However, it is very 
important that the Investigator always make an assessment of causality for every SAE prior to 
transmission of the SAE report. The Investigator may change his/her opinion of causality in light 
of follow-up information, amending the SAE report accordingly.  Any assessment of causality 
made by the Investigator should also be documented in the subject’s source medical record. 
11.2.2.3. Adverse Event Intensity/Severity Grading 
AEs will be classified according to the Rheumatology Common Toxicity Criteria, version 2.0 
(Woodworth et al. 2007).  The general framework for grading AEs is provided below, and the 
full scale is provided in Section 19.1 of the protocol. 
• Grade 1 (mild) 
AE that is usually transient of short duration; or involves mild or minor 
symptoms which are of marginal clinical relevance; or is asymptomatic consisting of clinical 
or diagnostic observations alone; no intervention or only minimal treatment with non-
prescription intervention was required. The event does not generally interfere with usual 
activities of daily living. 
• Grade 2 (moderate) 
AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living (e.g., shopping, laundry, 
transportation, or ability to conduct finances), causing discomfort but poses no significant or 
permanent risk or harm to the subject. 
• Grade 3 (severe) AE that is medically significant/important but not life-threatening; may 
require brief hospitalization to prevent the event from worsening; interrupts usual activities 
of daily living, or significantly affects clinical status, or may require intensive therapeutic 
intervention. 
• Grade 4 (life-threatening) An AE, and/or its immediate sequelae, which is associated with an 
imminent risk of death or which is associated with physical or mental disabilities that affect 
or limit the ability of a person to perform activities of daily living (eating, ambulation, 
toileting, etc.); disability may be persistent or result in significant disability, incapacity or 
limitation of self-care activities.  
For an assessment of anaphylaxis, the clinical criteria for the diagnosis of anaphylaxis will be 
based on the National Institute of Allergy and Infectious Diseases (NIAID)/ Food Allergy & 
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11.2.2.4. Assessment of Outcome 
The result or conclusion of the adverse event will be assessed and recorded by the Investigator 
as: 
• Fatal 
• Not recovered/not resolved (the AE has not improved or subject has not recuperated). 
• Recovered/resolved (the AE has improved or subject has recuperated) 
• Recovered/resolved with sequelae (recuperated but retained pathological conditions resulting 
from the AE) 
• Recovering/resolving (the subject is improving but the AE has not yet resolved) 
• Unknown (not known, not observed, not recorded, or refused) 
11.2.2.5. Action taken with study drug 
The action taken in regards to study drug will be assessed by the investigator as: 
• Dose not changed (dose completed) 
• Dose reduced (IV infusion was modified by subtraction by changing the amount dosed) 
• Dose interrupted (IV infusion was temporally modified by temporarily stopping the infusion; 
slowing of the rate of infusion should also be classified as interrupted) 
• Drug withdrawn (IV infusion was modified through termination of the infusion) 
A response option for increasing the dose is not an available course of action in this study. 
11.2.2.6. Laboratory and Diagnostic Abnormalities as Adverse Events 
Clinically significant abnormal laboratory findings or other abnormal diagnostic assessments 
(e.g., ECGs, vital signs) that are detected in dosed subjects or that significantly worsen relative to 
baseline in dosed subjects will be reported as AEs or SAEs.  Clinically significant is based on 
investigator judgment but will typically include findings that results in study withdrawal, result 
in active management of the subject, or are associated with clinical signs and symptoms.  Since 
the study requires subjects with elevated or abnormal uric acid levels, abnormal uric acid levels 
will typically not be an AE unless judged by the Investigator as being more severe than expected 
for the subject. 
11.2.2.7. Pregnancy 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or a SAE and 
followed.  The outcome of all pregnancies must be followed up and documented even if the 
subject is no longer a study participant. 


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The Investigator, or his/her designee, will collect pregnancy information on every female who 
becomes pregnant while enrolled in this study and on every female partner of a male subject who 
becomes pregnant while the male partner is enrolled in this study. The Investigator will report to 
the Sponsor or Sponsor’s designee within 24 hours of learning of a subject’s or female partner of 
a subject’s pregnancy. The subject or female partner of a subject must also be followed to 
determine the outcome of the pregnancy.  Information on the status of the mother and child will 
be forwarded to the Sponsor or Sponsor Designee, as appropriate. Follow-up on the child will be 
to the first well-child visit. Any premature termination of the pregnancy will be reported. 
A spontaneous abortion, congenital abnormalities/birth defects will be considered SAEs and will 
be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is 
considered reasonably related to the study drug by the Investigator, will be reported to the 
Sponsor.  
11.3. 
Reporting Adverse Events 
11.3.1. 
Adverse Event Reporting Period 
The study period during which AEs must be reported is from the time the subject is dosed until 
the End of Study.  During the Screening Phase (from time informed consent is signed up to the time 
of dosing) any clinically significant changes in the subject’s health will be recorded in the subject’s 
medical history.   
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the Investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably related to the study 
drug, the Investigator should promptly notify the Sponsor. 
11.3.2. 
SAE Reporting Procedures 
If SAEs occur, all investigators should immediately, but not later than 24 hours of observing or 
learning of the event, complete and fax the SAE form to INC Drug Safety. 
Facsimile (for SAE only):  877-464-7787 
Email (for SAE only):  INCDrugSafety@INCResearch.com 
The investigator will complete the SAE form and provide all case information available at the 
time of the initial report. The investigator must include the following mandatory case 
information: 
i. 
the subject identification number 
ii. 
the event description 
iii. 
the seriousness criteria 
iv. 
the investigator’s causality assessment 
The reporting investigator must send the written and signed SAE report by facsimile or email, 
within 24 hours of observing, notification of, or learning of the SAE to INC Drug Safety as 
described above.  Follow-up information regarding an SAE and the supporting data, including 


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laboratory findings and discharge summaries, should be sent by facsimile or email to INC Drug 
Safety within 24 hours of receipt of the information. 
If the Investigator does not have all information regarding an SAE, the Investigator will not wait 
to receive additional information before completing as much of the form as possible and 
notifying the safety group. The form will be updated when additional information is received. 
The Investigator will always provide at minimum:  1) AE term or event name/description, 2) 
subject identifier, 3) an assessment of causality (see Section 11.2.2.2).  
11.3.3. 
Regulatory Reporting Requirements for SAEs  
The Sponsor or Sponsor representative will report fatal or life-threatening SAEs that are 
unexpected suspected adverse reactions to the FDA within 7 calendar days, and non-fatal or life-
threatening SAEs that are unexpected suspected adverse reactions within 15 calendar days as 
Investigational New Drug (IND) Safety Reports, in accordance with 21 CFR 312.32.  Prompt 
notification of SAEs by the Investigator to the appropriate project contact for SAE receipt is 
essential so that legal obligations and ethical responsibilities towards the safety of other subjects 
are met.  
11.3.4. 
Reporting Safety Information to the IRB  
The Investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to the Institutional 
Review Board (IRB) / Institutional Ethics Committee (IEC). 
All Investigators involved in studies with this drug will receive a copy of each IND Safety 
Report.  When an Investigator receives an IND Safety Report or other safety information (e.g., 
revised Clinical Investigator’s Brochure/Investigator’s Brochure), the responsible person 
according to local requirements is required to promptly notify his or her IRB. 
11.4. 
Follow-up of Adverse Events  
The Investigator is required to proactively follow each subject and provide further information to 
in regards to AEs and SAEs. All AEs and SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to follow-
up.  Once resolved, the appropriate CRF entries and event reporting forms will be updated, as 
appropriate.  
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts.  The Investigator will ensure that follow-up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality of the 
AE or SAE. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.  
The Sponsor or the Sponsor’s designee may request that the Investigator perform or arrange for 
the conduct of supplemental measurements and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The Investigator is obligated to assist. If a subject 


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dies during participation in the study or during a recognized follow-up period, the Sponsor will 
be provided with a copy of any post-mortem findings, including histopathology.  
New or updated information will be recorded on the originally completed SAE forms, with all 
changes signed and dated by the Investigator. This information will also be entered into the CRF.  
12. 
STATISTICS 
12.1. 
Sample Size Determination 
The sample size is designed to have a sufficient number of subjects per cohort to meet the 
objectives of the study which are to evaluate the safety, tolerability and pharmacokinetics, 
pharmacodynamics of a multiple IV infusions of SEL-212 and the safety, tolerability, 
pharmacokinetics, and pharmacodynamics of SEL-037 after multiple infusions.  
12.2. 
Safety Analysis Set 
All dosed subjects with any available post dose safety information will be included in the safety 
analysis. 
12.3. 
PK Analysis Set 
The PK analysis dataset will include all dosed subjects for which PK data is available with no 
significant protocol deviations that would significantly affect the PK evaluation of the drug. 
Factors that may influence serum SEL-037 concentrations and/or the whole blood rapamycin 
concentrations (e.g., interruptions in the infusion or changes in the infusion rate) will be 
reviewed.  If an influencing factor is present, a decision will be made by the responsible 
pharmacokineticist, whether to include or exclude the specific sample or subject.  All subjects 
and samples excluded from the analysis will be clearly documented in the study report. 
12.4. 
PK Analyses 
Data will be listed for all individual subjects with available SEL-037 serum concentrations and 
rapamycin whole blood levels. All concentrations below the lower limit of quantification 
(LLOQ) or missing data will be labeled as such in the concentration data listings. Concentrations 
below the LLOQ will be treated as zero in the estimation of pharmacokinetic parameters. 
For each dose, descriptive statistics, including arithmetic mean, standard deviation, geometric 
mean, coefficient of variation, median, minimum, and maximum will be calculated for 
rapamycin in whole blood and SEL-037 serum concentrations at each sampling time and for all 
PK parameters. 
Graphical representations of the results will include (but are not limited to) the following graphs 
as appropriate: 
• Log-linear and linear-linear concentration-time profiles for each individual 


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• Log-linear and linear-linear concentration-time profiles for the mean values per dose 
• Log-linear and linear-linear concentration-time profiles for the median values per dose 
• Log-linear and linear-linear overlay plots of the individual concentration-time profiles for 
each dose 
In addition, the relationship between PK parameters and dose will be evaluated graphically. 
12.5. 
Pharmacodynamic Analyses 
Pharmacodynamic analysis will be as described in the Statistical Analysis Plan.   
Data will be listed for all individual subjects with available uric acid serum concentrations.  For 
each dose, descriptive statistics, including arithmetic mean, standard deviation, and geometric 
mean, coefficient of variation, median, minimum, and maximum will be calculated at each 
sampling time. 
The relationship of PK and PD will be explored and may be analyzed by Spearman rank-order 
correlations between serum uricase concentration and serum uric acid concentrations by each 
time point and overall time points. The corresponding p-values will also be provided. 
12.6. 
Radiologic Analysis 
Radiologic analysis will be as described in the Study procedure manual. 
12.7. 
Inflammatory Markers Analysis 
Change from baseline will be analyzed as described in the Study procedure manual. 
12.8. 
Safety Analyses 
Includes subjects in the safety analysis population.  Baseline for all laboratory evaluations, vital 
signs, and ECG measurements will be defined as the last evaluation done before study drug 
administration.  
12.8.1. 
Demographic and Baseline Characteristics 
Baseline characteristics and demographics will be listed and summarized.  Medical history will 
be listed only. 
Extent of exposure to study drug will be listed by dose. 
12.8.2. 
Adverse Events 
The verbatim AE terms in the CRFs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA).  By definition, the study only collects treatment-emergent adverse events 
(TEAE) so all AEs are TEAEs.  The percentage of subjects with specific TEAEs will be 
summarized for each dose. 


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All adverse events will be listed sorted by dose, subject, system organ class and preferred term. 
TEAEs will be summarized (number of events, number and % of subjects having experienced at 
least one event) by dose, system organ class and preferred term. TEAEs will be also summarized 
by intensity, and by causality. SAEs will be only listed.  A narrative will be produced for those 
subjects who have discontinued treatment due to an adverse event or who experienced a Grade 3 
or higher events. 
12.8.3. 
Clinical Laboratory Tests 
Laboratory data will be summarized by the type of laboratory test. Normal reference ranges and 
markedly abnormal results will be used in the summary of laboratory data. Data will be flagged 
according to the reference limits (High or Low) if applicable. Descriptive statistics will be 
calculated for each laboratory analyte at baseline and at each scheduled time point for each dose 
and each treatment. Changes from baseline results will be presented descriptively as well as in 
pre- versus post-treatment cross tabulations (with classes for below, within, and above normal 
ranges).  A listing of subjects with any laboratory results outside the reference ranges will be 
provided. 
12.8.4. 
Cardiovascular Safety 
The ECG variables that will be analyzed are heart rate, RR interval, PR interval, QRS interval, 
QT interval, QTcB, and QTcF.  The ECG measurements will be summarized at each time point 
of measurement. The change from baseline will be summarized. Descriptive statistics on actual 
values and changes from baseline by dose and time will be computed.  Plots (mean ± standard 
error of the mean (SEM)) on changes from baseline over time will be provided.  Listing of 
abnormal clinically significant evaluation as well as a listing of subjects with abnormal QTc 
values (>450, >480 and >500ms) and of subjects with abnormal QTc changes from baseline (≥ 
30 but <60; ≥ 60) will be provided. 
All-important abnormalities from the ECG readings, including changes in T wave morphology 
and/or the occurrence of U waves versus baseline recordings, will be reported. 
12.8.5. 
Vital Signs 
Pulse, temperature, respiration rate, and systolic blood pressure and diastolic blood pressure will 
be analyzed. Data will be flagged according to the reference limits (High or Low) if applicable. 
Descriptive statistics on actual values and changes from baseline by dose will be computed at 
each scheduled time point.  Plots (mean± SEM) on changes from baseline over time will be 
given as appropriate. 
12.8.6. 
Physical Examination 
Results of physical examinations will be listed and frequency tables computed. 


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12.8.7. 
Immunogenicity 
Immunogenicity data will be listed.   
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
13.1. 
Study Monitoring 
In accordance with applicable regulations, ICH-GCP and procedures covering the study, a 
monitor will contact the site prior to the subject enrollment to review the protocol and data 
collection procedures with site staff. In addition, the monitor will periodically contact the site, 
including conducting on-site visits at an appropriate frequency to ensure data quality and to 
ensure the safety and rights of subjects are being protected.  
The investigator agrees to allow the monitor direct access to all relevant documents and to 
allocate his/her time and the time of his/her staff to the monitor to discuss findings and any 
relevant issues.  
At study closure, monitors will also conduct all activities described in Section 16.3. 
13.2. 
Audits and Inspections 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
quality assurance audits may occur during the study or after the study is complete. Authorized 
representatives of the Sponsor, the CRO conducting the study, a regulatory authority, an IRB 
may visit the site to perform audits or inspections to examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH-GCP, and any applicable 
regulatory requirements.  
If an audit or inspection occurs, the Investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her staff to the auditor/inspector to discuss findings and any relevant issues. The 
Investigator should contact the Sponsor immediately if contacted by a regulatory agency about 
an inspection. 
13.3. 
Institutional Review Board (IRB) 
This study will be conducted in full compliance with the Institutional Review Board (IRB) 
regulations in 21 CFR 56 and applicable local regulatory guidance, in accordance with ICH-
GCP.  
IRB approval for the investigation must be obtained before the study is initiated. Initial IRB 
approval, and all materials approved by the IRB for this study including the patient consent form 
and recruitment materials must be maintained by the Investigator and made available for 
inspection. 


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14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, the 
Sponsor (or Sponsor representative) may conduct a quality assurance audit. Please see Section 13.2 
and Section 16.5 for more details regarding the audit process at any time during the conduct of the 
study or after study completion.  
14.1. 
Regulatory Authority Approval  
The Sponsor will obtain approval to conduct the study from the Food and Drug Administration 
(FDA) in accordance with FDA regulatory requirements prior to conducting the study.  
14.2. 
Protocol Modifications  
The initial protocol as well as all protocol amendments must be signed and dated by the Investigator 
and approved by the IRB prior to implementation of the original protocol and any amendment. The 
Principal Investigator must submit all protocol modifications to the IRB, as applicable for specific 
Investigators, or applicable local regulatory authority.  The Sponsor or designee will submit protocol 
modifications to the FDA as needed.  
Departures from the protocol will be determined as allowable on a case-by-case basis or in event of 
an emergency involving subject safety. The Investigator or other physician in attendance must 
contact the Medical Monitor as soon as possible to discuss the circumstances of the emergency. The 
Medical Monitor, in concurrence with the Investigator, will decide whether the patient should 
continue to participate in the study. All protocol deviations and the reason for such deviations must 
be noted on the source document and in the CRF, and reported to the IRB as appropriate. 
15. 
ETHICS 
15.1. 
Ethics Review 
The Investigator is responsible for ensuring that this protocol, the site’s informed consent form 
(ICF), and any other information that will be presented to potential subjects (e.g., advertisements 
or information that supports or supplements the informed consent) are reviewed and approved by 
the appropriate IRB. The Investigator agrees to allow the IRB direct access to all relevant 
documents. The IRB must be constituted in accordance with all applicable regulatory 
requirements. The Sponsor or contract research organization (CRO) will provide the Investigator 
with relevant document(s)/data that are needed for IRB review and approval of the study. The 
IRB must approve the study and ICF before study drug(s) and other study material can be 
shipped to the site.  
If the protocol, the ICF, or any other information that the IRB has approved for presentation to 
potential subjects is amended during the study, the Investigator is responsible for ensuring the 
IRB reviews and approves these amended documents, where applicable. The Investigator must 
follow all applicable regulatory requirements pertaining to the use of an amended ICF including 


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obtaining IRB approval of the amended form before new subjects consent to take part in the 
study using this version of the form. Copies of the IRB approval of the amended ICF/other 
information and the approved amended ICF/other information must be forwarded to the Sponsor 
or CRO managing the study, as appropriate.  
15.2. 
Ethical Conduct of the Study  
This study will be conducted in accordance with ICH-GCP guidelines and all applicable 
regulatory requirements, including, where applicable, the Declaration of Helsinki.  
15.3. 
Written Informed Consent  
This study will be conducted in full compliance with the informed consent regulations in 21 CFR 
50. The consent form must be reviewed and approved by the Sponsor prior to submission to the 
IRB. The consent form must be approved by the IRB prior to initiation of the study. The 
Investigator is responsible for obtaining written consent (signed and dated ICF) from potential 
subjects prior to performing any trial tests or assessments required by the protocol. A copy of the 
signed consent document will be given to the patient and the original retained by the 
Investigator. 
No Investigator may involve a human being as a subject in research unless the Investigator has 
obtained the legally effective informed consent of the subject or the subject's legally authorized 
representative. An Investigator may seek such consent only under circumstances that provide the 
prospective subject or the representative sufficient opportunity to consider whether to participate 
and that minimize the possibility of coercion or undue influence. The information given to the 
subject or the representative must be in a language understandable to the subject or the 
representative. No informed consent, whether oral or written, may include any exculpatory 
language through which the subject or the representative is made to waive or appear to waive any 
of the subject's legal rights, or releases or appears to release the Investigator, the institution, the 
Sponsor, or its agents from liability for negligence.  
An IRB-approved consent form should inform each prospective subject or the legally authorized 
representative of each prospective subject of the purpose and the nature of the study, its possible 
hazards and benefits, and the subject's right to withdraw from the study at any time without 
prejudice to further treatment. Exemptions to the requirement for informed consent in the United 
States are described in 21 CFR 50.23.  
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the study. Patients 
must also be notified that they are free to discontinue from the study at any time. The patient 
should be given the opportunity to ask questions and allowed time to consider the information 
provided.  


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16. 
DATA HANDLING AND RECORDKEEPING 
16.1. 
Case Report Form Completion and Source Documentation  
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record observations and other data pertinent to the study for each study participant. 
Subject data are collected by the investigator or designee using source documents that are 
entered into a CRF, defined by the Sponsor.  Subject data necessary for analysis and reporting 
will be first collected in the source documents and then entered into the validated CRF database 
system.  
All information recorded on CRFs must be consistent with the subject's source documentation 
(i.e., medical records). The Investigator is responsible for the accuracy of the data transcribed 
from all source documentation. All CRF entries should be made within a reasonable timeframe 
from the time of a subject’s visit. A monitor representing the sponsor will verify the CRF 
documentation for each patient against the source documents at the study center. Instances of 
missing or uninterpretable data will be brought to the attention of the investigator and/or sponsor 
for resolution.  
16.2. 
Data Management  
Clinical data management will be performed in accordance with applicable study standards and data 
cleaning procedures. Database lock will occur when data management quality control procedures are 
completed.  
16.3. 
Study Site Close-Out  
Upon completion of the study, the monitor may conduct the following activities in conjunction with 
the investigator or site staff, as appropriate:  
1. Resolve data queries.  
2. Accountability, reconciliation, and return of unused study drug(s).  
3. Review of final site study records for completeness.  
4. Return all study-specific equipment to the appropriate vendor as required.  
16.4. 
Retention of Study Documents and Records  
Following closure of the study, the Investigator must maintain all site study records in a safe and 
secure location. All CRF data will be retained by and are the sole property of the Sponsor. The 
investigator will retain a copy of all source documents and CRF data (i.e., either hard copies if a 
paper CRF or DVD-ROM containing pdf files of CRFs provided by the sponsor) for the subjects 
enrolled at the site. The records must be maintained to allow easy and timely retrieval, when 
needed (e.g., audit or inspection). Where permitted by local laws/regulations or institutional 
policy, some or all of these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before such action is 


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taken. The Investigator must assure that all reproductions are legible and are a true and accurate 
copy of the original and meet accessibility and retrieval standards, including re-generating a hard 
copy, if required. Furthermore, the Investigator must ensure there is an acceptable back-up of 
these reproductions and that an acceptable quality control process exists for making these 
reproductions.  
The Sponsor will inform the Investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by any institutional requirements or local 
laws or regulations, or the Sponsor standards/procedures; otherwise, the retention period will 
default to 15 years.  
The Investigator must notify the Sponsor of any changes in the archival arrangements, including, 
but not limited to, the following: archival at an off-site facility, transfer of ownership of the 
records in the event the Investigator leaves the site. 
16.5. 
Inspection of Records 
The Sponsor (or Sponsor representative) will be allowed to conduct site visits to the investigation 
facilities for the purpose of monitoring any aspect of the study. The Investigator agrees to allow 
the monitor to inspect the drug storage area, study drug stocks, drug accountability records, 
subject charts and study source documents, and other records relative to study conduct. 
17. 
PUBLICATION POLICY 
In the event of a conflict between the provisions of this section and a written contract regarding 
the conduct of Study between Sponsor (or a contract research organization) and the site, the 
Investigator or any person assisting Investigator with the Study, the terms of that contract shall 
control.  
17.1. 
Ownership  
All information provided by or on behalf of Sponsor and all data and information generated by 
the site, the Investigator or any person assisting Investigator with the Study as part of or in 
connection with the Study (other than a subject’s medical records), is the sole and exclusive 
property of Sponsor. All rights, title, and interests in and to any inventions, discoveries or know-
how made, conceived, learned or first reduced to practice by the site, Investigator or any person 
assisting Investigator with the Study during the course of, in relation to, or as a result of the 
Study (and any intellectual property rights related thereto) are the sole and exclusive property of 
the Sponsor, and are hereby assigned to Sponsor.  
17.2. 
Confidentiality  
All information provided by the Sponsor and all data and information generated by the site as 
part of or in relation to the Study (other than a subject’s medical records) will be kept 
confidential by the Investigator, the site, and any person assisting Investigator with the Study. 


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This information and data shall not be used by the site, Investigator, or any person assisting 
Investigator with the Study for any purpose other than conducting the Study. These restrictions 
do not apply to: 1) information which becomes publicly available through no fault of the site, 
Investigator or any person assisting Investigator with the Study; 2) information which it is 
necessary to disclose in confidence to an IRB solely for the evaluation of the Study; 3) 
information which it is necessary to disclose in order to provide appropriate medical care to a 
Study subject; or 4) Study results which are permitted to be published as described in the next 
section.  
17.3. 
Publication  
If the Study is a multi-center study, the first publication or disclosure of Study results shall 
include data from all sites.  
Investigator may publish the results of the Study only for noncommercial, educational or 
academic purposes provided that: 1) said publication is made after the multi-center publication; 
and 2) prior to making the publication, or otherwise disclosing the Study results, Investigator 
provides Sponsor with a copy of the proposed publication and allows Sponsor a reasonable 
period to review. Proposed publications shall not include the Sponsor confidential information 
(other than the Study results) or personal data with respect to any subject (such as name or 
initials) and if the Sponsor identifies any such the Sponsor confidential information in a proposed 
publication, it shall be removed.  
At the Sponsor’s request, the submission, publication or other disclosure of a proposed 
publication will be delayed a sufficient time to allow the Sponsor to seek patent or similar 
protection of any inventions, know-how or other intellectual or industrial property rights 
contained in such proposed publication. 


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18. 
LIST OF REFERENCE 
Barlow, A. D., Nicholson, M. L. and Herbert, T. P. (2013). "Evidence for rapamycin toxicity in 
pancreatic beta-cells and a review of the underlying molecular mechanisms." Diabetes 62(8): 
2674-2682; 
 
Biggers, K. and Scheinfeld, N. (2008). "Pegloticase, a polyethylene glycol conjugate of uricase 
for the potential intravenous treatment of gout." Curr Opin Investig Drugs 9(4): 422-429; 
 
Bomalaski, J. S., Holtsberg, F. W., Ensor, C. M. and Clark, M. A. (2002). "Uricase formulated 
with polyethylene glycol (uricase-PEG 20): biochemical rationale and preclinical studies." J 
Rheumatol 29(9): 1942-1949; 
 
Cammalleri, L. and Malaguarnera, M. (2007). "Rasburicase represents a new tool for 
hyperuricemia in tumor lysis syndrome and in gout." Int J Med Sci 4(2): 83-93; 
 
Campion, E. W., Glynn, R. J. and DeLabry, L. O. (1987). "Asymptomatic hyperuricemia. Risks 
and consequences in the Normative Aging Study." Am J Med 82(3): 421-426; 
 
Chen, Y., Zhang, Z., Lin, Y., Lin, H., Li, M., Nie, P., Chen, L., Qiu, J., Lu, Y., Chen, L., Xu, B., 
Lin, W., Zhang, J., Du, H., Liang, J. and Zhang, Z. (2013).  "Long-term Impact of 
Immunosuppressants at Therapeutic Doses on Male Reproductive System in Unilateral 
Nephrectomized Rats:  A Comparative Study."  BioMed Res Int 2013:690382. doi: 
10.1155/2013/690382; 
 
Choi, H. (2006). "Epidemiology of crystal arthropathy." Rheum Dis Clin North Am 32(2): 255-
273, v; 
 
Cortes, J., Moore, J. O., Maziarz, R. T., Wetzler, M., Craig, M., Matous, J., Luger, S., Dey, B. 
R., Schiller, G. J., Pham, D., Abboud, C. N., Krishnamurthy, M., Brown, A., Jr., Laadem, A. and 
Seiter, K. (2010). "Control of plasma uric acid in adults at risk for tumor Lysis syndrome: 
efficacy and safety of rasburicase alone and rasburicase followed by allopurinol compared with 
allopurinol alone--results of a multicenter phase III study." J Clin Oncol 28(27): 4207-4213; 
 
Deutsch, M.A., Kaczmarek, I., Huber, S., Schmauss, D., Beiras-Fernandez, A., Schmoeckel, M., 
Ochsenkuehn, R., Meiser, B., Mueller-Hoecker, J. and Reichart, B. (2007). " Sirolimus-
associated infertility: case report and literature review of possible mechanisms." Am J 
Transplant. 7(10):2414-21. 
 
Fishburn, C. S. (2008). "The pharmacology of PEGylation: balancing PD with PK to generate 
novel therapeutics." J Pharm Sci 97(10): 4167-4183; 
 


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Ghisdal, L., Van Laecke, S., Abramowicz, M. J., Vanholder, R. and Abramowicz, D. (2012). 
"New-onset diabetes after renal transplantation: risk assessment and management." Diabetes 
Care 35(1): 181-188; 
 
Goldman, S. C., Holcenberg, J. S., Finklestein, J. Z., Hutchinson, R., Kreissman, S., Johnson, F. 
L., Tou, C., Harvey, E., Morris, E. and Cairo, M. S. (2001). "A randomized comparison between 
rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis." 
Blood 97(10): 2998-3003; 
 
Gray, L.E., Wilson, V., Noriega, N., Lambright, C., Furr, J., Stoker, T.E., Laws, S.C., Goldman, 
J., Cooper, R.L. and Foster, P.M.D. (2004).  "Use of the Laboratory Rat as a Model in Endocrine 
Disruptor Screening and Testing."  ILAR J 45: 425-437; 
 
Hakeam, H. A., Al-Jedai, A. H., Raza, S. M. and Hamawi, K. (2008). "Sirolimus induced 
dyslipidemia in tacrolimus based vs. tacrolimus free immunosuppressive regimens in renal 
transplant recipients." Ann Transplant 13(2): 46-53; 
 
Johnston, O., Rose, C. L., Webster, A. C. and Gill, J. S. (2008). "Sirolimus is associated with 
new-onset diabetes in kidney transplant recipients." J Am Soc Nephrol 19(7): 1411-1418; 
 
Khanna, D., Fitzgerald, J. D., Khanna, P. P., Bae, S., Singh, M. K., Neogi, T., Pillinger, M. H., 
Merill, J., Lee, S., Prakash, S., Kaldas, M., Gogia, M., Perez-Ruiz, F., Taylor, W., Liote, F., 
Choi, H., Singh, J. A., Dalbeth, N., Kaplan, S., Niyyar, V., Jones, D., Yarows, S. A., Roessler, 
B., Kerr, G., King, C., Levy, G., Furst, D. E., Edwards, N. L., Mandell, B., Schumacher, H. R., 
Robbins, M., Wenger, N., Terkeltaub, R. and American College of, R. (2012a). "2012 American 
College of Rheumatology guidelines for management of gout. Part 1: systematic 
nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia." Arthritis Care 
Res (Hoboken) 64(10): 1431-1446; 
 
Khanna, D., Khanna, P. P., Fitzgerald, J. D., Singh, M. K., Bae, S., Neogi, T., Pillinger, M. H., 
Merill, J., Lee, S., Prakash, S., Kaldas, M., Gogia, M., Perez-Ruiz, F., Taylor, W., Liote, F., 
Choi, H., Singh, J. A., Dalbeth, N., Kaplan, S., Niyyar, V., Jones, D., Yarows, S. A., Roessler, 
B., Kerr, G., King, C., Levy, G., Furst, D. E., Edwards, N. L., Mandell, B., Schumacher, H. R., 
Robbins, M., Wenger, N., Terkeltaub, R. and American College of, R. (2012b). "2012 American 
College of Rheumatology guidelines for management of gout. Part 2: therapy and 
antiinflammatory prophylaxis of acute gouty arthritis." Arthritis Care Res (Hoboken) 64(10): 
1447-1461; 
 
Koyama, Y., Ichikawa, T. and Nakano, E. (1996). "Cloning, sequence analysis, and expression in 
Escherichia coli of the gene encoding the Candida utilis urate oxidase (uricase)." J Biochem 
120(5): 969-973; 
 
Lipsky, P. E., Calabrese, L. H., Kavanaugh, A., Sundy, J. S., Wright, D., Wolfson, M. and 
Becker, M. A. (2014). "Pegloticase immunogenicity: the relationship between efficacy and 


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antibody development in patients treated for refractory chronic gout." Arthritis Res Ther 16(2): 
R60; 
 
Mehvar, R. (2000). "Modulation of the pharmacokinetics and pharmacodynamics of proteins by 
polyethylene glycol conjugation." J Pharm Pharm Sci 3(1): 125-136; 
 
Oda, M., Satta, Y., Takenaka, O. and Takahata, N. (2002). "Loss of urate oxidase activity in 
hominoids and its evolutionary implications." Mol Biol Evol 19(5): 640-653; 
 
Oldfield, V. and Perry, C. M. (2006). "Rasburicase: a review of its use in the management of 
anticancer therapy-induced hyperuricaemia." Drugs 66(4): 529-545; 
 
Pereira, M. J., Palming, J., Rizell, M., Aureliano, M., Carvalho, E., Svensson, M. K. and 
Eriksson, J. W. (2012). "mTOR inhibition with rapamycin causes impaired insulin signalling and 
glucose uptake in human subcutaneous and omental adipocytes." Mol Cell Endocrinol 355(1): 
96-105; 
 
Roa, J., Garcia-Galiano, D., Varela, L., Sanchez-Garrido, M. A., Pineda, R., Castellano, J. M., 
Ruiz-Pino, F., Romero, M., Aguilar, E., Lopez, M., Gaytan, F., Dieguez, C., Pinilla, L. and Tena-
Sempere, M. (2009). "The mammalian target of rapamycin as novel central regulator of puberty 
onset via modulation of hypothalamic Kiss1 system." Endocrinology 150(11): 5016-5026; 
 
Rovira J., Diekmann F., Ramírez-Bajo M.J., Bañón-Maneus E., Moya-Rull D., and Campistol 
J.M. (2012). "Sirolimus-associated testicular toxicity: detrimental but reversible." 
Transplantation 93(9):874-9; 
 
Sampson, H. A., Munoz-Furlong, A., Campbell, R. L., Adkinson, N. F., Jr., Bock, S. A., 
Branum, A., Brown, S. G., Camargo, C. A., Jr., Cydulka, R., Galli, S. J., Gidudu, J., Gruchalla, 
R. S., Harlor, A. D., Jr., Hepner, D. L., Lewis, L. M., Lieberman, P. L., Metcalfe, D. D., 
O'Connor, R., Muraro, A., Rudman, A., Schmitt, C., Scherrer, D., Simons, F. E., Thomas, S., 
Wood, J. P. and Decker, W. W. (2006). "Second symposium on the definition and management 
of anaphylaxis: summary report--Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium." J Allergy Clin Immunol 117(2): 
391-397; 
 
Sherman, M. R., Saifer, M. G. and Perez-Ruiz, F. (2008). "PEG-uricase in the management of 
treatment-resistant gout and hyperuricemia." Adv Drug Deliv Rev 60(1): 59-68; 
 
Shivaswamy, V. (2013). "Immunosupppression and Endocrine Dysfunction." Journal of 
Transplantation Technologies & Research 01(S2); 
 
Skrzypek, J. and Krause, W. (2007). " Azoospermia in a renal transplant recipient during 
sirolimus (rapamycin) treatment." Andrologia. 39(5):198-9; 
 


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So, A. (2008). "Developments in the scientific and clinical understanding of gout." Arthritis Res 
Ther 10(5): 221; 
 
Soefje, S.A.,Karnad, A., Brenner, A.J.(2011)."Common toxicities of mammalian target 
rapamycin inhibitors." Target Oncology 6:125-129 
 
Sundy, J. S., Baraf, H. S., Yood, R. A., Edwards, N. L., Gutierrez-Urena, S. R., Treadwell, E. L., 
Vazquez-Mellado, J., White, W. B., Lipsky, P. E., Horowitz, Z., Huang, W., Maroli, A. N., 
Waltrip, R. W., 2nd, Hamburger, S. A. and Becker, M. A. (2011). "Efficacy and tolerability of 
pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two 
randomized controlled trials." JAMA 306(7): 711-720; 
 
Sundy, J. S., Ganson, N. J., Kelly, S. J., Scarlett, E. L., Rehrig, C. D., Huang, W. and Hershfield, 
M. S. (2007). "Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant 
mammalian urate oxidase in patients with refractory gout." Arthritis Rheum 56(3): 1021-1028; 
 
Veronese, F. M. and Mero, A. (2008). "The impact of PEGylation on biological therapies." 
BioDrugs 22(5): 315-329; 
 
Woodworth, T., Furst, D. E., Alten, R., Bingham, C. O., 3rd, Yocum, D., Sloan, V., Tsuji, W., 
Stevens, R., Fries, J., Witter, J., Johnson, K., Lassere, M. and Brooks, P. (2007). "Standardizing 
assessment and reporting of adverse effects in rheumatology clinical trials II: the Rheumatology 
Common Toxicity Criteria v.2.0." J Rheumatol 34(6): 1401-1414; 
 
Wortmann, R. L., Firestein, G. S., Budd, R. C., Gabriel, S. E., McInnes, I. B. and O'Dell, J. R. 
(2008). Gout and Hyperuricemia. Kelley's Textbook of Rheumatol, Elsevier: 1481-1506. 
 
Wu, X. W., Lee, C. C., Muzny, D. M. and Caskey, C. T. (1989). "Urate oxidase: primary 
structure and evolutionary implications." Proc Natl Acad Sci U S A 86(23): 9412-9416; 
 
Wu, X. W., Muzny, D. M., Lee, C. C. and Caskey, C. T. (1992). "Two independent mutational 
events in the loss of urate oxidase during hominoid evolution." J Mol Evol 34(1): 78-84; 
 
Zalipsky, S. and Lee, C. (1992). Use of Functionalized Poly(Ethylene Glycol)s for Modification 
of Polypeptides. Poly(Ethylene Glycol) Chemistry. J. M. Harris, Springer US: 347-370. 
 
Zuber, J., Anglicheau, D., Elie, C., Bererhi, L., Timsit, M.O., Mamzer-Bruneel, M.F., Ciroldi, 
M., Martinez, F., Snanoudj, R., Hiesse, C., Kreis, H., Eustache, F., Laborde, K., Thervet, E. and 
Legendre, C. (2008). "Sirolimus may reduce fertility in male renal transplant recipients." Am J 
Transplant. 8(7):1471-9. 


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19. 
APPENDICES 
19.1. 
Common Toxicity Criteria for Rheumatology, version 2.0  
(Woodworth, 2007) 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
 
Asymptomatic, or transient 
Symptomatic 
Prolonged symptoms, 
reversible 
At risk of death 
 
Short duration 
(< 1 week) 
Duration 1–2 weeks 
Major functional impairment 
Substantial disability, 
especially if permanent 
 
No change in lifestyle 
Alter lifestyle occasionally 
 
 
 
No medication or 
over-the-counter 
medications 
Medications give relief 
(may be prescription) 
Prescription 
medications/partial relief; 
hospitalized <24 hours 
Hospitalized >24 hours 
 
 
 
Temporary or permanent 
study drug discontinuation 
Permanent study drug 
discontinuation 
19.1.1. 
Clinical Signs and Symptoms 
A. Allergic/Immunologic 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
A1. Allergic reaction/  
hypersensitivity 
(includes drug fever) 
Transient rash; drug fever 
<38°C; transient, 
asymptomatic 
bronchospasm 
Generalized urticaria 
responsive to meds; drug 
fever >38°C; reversible 
bronchospasm 
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with 
meds; allergy-related 
edema/angioedema 
Anaphylaxis; laryngeal/ 
pharyngeal edema 
requiring resuscitation 
A2. Autoimmune reaction 
Serologic or other evidence 
of autoimmune reaction, but 
patient asymptomatic, all 
organ function normal and 
no treatment is required 
(e.g. vitiligo) 
Evidence of autoimmune 
reaction involving a non-
essential organ or functions, 
requiring treatment other 
than immunosuppressive 
drugs (e.g. hypothyroidism) 
Reversible autoimmune 
reaction involving function of 
a major organ or toxicity 
requiring short term 
immunosuppressive treatment 
(e.g. transient colitis or 
anemia) 
Causes major organ 
dysfunction; or 
progressive, not 
reversible, or requires 
long term administration 
of high dose 
immunosuppressive 
therapy 
A3. Rhinitis (including 
sneezing, nasal 
stuffiness, post-nasal 
discharge) 
Transient, non-prescription 
meds relieve 
Prescription med required, 
slow response to meds 
Corticosteroids or other 
prescription med with 
persistent disabling symptoms 
such as impaired exercise 
tolerance 
N/A 
A4. Serum sickness 
Transient, non-prescription 
meds relieve 
Symptomatic, slow 
response to meds (e.g. oral 
corticosteroids) 
Prolonged; symptoms only 
partially relieved by meds; 
parenteral corticosteroids 
required 
Major organ dysfunction, 
requires long-term high-
dose immunosuppressive 
therapy 
A5. Vasculitis 
Localized, not requiring 
treatment; or rapid response 
to meds; cutaneous 
Symptomatic, slow 
response to meds (e.g. oral 
corticosteroids) 
Generalized, parenteral 
corticosteroids required 
or/and short duration 
hospitalization 
Prolonged, 
hospitalization, ischemic 
changes, amputation 
 
 


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B. Cardiac 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
B1. Arrhythmia 
Transient, asymptomatic 
Transient, but symptomatic 
or recurrent, responds to 
meds 
Recurrent/persistent; 
maintenance prescription 
Unstable, hospitalization 
required; parenteral meds 
B2. Cardiac function 
decreased 
Asymptomatic decline in 
resting ejection fraction by 
>10%, but <20% of 
baseline value 
Asymptomatic decline of 
resting ejection fraction 
≥20% of baseline value 
CHF responsive to treatment Severe or refractory CHF 
B3. Edema 
Asymptomatic (e.g. 1+ 
feet/calves), self-limited, no 
therapy required 
Symptomatic (e.g. 2+ 
feet/calves), requires 
therapy 
Symptoms limiting function 
(e.g. 3+ feet/calves, 2+ 
thighs), partial relief with 
treatment, prolonged 
Anasarca; no response to 
treatment 
B4. Hypertension (new 
onset or worsening) 
Asymptomatic, transient 
increase by >20 mm Hg 
(diastolic) or to >150/100 if 
previously normal, no 
therapy required 
Recurrent or persistent 
increase >150/100 or by 
>10 mm Hg (diastolic), 
requiring and responding 
readily to treatment 
Symptomatic increase 
>150/100, >20 mm Hg, 
persistent, requiring multi-
agent therapy, difficult to 
control 
Hypertensive crisis 
B5. Hypotension (without 
underlying diagnosis) 
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
>20 mm Hg 
Symptomatic, without 
interference with function, 
recurrent or persistent >20 
mm Hg decrease, responds 
to treatment 
Syncope or symptomatic, 
interferes with function, 
requiring therapy and 
sustained medical attention, 
dose adjustment or drug 
discontinuation 
Shock 
B6. Myocardial ischemia 
Transient chest pain/ECG 
changes; rapid relief with 
nitro 
Recurring chest pain, 
transient ECG ST-T 
changes; treatment relieves 
Angina with infraction, no or 
minimal functional 
compromise, reduce dose or 
discontinue study drug 
Acute myocardial 
infarction, arrhythmia 
and/or CHF 
B7. Pericarditis/ pericardial 
effusion 
Rub heard, asymptomatic 
Detectable effusion by 
echocardiogram, 
symptomatic NSAID 
required 
Detectable on chest X-ray, 
dyspnea; or 
pericardiocentesis; requires 
corticosteroids 
Pulsus alternates with low 
cardiac output; requires 
surgery 
B8. Phlebitis/ thrombosis/ 
embolism (excludes 
injection site) 
Asymptomatic, superficial, 
transient, local, or no 
treatment required 
Symptomatic, recurrent, 
deep vein thrombosis, no 
anticoagulant therapy 
required 
Deep vein thrombosis 
requiring anticoagulant 
therapy 
Pulmonary embolism 
C. General (Constitutional) 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
C1. Fatigue/malaise 
(asthenia) 
Increase over baseline; 
most usual daily functions 
maintained, short term 
Limits daily function 
intermittently over time 
Interferes with basic ADL, 
persistent 
Unable to care for self, 
bed or wheelchair bound 
>50% of day debilitating, 
hospitalization 
C2. Fever (pyrexia) (note: 
fever due to drug 
allergy should be 
coded as allergy) 
Transient, few symptoms 
37.7-38.5°C 
Symptomatic, recurrent 
38.6-39.9°C; relieved by 
meds 
>40°C; <24h, persistent 
symptoms; partial response to 
meds. 
>40°C, debilitating, >24 
hr, hospitalization; no 
relief with meds 
C3. Headache 
Transient or intermittent, no 
meds or relieved with OTC 
Persistent, recurring, non-
narcotic analgesics relieve 
Prolonged with limited 
response to narcotic medicine 
Intractable, debilitating, 
requires parenteral meds. 
C4. Insomnia 
Difficulty sleeping, short 
term, not interfering with 
function 
Difficulty sleeping, short 
term, interfering with 
function, use of prescription 
med. 
Prolonged symptoms, with 
limited response to narcotic 
meds. 
Debilitating, 
hospitalization; no relief 
with meds 
C5. Rigors, chills 
Asymptomatic, transient, no 
meds, or non-narcotic meds 
relieve 
Symptomatic, narcotic 
meds relieve. 
Prolonged symptoms, with 
limited response to narcotic 
meds. 
Debilitating, 
hospitalization; no relief 
with meds 
C6. Sweating (diaphoresis) Episodic, transient 
Frequent, short term 
Frequent, drenching, 
disabling 
Dehydration, requiring IV 
fluids/ hospitalization >24 
hr 
C7. Weight gain 
5-9.9% 
10-19.9% 
20-30% 
N/A 
C8.  Weight loss 
5-9.9% 
10-19.9% 
20-30% 
N/A 
 
 


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D. Dermatologic 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
D1. Alopecia 
Subjective, transient 
Objective, fully reversible 
Patchy, wig used, partly 
reversible 
Complete, or irreversible 
even if patchy 
D2. Bullous eruption 
Localized, asymptomatic 
Localized, symptomatic, 
requiring treatment 
Generalized, responsive to 
treatment, reversible 
Prolonged, generalized, or 
requiring hospitalization 
for treatment 
D3. Dry skin 
Asymptomatic, controlled 
with emollients 
Symptoms eventually (1-2 
wks) controlled with 
emollients 
Generalized, interfering with 
ADL >2 wks, persistent 
pruritis, partially responsive 
to treatment 
Disabling for extended 
period, unresponsive to 
ancillary therapy and 
requiring study drug 
discontinuation for relief 
D4. Injection site reaction 
Local erythema, pain, 
pruritis, <few days 
Erythema, pain, edema, 
may include superficial 
phlebitis, 1-2 wks 
Prolonged induration, 
superficial ulceration; 
includes thrombosis 
Major ulceration necrosis 
requiring surgery 
D5. Petechiae (without 
vasculitis) 
Few, transient 
asymptomatic 
Dependent areas, persistent 
up to 2 wks 
Generalized, responsive to 
treatment; reversible 
Prolonged, irreversible, 
disabling 
D6. Photosensitivity 
Transient erythema 
Painful erythema and 
edema requiring topical 
treatment 
Blistering or desquamation, 
requires systematic 
corticosteroids 
Generalized exfoliation or 
hospitalization 
D7. Pruritis 
Localized, asymptomatic, 
transient, local treatment 
Intense or generalized, 
relieved by systematic 
medication 
Intense or generalized, poorly 
controlled despite treatment 
Disabling, irreversible 
D8. Rash (not bullous) 
Erythema, scattered 
macular/popular eruption; 
pruritis transient; TOC or 
no meds 
Diffuse macular/popular 
eruption or erythema with 
pruritis; dry desquamation; 
treatment required 
Generalized, moist 
desquamation, requires 
systematic corticosteroids; 
responsive to treatment; 
reversible 
Exfoliative or ulcerating; 
or requires 
hospitalization; or 
parenteral corticosteroids 
D9. Indurartion/fibrosis/ 
thickening (not 
sclerodermal) 
Localized, high density on 
palpation, reversible, no 
effect on ADL and not 
disfiguring 
Local areas <50% body 
surface, not disfiguring, 
transient interference with 
ADL, reversible 
Generalized, disfiguring, 
interferes with ADL, 
reversible 
Disabling, irreversible, 
systemic symptoms 
E. Ear/Nose/Throat 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
E1. Hearing loss 
Transient, intermittent, no 
interference with function 
Symptomatic, treatment 
required, reversible 
Interferes with function, 
incomplete response to 
treatment 
Irreversible deafness 
E2. Sense of smell 
Slightly altered 
Markedly altered 
Complete loss, reversible 
Complete loss, without 
recovery 
E3. Stomatitis 
Asymptomatic 
Painful, multiple, can eat 
Interferes with nutrition. 
Slowly reversible 
Requires enteral support; 
residual dysfunction 
E4. Taste disturbance 
(dysgeusia) 
Transiently altered; metallic Persistently altered, limited 
effect on eating 
Disabling, effect on nutrition N/A 
E5. Tinnitus 
Intermittent, transient, no 
interference with function 
Requires treatment, 
reversible 
Disabling, or associated with 
hearing loss 
Irreversible deafness 
E6. Voice changes 
(includes hoarseness, 
loss of voice, 
laryngitis) 
Intermittent hoarseness, 
able to vocalize 
Persistent hoarseness, able 
to vocalize 
Whispered speech, slow 
return of ability to vocalize 
Unable to vocalize for 
extended period 
E7. Xerostomia (dry mouth) Transient dryness 
Relief with meds 
Interferes with nutrition, 
slowly reversible 
Extended duration 
interference with 
nutrition, requires 
parenteral nutrition 
 
 


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F. Eye/Ophthalmologic 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
F1. Cataract 
Asymptomatic, no change 
in vision, non-progressive 
Symptomatic, partial visual 
loss, progressive 
Symptoms impairing 
function, vision loss requiring 
treatment, including surgery 
N/A 
F2. Conjunctivitis 
Asymptomatic, transient, 
rapid response to treatment 
Symptomatic, responds to 
treatment, changes not 
interfering with function 
Symptoms prolonged, partial 
response to treatment, 
interferes with function 
N/A 
F3. Lacrimation increased 
(tearing, watery eyes) 
Symptoms not requiring 
treatment, transient 
Symptomatic, treatment 
required, reversible 
Unresponsive to treatment 
with major effect on function 
N/A 
F4. Retinopathy 
Asymptomatic, non-
progressive, no treatment  
Reversible change in 
vision; readily responsive to 
treatment 
Disabling change in vision 
ophthalmological findings 
reversible, sight improves 
over time 
Loss of sight 
F5. Vision changes (e.g. 
blurred, photophobia, 
night blindness, 
vitreous floaters) 
Asymptomatic, transient, no 
treatment required 
Symptomatic, vision 
changes not interfering with 
function, reversible 
Symptomatic, vision changes 
interfering with function 
Loss of sight 
F6. Xerophtalmia (dry eyes) Mild scratchiness 
Symptomatic without 
interfering with function, 
requires artificial tears 
Interferes with 
vision/function, corneal 
ulceration 
Loss of sight 
G. Gastrointestinal 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
G1. Anorexia 
Adequate food intake, 
minimal weight loss 
Symptoms requiring oral 
nutritional supplementation 
Prolonged, requiring IV 
support 
Requires hospitalization 
for nutritional support 
G2. Constipation 
Asymptomatic, transient, 
responds to stool softener, 
OTC laxatives 
Symptomatic, requiring 
prescription laxatives, 
reversible 
Obstipation requiring medical 
intervention 
Bowel obstruction, 
surgery required. 
G3. Diarrhea 
Transient, increase of 2-3 
stools/day over pre-
treatment (no blood or 
mucus), OTC agents relieve 
Symptomatic, increase 4-6 
stools/day, nocturnal stools, 
cramping, requires 
treatment with prescription 
meds. 
Increase >6 stools/day, 
associated with disabling 
symptoms, e.g. incontinence, 
severe cramping, partial 
response to treatment. 
Prolonged, dehydration, 
unresponsive to 
treatment, requires 
hospitalization. 
G4. Dyspepsia (heartburn) 
Transient, intermittent, 
responds to OTC antacids, 
H-2 blockers 
Prolonged, recurrent, 
requires prescription meds. 
relieved by meds 
Persistent despite treatment, 
interferes with function, 
associated with GI bleeding 
N/A 
G5. GI bleed (gastritis, 
gastric or duodenal 
ulcer diagnosed-
defined etiology) 
Asymptomatic, endoscopic 
finding, hemocult + stools, 
no transfusion, responds 
rapidly to treatment 
Symptomatic, transfusion 
≤2 units needed; responds 
to treatment 
Hematemesis, transfusion 3-4 
units, prolonged interference 
with function 
Recurrent, transfusion > 4 
units, perforation, 
requiring surgery, 
hospitalization 
G6. Hematochezia (rectal 
bleeding) 
Hemorrhodial, 
asymptomatic, no 
transfusion 
Symptomatic, transfusion ≤ 
2 units, reversible 
Recurrent, transfusion  >3-4 
units 
> 4 units, hypotension, 
requiring hospitalization 
G7. Hepatitis 
Laboratory abnormalities, 
asymptomatic, reversible 
Symptomatic laboratory 
abnormalities, not 
interfering with function, 
slowly reversible 
Laboratory abnormalities 
persistent > 2 wks, symptoms 
interfere with function 
Progressive, hepato-renal, 
anasarca, pre-coma or 
coma 
G8. Nausea or 
nausea/vomiting (use 
diagnostic term) 
Transient, intermittent, 
minimal interference with 
intake, rapid response to 
meds. 
Persistent, recurrent, 
requires prescription meds, 
intake maintained 
Prolonged, interferes with 
daily function and nutritional 
intake, periodic IV fluids 
Hypotensive, 
hospitalization, parenteral 
nutrition, unresponsive to 
out-patient management 
G9. Pancreatitis 
Amylase elevation, 
intermittent 
nausea/vomiting, transient, 
responds rapidly to 
treatment 
Amylase elevation with 
abdominal pain, nausea, 
occasional vomiting, 
responsive to treatment 
Severe, persistent abdominal 
pain with pancreatic enzyme 
elevation, incomplete or slow 
response to treatment 
Complicated by shock, 
haemorrhage (acute 
circulatory failure) 
G10. Procitis 
Perianal pruritus, 
haemorrhoids (new onset), 
transient, or intermittent, 
relieved by OTC meds 
Tenesmus or ulcerations, 
anal fissure, responsive to 
treatment, minimal 
interference with function 
Unresponsive to treatment, 
marked interference with 
function 
Mucosal necrosis with 
haemorrhage, infection, 
surgery required 
 
 


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H. Musculoskeletal 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
H1. Avascular necrosis 
Asymptomatic MRI 
changes, non-progressive 
MRI changes and 
symptoms responsive to 
rest and analgesia 
MRI changes, symptoms 
requiring surgical 
intervention 
Wheelchair bound; 
surgical repair not 
possible 
H2. Arthralgia 
Intermittent transient 
symptoms, no meds or 
relieved by OTC meds 
Persistent or recurrent 
symptoms, resolve with 
meds, little effect on 
function 
Severe symptoms despite 
meds, impairs function 
Debilitating, 
hospitalization required 
for treatment 
H3. Leg cramps 
Transient, intermittent, does 
not interfere with function 
Recurrent symptoms, 
minimally interferes with 
function or sleep, responds 
to meds 
Persistent, prolonged 
interference with function or 
sleep, partial or no response 
to meds 
N/A 
H4. Myalgia 
Occasional; does not 
interfere with function 
Frequent, requires meds 
(non-narcotic); minor 
effects on function 
Major change in 
function/lifestyle, narcotic 
pain meds 
Debilitating, profound 
weakness, requires 
wheelchair, unresponsive 
to meds 
I. Neuropsychiatric  
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
I1. Anxiety or Depression 
(mood alteration) 
Symptomatic, does not 
interfere with function; no 
meds 
Frequent symptoms, 
responds to meds; interferes 
with ADL at times 
Persistent, prolonged 
symptoms, partial or no 
response to meds, limits daily 
function 
Suicidal ideation or 
danger to self 
I2. Cerebrovascular 
ischaemia 
N/A 
Single transient ischemic 
event, responsive to 
treatment 
Recurrent transient ischemic 
events 
Cerebrovascular accident 
with permanent disability 
I3. Cognitive disturbance 
Subjective symptoms, 
transient, intermittent, not 
interfering with function 
Objective symptoms, 
persisting, interferes with 
daily function occasionally 
Persistent or worsening 
objective symptoms; 
interferes with routine daily 
Debilitating/disabling and 
permanent; toxic 
psychosis 
I4. Depressed 
consciousness 
(somnolence) 
Observed, transient, 
intermittent, not interfering 
with function 
Somnolence or sedation, 
interfering with function 
Persistent, progressive, 
obtundation, stupor 
Coma 
I5. Inability to concentrate 
Subjective symptoms, does 
not interfere with function 
Objective findings, 
interferes with function 
Persistent, prolonged 
objective findings or organic 
cause 
N/A 
I6. Insomnia (in absence of 
pain) 
Occasional difficulty 
sleeping, transient 
intermittent, not interfering 
with function 
Recurrent difficulty 
sleeping; requires meds for 
relief; occasional 
interference with function 
Persistent or worsening 
difficulty sleeping; severely 
interferes with routine daily 
function 
N/A 
I7. Libido decreased 
Decrease in interest 
Loss of interest; influences 
relationship 
Persistent, prolonged 
interfering with relationship 
N/A 
I8. Peripheral motor 
neuropathy 
Subjective or transient loss 
of deep tendon reflexes; 
function maintained 
Objective weakness, 
persistent, no significant 
impairment of daily 
function 
Objective weakness with 
substantial impairment of 
function 
Paralysis 
I9. Peripheral sensory 
neuropathy (sensory 
disturbance) 
Subjective symptoms 
without objective findings, 
transient, not interfering 
with function 
Objective sensory loss, 
persistent, not interfering 
with function 
Prolonged sensory loss or 
paraesthesias interfering with 
function 
N/A 
I10. Seizure 
N/A 
Recurrence of old seizures, 
controlled with adjustment 
of medication 
Recurrence/exacerbation with 
partial response to medication 
Recurrence not 
controlled, requiring 
hospitalization; new 
seizures 
I11. Vertigo (dizziness) 
Subjective symptoms, 
transient, intermittent, no 
treatment 
Objective findings, 
recurrent, meds relieve, 
occasionally interfering 
with function 
Persistent, prolonged, 
interfering with daily 
function; partial response to 
medication 
Debilitating without 
response to medication, 
hospitalization 
 
 


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J. Pulmonary 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
J1. Asthma 
Occasional wheeze, no 
interference with activities 
Wheezing, requires oral 
meds, occasional 
interference with function 
Debilitating requires nasal O2  Requires ventilator 
assistance 
J2. Cough 
Transient, intermittent, 
occasional OTC meds 
relieve 
Persistent, requires narcotic 
or other prescription meds 
for relief 
Recurrent, persistent 
coughing spasms without 
consistent relief by meds, 
interferes with function 
Interferes with 
oxygenation; debilitating 
J3. Dyspnea 
Subjective, transient, no 
interference with function 
Symptomatic, intermittent 
or recurring, interferes with 
exertional activities 
Symptomatic during daily 
routine activities, interferes 
with function, treatment with 
intermittent nasal O2 relieves 
Symptomatic at rest, 
debilitating, requires 
constant nasal O2 
J4. Pleuritic pain (pleurisy) Transient, intermittent 
symptoms, no treatment or 
OTC meds relieve 
Persistent symptoms, 
requires prescription meds 
for relief 
Prolonged symptoms, 
interferes with function, 
requires frequent narcotic 
pain relief 
Debilitating, requiring 
hospitalization 
J5. Pneumonitis (pulmonary 
infiltrates) 
Asymptomatic radiographic 
changes, transient, no 
treatment required 
Symptomatic, persistent, 
requiring corticosteroids 
Symptomatic, requiring 
treatment including O2 
Debilitating, not 
reversible; or requiring 
assisted ventilation 
J6. Pulmonary function 
decreased (FVC or 
carbon monoxide 
diffusion capacity-
DLCO) 
76 - 90 % of pre-treatment 
value 
51-75 % of pre-treatment 
value 
26-50 % of pre-treatment 
value 
<25 % of pre-treatment 
value 
19.1.2. 
Laboratory Data 
K. Hematology 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
K1. Hgb (g/dL) decrease 
from pre-treatment 
1.0-1.4 
1.5-2.0 
2.1-2.9, or Hgb <8.0, >7.0 
>3.0; or Hgb <7.0 
K2. Leukopenia (total 
WCB) X 1000 
3.0-3.9 
2.0-2.9 
1.0-1.9 
<1.0 
K3. Neutopenia (X 1000) 
1.5-1.9 
1.0-1.4 
0.5-0.9 
<0.5 
K4. Lymphopenia (X 1000) 1.5-1.9 
1.0-1.4 
0.5-0.9 
<0.5 
K5. Platelets (X 1000) 
75-LLN 
50-74.9 
20-49.9; platelet transfusion 
required 
<20; recurrent platelet 
transfusions 
 
 


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L. Chemistry 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
L1. Hypercalcaemia 
(mg/dL) 
1.1 x ULN-11.5 
11.6-12.5 
12.6-13.5; or symptoms 
present 
>13.5; or associated coma 
L2. Hyperglycemia 
(mg/dL) (fasting) 
140-160 
161-250 
251-500 
>500, or associated with 
ketoacidosis 
L3. Hyperkalaemia (mg/dL) 5.50-5.9 
6.0-6.4 
6.5-7.0 or any ECG change 
>7.0 or any arrhythmia 
L4.  
- 
-- 
-- 
-- 
L5. Hypocalcaemia 
(mg/dL) 
0.9 X LLN-7.8 
7.7-7.0 
6.9-6.5; or associated with 
symptoms 
6.5 or occurrence of  
tetany 
L6. Hypoglycemia (mg/dL) 55-64 (no symptoms) 
40-54 (or symptoms 
present) 
30-39 (symptoms impair 
function) 
<30 or coma 
L7. Hyponatraemia 
(mg/dL) 
N/A 
125-129 
120-124 
<120 
L8. Hypokalaemia (mg/dL) N/A 
3.0-3.4 
2.5-2.9 
<2.5 
L9. CPK (also if 
polymyosis) 
1.2-1.9 X ULN 
2.0-4.0 X ULN 
4.0 X ULN with weakness 
but without life-threatening 
signs or symptoms 
>4.0 X ULN with signs or 
symptoms of 
rhabdomyolsis or life-
threatening 
L10. Serum uric acid 
1.2-1.6 X ULN 
1.7-2.9 X ULN 
3.0-5.0 X ULN or gout 
N/A 
L11. Creatinine (mg/dL) 
1.1-1.3 X ULN 
1.3-1.8 X ULN 
1.9-3.0 X ULN 
>3.0 X ULN 
L12. SGOT (AST) 
1.2-1.5 X ULN 
1.6-3.0 X ULN 
3.1-8.0 X ULN 
>8.0 X ULN 
L13. SGPT (ALT) 
1.2-1.5 X ULN 
1.6-3.0 X ULN 
3.0-8.0 X ULN 
>8.0 X ULN 
L14. Alkaline phosphatase 1.1-2.0 X ULN 
1.6-3.0 X ULN 
3.0-5.0 X ULN 
>5.0 X ULN 
L15. Total bilirubin 
1.1-1.4 X ULN 
1.5-1.9 X ULN 
2.0-3.0 X ULN 
>3.0 X ULN 
L16. LDH 
1.3-2.4 X ULN 
2.5-5.0 X ULN 
5.1-10 X ULN 
>10 X ULN 
M. Urinalysis 
 
1 (Mild) 
2 (Moderate) 
3 (Severe) 
4 (Life-Threatening) 
M1. Hematuria 
Micro only 
Gross, no clots 
Clots, transfusion <2 units 
Transfusion required 
M2. Proteinuria (per 24 h) 
300–500 mg (tr/1+) 
501–1999 mg (2+) 
2-5.0 g (3+) nephrotic 
syndrome 
5.0 g (4+) anasarca 
M3. WBC in urine 
N/A 
N/A 
Indicating acute interstitial 
nephritis 
Associated with acute 
renal failure 
M4. Uric acid crystals 
Present without symptoms 
N/A 
With stones or symptoms of 
stones (e.g. renal colic) 
Causing renal outflow 
obstruction and 
hospitalization 
OTC: over-the-counter medication; ADL: activities of daily living; IV: intravenous; ECG: electrocardiogram; CHF: 
congestive heart failure; MRI: magnetic resonance imaging; Hb: hemoglobin; LLN: upper limit of normal; ULN: 
upper limit of normal; WBC: white blood cells; SLE: systemic lupus erythematosus; ANA: antinuclear 
antibodies;H-2: histamine-2 blockers; FVC: forced vital capacity 
 


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19.2. 
NIAID/FAAN Clinical Criteria for Anaphylaxis 
From the Second Symposium on the Definition and Management of Anaphylaxis (Sampson, 
2006). 
Anaphylaxis is highly likely when any one of the following 3 criteria are present 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)  
AND AT LEAST ONE OF THE FOLLOWING 
a. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
b. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence) 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia) 
c. Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d. Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
a. Infants and children: low systolic blood pressure (age specific) or greater than 30% 
decrease in systolic blood pressure 
b. Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease 
from that person’s baseline 
*Note:  Item 1 will generally apply to subjects in this study since SEL-037 will not be a known 
or a likely antigen for these subjects. 


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19.3. 
Reconstitution and Dilution for Infusion Instructions 
19.3.1. 
SEL-037 Instructions 
Follow instructions below: 
1. Convert weight of subject to kg, as needed (weight in pounds divided by 2.2046). 
2. Calculate the mL of reconstituted SEL-037 required for a subject 
Volume (ml) reconstituted SEL-037 required for each infusion = 
 
(dose in mg/kg) x (subject weight in kg) / (concentration of SEL-037 per ml in vial i.e., 6 mg/mL) 
3. Since each vial, once reconstituted, will yield about 1 mL of product that can be 
withdrawn from the vial, the number of vials required for a subject equals the number of 
ml of reconstituted SEL-037 needed for the infusion rounded up to the next whole 
number. 
4. Reconstitute the required number of vials each with 1.1 mL of room temperature sterile 
water for injection, USP.  Invert (don’t shake) each vial several times to ensure product 
is reconstituted.  Do not use any vials with visible clumping.  Reconstituted SEL-037 
should be diluted as in Step 5 as soon as possible but reconstituted SEL-037 is stable at 
room temperature and normal light conditions for 8 hours.   
5. Dilute required volume of reconstituted SEL-037 by adding it to 100 mL of 0.9% saline 
for injection, USP.   
6. Infuse total volume of the SEL-037-normal saline solution over 60 minutes (+/- 2 
minutes). If necessary the infusion time may be extended in order to ensure the infusion 
of the study medication in entirety.  The SEL-037-normal saline solution is stable for up 
to 6 hours at room temperature (i.e., the infusion should be completed within 6 hours of 
dilution) but it is recommended that the infusion of SEL-037 be started as soon as 
possible to account for any potential interruptions in dosing.  No infusion of the SEL-
037-normal saline solution should start if 5 hours have lapsed between diluting SEL-037 
and the start of infusion. 
7. At the conclusion of the infusion, using the port closest to the IV pump, flush the IV drip 
set using a volume of 0.9% normal saline equal to the prime volume of the tubing. 
 
Example for subject weighing 200 pounds in Cohort 2 (0.4 mg/kg group)  
Step 1:  If not already done convert 
weight to kg: 
= 200 pounds / 2.2046 = 90.7 kg 
Step 2: Calculate volume of reconstituted 
SEL-037 needed: 
= (0.4 mg/kg) x (90.7 kg) / (6 mg/mL) 


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= 36.29/6 = 6.0 mL 
Step 3: number of vials needed: 
= Round up 6.048 mL = 7 vials 
Step 4 and 5: Reconstitute 7 vials and add 6.0 mL to 100 mL of 0.9% normal saline for injection, USP. 
Step 6:  Infuse 106.0 mL over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety 
Step 7: At the conclusion of the infusion, using the port closest to the IV pump, flush the IV 
drip set using a volume of 0.9% normal saline equal to the prime volume of the tubing 
 
 
 


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19.3.2. 
SEL-110 Instructions 
 
Follow instructions below: 
1. Convert weight of subject to kg, as needed (weight in pounds divided by 2.2046). 
2. Calculate the volume (mL) of SEL-110 required for a subject, with a maximum volume of 
6.0 mL (equivalent to 12 mg of rapamycin in SEL-110) per study visit per individual in 
cohorts receiving SEL-110 doses <0.10 mg/kg. If calculated required dose volume exceeds 
6.0 mL, dose volume should be set to 6.0 mL.  In cohorts receiving SEL-110 ≥0.10 mg/kg, 
there is no maximum volume of SEL-110, however their initial rate of SEL-110 is restricted 
to 5.5 mL/hr as described in section 9.5.  If calculated required dose volume exceeds 6.0 mL, 
for cohorts receiving SEL-110 ≥0.10 mg/kg, the full calculated dose volume should be used. 
 
Volume (mL) SEL-110 required =  
(dose in mg/kg) x (subject weight in kg) / (concentration of SEL-110 per ml in vial i.e., 2 mg/mL) 
 
3. Calculate the number of vials of SEL-110 required for a subject.  Round the calculation up 
to the next whole number. 
 
Number of SEL-110 vials required = 
[Volume (mL) SEL-110 required + priming volume (mL)]/ (5 mL/vial) 
 
4. Thaw the required number of vials at room temperature for at least 2 hours.  Once the vials 
are thawed, invert slowly (don’t shake) each vial twenty times to ensure product is uniform.  
Do not use any vials with visible clumping. Thawed SEL-110 should be administered as soon 
as possible but thawed SEL-110 is stable at room temperature and normal light conditions for 
24 hours. 
5. Load a syringe with the appropriate size for the dose.  In order to prime the line between 
the syringe and the injection site valve, an additional priming volume of SEL-110 
(approximately 1.5mL), equal to the volume of the connecting line used (approximately 
0.65mL) and the prime volume of the 5 micrometer membrane filter (Pall Medical, PN 
HP1050; 0.85 mL) used, should be added to the syringe.  When loading syringes, do not 
bubble air through the product to avoid the formation of foam. 
6. Start an infusion of 125 mL of normal saline solution over 60 minutes using an IV set with 
an injection site valve.   
7. Start an infusion of SEL-110 as described below concurrently with the saline infusion of 
Step 6: 
a) For cohorts receiving SEL-110 doses <0.1 mg/kg, using the injection site valve, 
immediately after starting the normal saline IV, slowly inject the SEL-110 using a 
syringe infusion pump at a single steady rate to deliver the dose over a period of 55 
minutes. A 5 µm syringe filter (5 µm syringe filter Supor (PES) membrane, Pall Medical 
P/N HP1050) for single use must be included in the SEL-110 line downstream of the 
syringe and proximal to the injection site valve.   
b) For cohorts receiving SEL-110 doses ≥0.1 mg/kg, using the injection site valve, 
immediately after starting the normal saline IV, slowly inject the SEL-110 using a syringe 


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infusion pump at an initial infusion rate equal to 5.5 mL/hour for the first 30 minutes of 
infusion and, then, change to a steady rate sufficient to deliver the remainder of the dose 
volume for the additional 25 minutes. A 5 µm syringe filter (5 µm syringe filter Supor 
(PES) membrane, Pall Medical P/N HP1050) for single use must be included in the 
SEL-110 line downstream of the syringe and proximal to the injection site valve.   
At the end of the 55 minutes, continue the saline infusion for the additional 5 minutes after the 
SEL-110 infusion stops to flush the main line. Do not flush the line between the syringe and the 
injection site valve.   
 
Example for subject weighing 200 pounds in Cohort _5__ (0.08 mg/kg group) 
Step 1: If not already done convert weight to kg: 
= 200 pounds / 2.20462 = 90.7 kg 
Step 2: Calculate volume of SEL-110 needed, with a maximum volume of 6.0 mL 
(equivalent to 12 mg of rapamycin in SEL-110) per study visit per individual, since the example 
cohort 5 is receiving <0.1 mg/kg SEL-110.  If calculated required dose volume exceeds 6.0 mL, 
dose volume should be set to 6.0 mL: 
= (0.08 mg/kg) x (90.7 kg) / (2 mg/mL) 
= 7.26/2 = 3.6 mL SEL-110 
Step 3: Calculate number of vials needed (assumes 1.5 mL prime volume):  
= [3.6 mL SEL-110 required + 1.5mL]/ (5 mL/vial) 
= 1.02 vials.  Round up to 2 vials. 
Step 4 and 5: Thaw 2 vials and load syringe with 3.6 mL SEL-110 plus the priming volume 
(approximately 1.5 mL). 
Step 6: Start infusion of 125 mL of normal saline solution over 60 minutes. 
Step 7: Immediately after the start of the normal saline infusion, slowly inject 3.6 mL of SEL-
110 at a single steady rate over 55 minutes, using a 5 µm syringe filter proximal to the injection 
site valve. At the end of the 55 minutes, continue the saline infusion for the additional 5 minutes 
after the SEL-110 infusion stops to flush the main line.  
 
 
 
 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
114 
 
 
  
 
 
19.4. 
Laboratory Schedules by Cohort 
Table 9: 
Laboratory Schedule - Cohorts 1 & 2 (SEL-037) 
  
 
EOS / Early 
Termination
Labs
screen
predose
D7
D14
D21
D30
Safety labs
Alkaline phosphatase
x
x
x
x
ALT
x
x
x
x
APTT
x
x
x
AST
x
x
x
x
Electrolytes
x
x
x
Total Bilirubin
x
x
x
BUN
x
x
x
Calcium
x
Total Complement2
x
Creatinine
x
x
x
eGFR
x
Fibrinogen1
x
x
Glucose(fasting)
x
x
x
x
Hct
x
x
x
Hgb
x
x
x
HbA1c
x
Hep C Ab
x
HIV 1/2
x
INR
x
x
x
Phosphorous
x
CBC with platelets
x
x
x
x
WBC c diff
x
x
x
x
Lipid Panel     
total cholesterol
x
x
x
HDL
x
x
x
LDL
x
x
x
Triglycerides
x
x
x
Urinalysis
x
G6PD
x
Immunogenicity
Anti-Pegsiticase
x
x
x
x
x
Anti-Uricase
x
x
x
x
x
Anti-PEG
x
x
x
x
x
x
PK/PD
SEL-110 PK
SEL-037 PK
x2
x
x
x
x
Uricase Activity
x3
x
x
x
x
Uric Acid
x
x2
x
x
x
x
1 Collected at screening, results not required to determine eligibility
2 Additional samples collected during D0 and D1 as per Schedule of Events timing
3 Additional sample collected D1 as per Schedule of Events timing
Labs for SEL-037 Cohorts 1&2
Treatment 1-5


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
115 
 
 
  
 
 
Table 10: 
Laboratory Schedule - Cohorts 3-8, 10, 11, and 12 (SEL-212) 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering convention of 
associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
 
EOS / Early 
Termination
Labs
screen
predose D7
D14
D21
predose D7
D14
D21
D30
Safety labs
Alkaline phosphatase
x
x
x
x
x
x
ALT
x
x
x
x
x
x
APTT
x
x
x
x
AST
x
x
x
x
x
x
Electrolytes
x
x
x
x
Total Bilirubin
x
x
x
x
BUN
x
x
x
x
Calcium
x
Total Complement1
x
Creatinine
x
x
x
x
eGFR
x
Fibrinogen1
x
x
x
x
Glucose(fasting)
x
x
x
x
x
x
x
x
Hct
x
x
x
x
x
x
x
Hgb
x
x
x
x
x
x
x
HbA1c
x
Hep C Ab
x
HIV 1/2
x
INR
x
x
x
x
Phosphorous
x
x
x
x
x
x
x
x
CBC with platelets
x
x
x
x
x
x
x
x
x
x
WBC c diff
x
x
x
x
x
x
x
x
x
x
Lipid Panel     
total cholesterol
x
x
x
x
x
x
x
x
HDL
x
x
x
x
x
x
x
x
LDL
x
x
x
x
x
x
x
x
Triglycerides
x
x
x
x
x
x
x
x
Urinalysis
x
G6PD
x
Immunogenicity
Anti-Pegsiticase
x
x
x
x
x
x
x
x
x
Anti-Uricase
x
x
x
x
x
x
x
x
x
Anti-PEG
x
x
x
x
x
x
x
x
x
x
PK/PD
SEL-110 PK
x2
x
x
x
x4
x
SEL-037 PK
x2
x
x
x
x2
x
x
x
x
Uricase Activity
x3
x
x
x
x3
x
x
x
x
Uric Acid
x
x2
x
x
x
x2
x
x
x
x
Exploratory
Inflammatory markers
x5
x
T-cell recall
x5
x6
x7
x
1 Collected at screening, results not required to determine eligibility
2 Additional samples collected during D0 and D1 as per Schedule of Events timing
3 Additional sample collected D1 as per Schedule of Events timing
4 Predose sample only collected on Treatment Period 4 only
5 Predose sample only collected on Treatment Period 1 (Visit 4) only
6 Sample collected on Treatment Period 3 (Visit 18) only
7 Sample collected on Treatment Period 5 (Visit 30) only
Treatment Period 1-3
Treatment Period 4-5
Labs for SEL-212 Cohorts 3-8, 
10, 11, & 12


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
116 
 
 
  
 
 
Table 11 
Laboratory Schedule – Part C: Cohorts 13, 15, and 17 (SEL-212) 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the cohort numbering 
convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose. 
 
EOS / Early Termination
Labs
Screen
Predose
D7
D14
D21
D30
Safety labs
Alkaline phosphatase
x
x
x
x
ALT
x
x
x
x
APTT
x
x
x
AST
x
x
x
x
Electrolytes
x
x
x
Total Bilirubin
x
x
x
BUN
x
x
x
Calcium
x
Total Complement1
x
Creatinine
x
x
x
eGFR
x
Fibrinogen1
x
x
x
Glucose(fasting)
x
x
x
x
x
x
Hct
x
x
x
x
x
x
Hgb
x
x
x
x
x
x
HbA1c
x
Hep C Ab
x
HIV 1/2
x
INR
x
x
x
Phosphorous
x
x
x
x
x
x
CBC with platelets
x
x
x
x
x
x
WBC c diff
x
x
x
x
x
x
Lipid Panel     
total cholesterol
x
x
x
x
x
x
HDL
x
x
x
x
x
x
LDL
x
x
x
x
x
x
Triglycerides
x
x
x
x
x
x
Urinalysis
x
G6PD
x
Immunogenicity
Anti-Pegsiticase
x
x
x
x
x
Anti-Uricase
x
x
x
x
x
Anti-PEG
x
x
x
x
x
x
PK/PD
SEL-110 PK
x2
x
x
x
x
SEL-037 PK
x3
x
x
x
x
Uricase Activity
x2
x
x
x
x
Uric Acid7
x
x2
x
x
x
x
Exploratory
Inflammatory markers
x
x
x
T-cell recall
x5
x6
x
1 Collected at screening, results not required to determine eligibility
2 Additional samples collected during D0 and D1 as per Schedule of Events timing
3 Additional sample collected D1 as per Schedule of Events timing
4 Predose sample only collected on Treatment Period 4 only
5 Predose sample only collected on Treatment Period 1 (Visit 4) only
6 Sample collected on Treatment Period 3 (Visit 18)  and Treatment Period 5 (Visit 30) only
Labs for SEL-212
Treatment Period 1-5
7 Collect 2 blood samples at each timepoint for sUA measurement. Store and ship 1 sample at ambient temperature and 1 sample 
under frozen conditions. Refer to the Laboratory Manual for details about sample handling.


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
117 
 
 
  
 
 
Table 12.  
Laboratory Schedule for Suspected Infusion Reaction, All Cohorts 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering convention of 
associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. Cohorts 14 and 16 are intentionally omitted 
from this protocol in order to maintain the cohort numbering convention of associating odd numbered cohorts with 
the 0.2 mg/kg SEL-037 dose. 
 
19.5. 
 New York Heart Association Functional Classification 
 
Class I: 
Patients have cardiac disease but without the resulting limitations of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or 
anginal pain 
Class II: Patients have cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnoea or anginal pain 
Class III: Patients have cardiac disease resulting in marked limitation of physical activity. They 
are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, 
dyspnoea or anginal pain 
Class IV: Patients have cardiac disease resulting in inability to carry on any physical activity 
without discomfort. Symptoms of cardiac insufficiency or of the angina syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is 
increased 
 
 
Hour (h)
At 
Event
0.25h 0.5h 0.75h
1h
1.5h
2h
3h
6h
12h
24h
Safety Labs
Safety Labs - As indicated for predose  in individual schedules
X
Tryptase (total serum)
X
X
X
X
X
Histamine (plasma)
X
X
X
Anti-Pegsiticase
X
Anti-Uricase
X
Anti-PEG
X
a All times are ± 5 minutes from suspected IR
Post event (time after suspected IRa) 
Phases: Cohorts 1,2, 3-8, 10, 11, 12, 13, 15, & 17


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
118 
 
 
  
 
 
Revision History 
Version 
Reason for Change 
Date 
01 
Original protocol 
28JUL2016 
02 
Revised SEL-110 highest dose from 0.1 mg/kg to 0.08 mg/kg 
Updated Schedule of Events, Figure 1, Tables 7-9 
Updated description of potential risks of SEL-110 
05SEP2016 
03 
Revised methylprednisolone premedication dose from 16mg to 
40mg, its route of administration from oral to intravenous and 
its timing from 2 hours to 1 hour prior to study drug 
administration 
Updated Individual and cohort stopping rules 
07DEC2016 
04 
Revised fexofenadine premedication dose to 180 mg 
Revised gout flare premedication to colchicine 0.6mg QD 
Revised windows for screening and vital signs  
Updated Schedules of Events, Table 7 and dosing instructions 
Updated previous human clinical experience 
Updated Figure 1 for closure of Cohorts 1 and 2  
Updated cohort randomization and opening criteria    
Added observational visit and T-cell recall assay 
22DEC2016 
05 
Added Cohort 7 and 8 
Adding optional alternative premedication for 
methylprednisolone 
Added weight measurement at all Day 21 visits 
Clarified T-cell recall sample collection schedule and 
requirements for sampling   
Revised inflammatory marker schedule 
Updated Schedules of Events and Table 8 
Updated Figure 1 for inclusion of Cohorts 7 and 8 
Clarified windows for dosing and infusion reaction kit samples 
07FEB2017     


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
119 
 
 
  
 
 
05.1 
Increased number of subjects in Cohorts 5, 6, 7 & 8 
Clarified time windows for SEL-037 and SEL-110 dose 
administration and for suspected infusion reaction labs 
Updated Individual and cohort stopping rules 
04Apr2017  
06.0 
Added Cohorts 10 and 12 
Clarified randomization and cohort enrollment process 
Clarified infusion rates for SEL-110 doses >0.10 mg/kg 
Clarified dosing volumes 
Updated nonclinical and clinical data from completed studies 
Clarified inflammatory marker assessment time points 
12JUN2017 
06.1 
Removed Cohorts 10 and 12 
Increased number of subjects in Cohorts 6 & 8 
Updated enrollment status 
Clarified infusion rates for SEL-110 doses of 0.10 mg/kg 
Updated cohort stopping rules 
Updated nonclinical animal study information 
Updated dose selection rationale 
Clarified SEL-110 infusion preparation instructions 
28JUN2017 
06.2 
Added Cohorts 10 and 12 
Clarified infusion rates for SEL-110 doses ≥0.10 mg/kg 
Updated nonclinical and clinical data from completed studies 
09AUG2017 
06.3 
Added Cohort 11 
Updated enrollment status 
Clarified DECT scanning for Cohorts 10, 11, and 12 and for 
re-opened cohorts. Added DECT scan at Treatment Period 3 
for Cohorts 10, 11, and 12. 
20OCT2017 
07.0 
Addition of Part C (Cohorts 13 and 15) 
Updated enrollment status  
Updated dose selection rationale 
21DEC2017 


Study: SEL-212/201 
Version: 7.1 
Effective Date  
March 19, 2018 
 
 
120 
 
 
  
 
 
07.1 
Added Cohort 17 to Part C 
Clarified that for Part C, sUA used for individual stopping 
rules will be measured in blood samples stored at ambient 
temperatures similar to Parts A and B. 
Updated dose rationale 
Update Phase I study information 
19MAR2018 
 

SAP_001.pdf: 






1008142 
 
SELECTA Biosciences 
SEL – 212/201 
SAP Version: Final 2.0 
Statistical Analysis Plan 
 
This document is proprietary and confidential to Syneos Health LLC. 
03.007A.01   
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Page 4 of 76 
TABLE OF CONTENTS 
1. 
GLOSSARY OF ABBREVIATIONS ................................................................ 8 
2. 
PURPOSE ..................................................................................................... 10 
2.1. 
Responsibilities ................................................................................................................. 10 
2.2. 
Timing of Analyses ............................................................................................................ 10 
3. 
STUDY OBJECTIVES ................................................................................... 11 
3.1. 
Primary Objective .............................................................................................................. 11 
3.2. 
Secondary Objectives ....................................................................................................... 11 
3.3. 
Exploratory Objective ........................................................................................................ 11 
3.4. 
Brief Description ................................................................................................................ 11 
3.5. 
Subject Selection ............................................................................................................... 12 
3.5.1. 
Inclusion Criteria .............................................................................................................. 12 
3.5.2. 
Exclusion Criteria ............................................................................................................. 13 
3.6. 
Determination of Sample Size .......................................................................................... 15 
3.7. 
Treatment Assignment ...................................................................................................... 15 
3.8. 
Administration of Study Medication ................................................................................ 18 
3.9. 
Study Procedures and Flowchart ..................................................................................... 25 
4. 
ENDPOINTS .................................................................................................. 30 
4.1. 
Pharmacokinetic Endpoints ............................................................................................. 30 
4.2. 
Pharmacodynamic Endpoints .......................................................................................... 31 
4.3. 
Safety Endpoints ................................................................................................................ 31 
4.4. 
Immunogenicity endpoints ............................................................................................... 31 


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5. 
ANALYSIS SET ............................................................................................. 33 
5.1. 
Screened/Randomized Subjects ...................................................................................... 33 
5.2. 
Safety Analysis Set ............................................................................................................ 33 
5.3. 
Pharmacokinetic Analysis Set .......................................................................................... 33 
5.4. 
Pharmacodynamic analysis Set ....................................................................................... 33 
5.5. 
Protocol Deviations ........................................................................................................... 34 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ................................ 35 
6.1. 
General Methods ................................................................................................................ 35 
6.2. 
Key Definitions ................................................................................................................... 35 
6.3. 
Missing Data ....................................................................................................................... 35 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION ....................................................................................................... 36 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 36 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 36 
7.3. 
Medical History and Concomitant Diseases ................................................................... 36 
7.4. 
Medication .......................................................................................................................... 36 
8. 
ANALYSIS OF PHARMACOKINETICS ........................................................ 38 
8.1. 
Collection Schedule ........................................................................................................... 39 
8.2. 
Pharmacokinetic parameters ............................................................................................ 41 
8.4. 
Data Presentation for SEL-110 and SEL-037 .................................................................. 45 
8.5. 
Assessment of Dose Proportionality for SEL-110 .......................................................... 46 
8.6. 
Assessment of Dose Proportionality for SEL-037 .......................................................... 48 


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8.7. 
Aseessment of Effect of Various Doses of SEL-110 on Pharmacokinetics of SEL-037
 
48 
9. 
ANALYSIS OF PHARMACODYNAMICS ...................................................... 50 
10. 
ANALYSIS OF IMMUNOGENICITY .......................................................... 61 
11. 
SAFETY ..................................................................................................... 65 
11.1. 
Extent of Exposure ............................................................................................................ 65 
11.2. 
Treatment Compliance ...................................................................................................... 65 
11.3. 
Adverse Events .................................................................................................................. 65 
11.4. 
Laboratory Evaluations ..................................................................................................... 65 
11.5. 
Vital Signs ........................................................................................................................... 66 
11.6. 
Electrocardiogram ............................................................................................................. 66 
11.7. 
Physical Examination ........................................................................................................ 66 
12. 
INTERIM ANALYSES ................................................................................ 67 
13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ......................... 68 
14. 
REFERENCE LIST .................................................................................... 69 
15. 
PROGRAMMING CONSIDERATIONS ...................................................... 70 
15.1. 
General Considerations .................................................................................................... 70 
15.2. 
Table, Listing, and Figure Format .................................................................................... 70 
15.2.1. 
General ........................................................................................................................ 70 
15.2.2. 
Headers ....................................................................................................................... 71 
15.2.3. 
Display Titles ............................................................................................................... 71 
15.2.4. 
Column Headers ......................................................................................................... 71 
15.2.5. 
Body of the Data Display ............................................................................................. 72 
15.2.6. 
Footnotes .................................................................................................................... 75 


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16. 
QUALITY CONTROL ................................................................................. 76 
 
 


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1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
ADA 
Anti-drug antibody 
AE 
Adverse event 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUCinf 
Serum concentration-time curve from time 0 to infinity 
AUClast 
Serum concentration-time curve from time 0 to the time of 
last quantifiable concentration 
CBC 
Complete blood count 
CL 
Serum clearance of drug 
Cmax 
Maximum observed serum concentration 
CRF 
Case report form 
CRO 
Contract research organization 
D 
Day, Study day 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
FAAN 
Food Allergy & Anaphylaxis Network 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
H 
Hour 
HED 
Human equivalent dose 
HIV  
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
Kel 
Terminal elimination rate constant 
kg 
Kilograms 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
ml 
Milliliters 
MTD 
Maximum tolerated dose 
NIAID 
National Institute of Allergy and Infectious Diseases 
PD 
Pharmacodynamic 
PEG 
Polyethylene glycol 


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Abbreviation 
Description 
PK 
Pharmacokinetic 
PTT 
Partial thromboplastin time 
SAE  
Serious adverse event 
SAP 
Statistical Analysis Plan 
SEM 
Standard error of the mean 
t1/2 
Terminal half-life 
TEAE 
Treatment-emergent adverse events 
Tmax 
Time at which Cmax occurred 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia  
V 
Visit 
Vss 
Apparent volume of distribution at equilibrium 
Vd 
terminal volume of distribution  
Cmax/Cmin 
Maximum/minimal observed serum concentration 
Tmax/Tmin 
Time of maximum/minimal observed serum concentration 
CFBmax, CFBmin 
Maximum/minimum observed change from baseline in serum 
concentration 
TCFBmax, TCFBmin 
Time of maximum/minimal observed change from baseline in 
serum concentration 
AUECFBlast 
Area under the change from baseline in effect-time curve 
from time zero to the time of the last quantifiable 
concentration (effect – uric concentration) 
TA_AUECFBlast 
Time adjusted area under the effect-time curve from time 
zero to the time of last quantifiable concentration (effect – 
uric concentration) 
Tonset 
Time of onset of effect – time of reduction uric acid 
concentration >10% of baseline 
Tresolve 
Time of resolution of effect – time of return of uric acid 
concentration to baseline defined as <10% difference from 
pre-dose baseline 
Tduration 
Time of duration of effect, calculated as Tresolution - Tonset 
 


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2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.  
2.1. 
RESPONSIBILITIES 
Syneos Health will perform the statistical analyses and are responsible for the 
production and quality control of all tables, figures and listings. 
2.2. 
TIMING OF ANALYSES 
The analyses of safety, efficacy and pharmacokinetics (PK) is planned after all subjects 
complete the final study visit or terminate early from the study. 
 
 
 


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3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
To assess the safety and tolerability of multiple intravenous (IV) infusions of SEL-212.  
3.2. 
SECONDARY OBJECTIVES 
To assess the PK, pharmacodynamics (PD) (ability to reduce circulating uric acid) and 
immunogenicity (anti-uricase, anti-PEG and anti-pegsiticase antibodies) of SEL-037 after 
multiple IV infusions of SEL-037 with or without multiple doses of SEL-110. 
To assess the PK of rapamycin after multiple IV infusions of SEL-110 with multiple IV 
infusions of SEL-037. 
3.3. 
EXPLORATORY OBJECTIVE 
To assess the effect on uric acid deposits and/or total body uric acid deposited of 
multiple doses of SEL-037 alone or multiple doses of SEL-212 plus additional doses of 
SEL-037, as measured by Dual Energy Computed Tomography scan. 
3.4. 
BRIEF DESCRIPTION 
This is a Phase 2 (Part A) open-label multiple-dose clinical study of a combination drug 
(SEL-212) combined with an open-label multiple-dose clinical study of one drug 
(SEL-037) followed by (Part B) an open-label study of a single drug (SEL-037) to assess 
the safety, tolerability, PK, and PD of SEL-212 (the combination of SEL-110 [Rapamycin] 
and SEL-037 [pegsiticase]). Part C will involve patients naïve to SEL-212 who are treated 
with multiple doses of the combination drug (SEL-212).  
The safety, tolerability, PK and PD of multiple doses of SEL-037 will be assessed. 
Additionally, the ability of SEL-212 to reduce serum uric acid and prevent anti-drug 
antibodies to uricase and pegsiticase will be assessed. 
All enrolled subjects will be randomized initially to Cohorts 1, 2, 3, and 4 such that 
once 12 subjects total is reached for all 4 cohorts; each cohort will contain 3 subjects. 
The experience of these 12 subjects will guide the further conduct of the study. 
Adverse events, safety labs and the rate of infusion reactions in individual cohorts will 
dictate the continuance of a specific cohort. After the completion of at least one cycle, 
the subject experience will be evaluated before enrollment is opened to all cohorts. 
The future enrollment will be randomized between all open cohorts. At this time 


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Cohorts 1-10 are closed to enrollment. Randomization into the remaining open cohorts 
will continue until the cohorts are closed due to enrollment reaching 6-20 subjects per 
cohort or due to the stopping rules for individual cohorts. Cohorts that have closed due 
to enrollment levels may be re-opened to increase the enrollment to the maximum total 
number of subjects permitted. 
3.5. 
SUBJECT SELECTION 
3.5.1. 
Inclusion Criteria 
1. Has provided written informed consent prior to the conduct of any study specific 
procedures and continues to provide consent; 
2. Understands and is willing and able to comply with study requirements, including 
the schedule of follow-up visits, and has demonstrated compliance with study 
requirements during Screening; 
3. At the Screening Visit male age 21 - 75, inclusive or female age 21-75 of non-
child bearing potential; 
4. Has at the Screening Visit a serum uric acid ≥ 6 mg/dL, with established or 
symptomatic gout which is defined as having at least ONE of any of the 3 
following factors: 
a. ≥ 1 tophus 
b. 1 gout flare within the last 6 months 
c. Chronic gouty arthropathy 
5. The use of allopurinol, febuxostat (Uloric®), or probenecid as uric acid-lowering 
therapy is permissible if dosing has been stable for at least the month prior to 
the Screening Visit and remains stable during the Screening Phase (i.e., no 
initiation, change in dose or discontinuation 1 month prior to screening and 
during screening). 
6. Is negative for anti-PEG antibodies at the Screening Visit; 
7. Has not participated in a clinical trial within 30 days of the Screening Visit and 
agrees to not participate in a clinical trial for the duration of the study; 


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8. Negative serology for HIV-1/-2 and negative antibodies to hepatitis C; 
9. Has adequate venous access and able to receive IV therapy; 
10. If applicable, has fully recovered from any prior surgery; 
11. Is not presently receiving any vaccination scheme or have received a live virus 
vaccine in the previous 6 months. 
3.5.2. 
Exclusion Criteria 
1. History of anaphylaxis or severe allergic reactions; 
2. History of any allergy to pegylated products, including peginterferon alfa-2a 
(Pegasys®), peginterferon alfa-2b (PegIntron®), pegfilgrastim (Neulasta®), 
pegaptanib (Macugen®), pegaspargase (Oncaspar®), pegademase (Adagen®), peg-
epoetin beta (Mircera®), pegvisomant (Somavert®) certolizumab pegol 
(Cimzia®), 
naloxegol 
(Movantik®), 
peginesatide 
(Omontys®), 
pegaptanib 
(Macugen®) and doxorubicin liposome (Doxil®); 
3. Medications which are known CYP3A4 inhibitors or inducers MAY be 
exclusionary. Patients taking medications that are known CYP3A4 inhibitors or 
inducers including natural products such as St. John’s Wort or grapefruit juice 
may be included ONLY if they discontinue the medication 14 days before dosing 
and are able to remain off the medication for the duration of the study. 
4. Drugs known to interact with Rapamune such as cyclosporine, diltiazem, 
erythromycin, ketoconazole (and other antifungals), nicardipine (and other 
calcium channel blockers), rifampin, verapamil unless they are stopped 2 weeks 
prior to starting the trial and will not be used during the trial. 
5. Women of child bearing potential, Defined as:  
 
<6 weeks after surgical bilateral salpingooperhectony with or without 
hysterectomy 
 
Pre or perimenopausal (< less than 24 months of natural amenorrhea) 
6. Initiation or change in dose of hormone-replacement therapy for menopausal 
women less than 1 month prior to the Screening Visit or during the Screening 
Phase would be exclusionary. If after being on a stable dose of hormone-


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replacement therapy for one month the patient may be considered for the 
study if she continues to meet all other inclusion and exclusion criteria 
7. Uncontrolled diabetes with baseline HbA1c ≥8%; 
8. Fasting screening glucose greater than 240 mg/dL 
9. Fasting triglyceride greater than 300 mg/dl; 
10. Fasting LDL cholesterol greater than 200 mg/dl; 
11. Glucose-6-phosphate dehydrogenase deficiency;  
12. Uncontrolled hypertension: Blood pressure >170/100 at screening and 1 week 
prior to dosing 
13. Individual laboratory values which may be exclusionary 
 
White blood cell count less than 3.5 x109 /L 
 
Serum aspartate aminotransferase (AST) or alanine amino transferase 
greater than 3x upper limit of normal (ULN) in the absence of known 
active liver disease 
 
Glomerular filtration rate less than 40 ml/min/1.73 m2 
 
Hemoglobin less than 9 gm/dL 
 
Serum phosphate less than 2.0 mg/dL 
14. Ongoing treatment for arrhythmia, including placement of an implantable 
defibrillator; 
15. History of coronary artery disease, including myocardial infarction; 
16. Congestive heart failure, New York Heart Association Class III or IV; 
17. ECG with evidence of prior myocardial infarction, clinically significant 
arrhythmia, or other abnormalities that, in the opinion of the investigator, are 
consistent with significant underlying cardiac disease; 


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18. History of hematological or autoimmune disorders, is immunosuppressed or 
immunocompromised;  
19. Subject is currently taking dabigatran (Pradaxa®), rivaroxaban (Xarelto®), 
edoxaban (Savaysa®), warfarin (Coumadin®) and apixaban (Eliquis®). 
20. Prior exposure to any experimental or marketed uricase (e.g., rasburicase 
(Elitek, Fasturtec), pegloticase (Krystexxa®), pegsiticase (SEL-037) 
21. History of malignancy within the last 5 years other than basal skin cancer; 
22.  Subjects who, in the opinion of the investigator, present with a condition that 
would compromise their safety or that would make study completion unlikely. 
3.6. 
DETERMINATION OF SAMPLE SIZE 
The sample size is designed to have a sufficient number of subjects per cohort to meet 
the objectives of the study, which are to evaluate the safety, tolerability, PK, and PD of 
a multiple IV infusions of SEL-212 and the safety, tolerability, PK, and PD of SEL-037 
after multiple infusions. 
3.7. 
TREATMENT ASSIGNMENT 
Treatment and events are by the cohort to which each subject is assigned as following:  
 


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Overall scheme of trial (Part A and Part B) 
Note: Cohort 9 is intentionally omitted from this protocol in order to maintain the cohort numbering 
convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
 
 
 
 
 
 
 
 
SEL-037 (0.2 mg/kg)
Cohort 1 Part A
SEL-037 (0.4 mg/kg)
Cohort 2 Part A
SEL-212 (0.05 + 0.2 mg/kg)
Cohort 3 Part A
SEL-212 (0.05 + 0.4 mg/kg)
Cohort 4 Part A
SEL-037 (0.2 mg/kg)
Cohort 1 Part B
SEL-037 (0.4 mg/kg)
Cohort 2 Part B
SEL-037 (0.2 mg/kg)
Cohort 3 Part B
SEL-037 (0.4 mg/kg)
Cohort 4 Part B
SEL-212 (0.08 + 0.2 mg/kg)
Cohort 5 Part A
SEL-212 (0.08 + 0.4 mg/kg)
Cohort 6 Part A
SEL-037 (0.2 mg/kg)
Cohort 5 Part B
SEL-037 (0.4 mg/kg)
Cohort 6 Part B
SEL-212 (0.1 + 0.2 mg/kg)
Cohort 7 Part A
SEL-212 (0.1 + 0.4 mg/kg)
Cohort 8 Part A
SEL-037 (0.2 mg/kg)
Cohort 7 Part B
SEL-037 (0.4 mg/kg)
Cohort 8 Part B
SEL-212 (0.125 + 0.4 mg/kg)
Cohort 10 Part A
SEL-037 (0.4 mg/kg)
Cohort 10 Part B
SEL-212 (0.15 + 0.4 mg/kg)
Cohort 12 Part A
SEL-037 (0.4 mg/kg)
Cohort 12 Part B
Cohort
SEL-110
SEL-037
1 (Closed)
NA
0.2 mg/kg
2 (Closed)
NA
0.4 mg/kg
3 (Closed)
0.05 mg/kg
0.2 mg/kg
4 (Closed)
0.05 mg/kg
0.4 mg/kg
5 (Closed)
0.08 mg/kg
0.2 mg/kg
6 (Closed)
0.08 mg/kg
0.4 mg/kg
7 (Closed)
0.1 mg/kg
0.2 mg/kg
8 (Closed)
0.1 mg/kg
0.4 mg/kg
10 (Closed)
0.125 mg/kg
0.4 mg/kg
11
0.15 mg/kg
0.2 mg/kg
12
0.15 mg/kg
0.4 mg/kg
SEL-212 (0.15 + 0.2 mg/kg)
Cohort 11 Part A
SEL-037 (0.2 mg/kg)
Cohort 11 Part B


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Overall scheme of trial (Part C) 
 
Note: Cohorts 14 and 16 are intentionally omitted from this protocol in order to maintain the cohort 
numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose. 
 
In Part A and Part B, approximately 100 subjects will be divided into 11 dosing cohorts, 
each consisting of 6-20 subjects. Cohort 1 will receive SEL-037 (pegsiticase alone, 0.2 
mg/kg). Cohort 2 will receive SEL-037 (pegsiticase alone, 0.4 mg/kg), Cohort 3 will 
receive SEL-212 (with 0.05 mg/kg of SEL-110 + 0.2 mg/kg pegsiticase), Cohort 4 will 
receive SEL-212 (with 0.05 mg/kg of SEL-110 + 0.4 mg/kg pegsiticase), Cohort 5 will 
receive SEL-212 (with 0.08 mg/kg of SEL-110 + 0.2 mg/kg pegsiticase), Cohort 6 will 
receive SEL-212 (with 0.08 mg/kg of SEL-110 + 0.4 mg/kg pegsiticase), Cohort 7 will 
receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.2 mg/kg pegsiticase) and Cohort 8 will 
receive SEL-212 (with 0.1 mg/kg of SEL-110 + 0.4 mg/kg pegsiticase), Cohort 10 will 
receive SEL-212 (with 0.125 mg/kg of SEL-110 + 0.4 mg/kg pegsiticase), Cohort 11 will 
receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.2 mg/kg pegsiticase), and Cohort 12 
will receive SEL-212 (with 0.15 mg/kg of SEL-110 + 0.4 mg/kg pegsiticase). Note that 
Cohorts 9 is intentionally omitted in order to maintain the cohort numbering convention 
of associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose. 
In Part C, up to 40 patients naïve to SEL-212 will be enrolled. Patients enrolled in 
Cohort 13 will receive SEL-212 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037). Patients 
enrolled in Cohort 15 will receive an initial induction dose of SEL-212 (0.15 mg/kg SEL-
110 + 0.2 mg/kg SEL-037) and, then, four subsequent doses of SEL-212 (0.10 mg/kg SEL-
110 + 0.2 mg/kg SEL-037). Patients enrolled in Cohort 17 will receive SEL-212 (0.10 
mg/kg SEL-110 + 0.2 mg/kg SEL-037). (Note: Cohort 14 and 16 are intentionally omitted 
in order to maintain the cohort numbering convention of associating odd numbered 
cohorts with the 0.2 mg/kg SEL-037 dose.) Subjects who withdraw early, or have 
significant protocol violations or compliance issues may be replaced at the discretion of 
the Sponsor to assure completion of the objectives of the clinical study and to maintain 
the integrity of the data set.  


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3.8. 
ADMINISTRATION OF STUDY MEDICATION  
Duration of Treatment for Cohort 1 (0.2 mg/kg SEL-037 alone) and Cohort 2 (0.4 
mg/kg SEL-037 alone) – BOTH COHORTS 1 and 2 CLOSED. 
Part A - Treatment Period 1  
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when 
to start their premedication (date and medication, Day -7) for the prevention of gout 
flares. On the evening of Day -1 the subject will self-administer fexofenadine 180 mg as 
oral premedication. The day of initial dosing of study drug will be designated Day 0. In 
the morning (Day 0) subjects will report to the clinic for dosing of study drug. Two hours 
prior to the dosing of study drug SEL-037, subjects will receive fexofenadine 180 mg 
orally and 1 hour prior to the dosing of study drug SEL-037, subjects will receive 
methylprednisolone 40 (or equivalent drug) mg intravenously. Eligible subjects who 
have been assigned to Cohort 1 or 2 will receive a single IV infusion of normal saline (20 
mL) with a syringe infusion pump over a period of 55 minutes starting concurrently with 
a 60 minute infusion of 125 mL of normal saline. This will be followed (± 1 minute) by 
an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg 
for Cohort 2) diluted into 100 mL of normal saline delivered over 60 minutes. Subjects 
will remain in the clinic for 9 hours after the start of the saline infusion for safety 
evaluations and PK blood draws (see Schedule of Events below). Subjects will return to 
the clinic for PK and PD blood draws on Treatment Period 1, Days 1, 7, 14 and 21 and 
Antibody blood draws on Treatment Period 1, Days 7, 14 and 21 and safety blood draws 
on Treatment Period 1, Day 14.  
Part A - Treatment Period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 2, 
Day 0, subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 
hour prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 
40 mg (or equivalent drug) intravenously. Subjects will receive a single IV infusion of 
normal saline (20 mL) with a syringe infusion pump over a period of 55 minutes starting 
concurrently with a 60 minute infusion of 125 mL of normal saline. This will be followed 
(± 1 minute) by an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 
1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline delivered over 60 
minutes. Subjects will remain in the clinic for 9 hours after the start of the saline 
infusion for safety evaluations and PK blood draws (see Schedule of Events below). 
Subjects will return to the clinic for PK and PD blood draws on Treatment Period 2, Days 


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1, 7, 14 and 21 and Antibody blood draws on Treatment Period 2, Days 7, 14 and 21 and 
safety blood draws on Treatment Period 2, Day 14.  
Part A - Treatment Period 3  
On the evening of Treatment Period 3, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 3, 
Day 0, subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-037, subjects will receive fexofenadine 180 mg orally 1 hour 
prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 40 
mg (or equivalent drug) intravenously. Subjects will receive a single IV infusion of 
normal saline (20 mL) with a syringe infusion pump over a period of 55 minutes starting 
concurrently with a 60 minute infusion of 125 mL of normal saline. This will be followed 
(± 1 minute) by an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohort 
1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of normal saline delivered over 60 
minutes. Subjects will remain in the clinic for 9 hours after the start of the saline 
infusion for safety evaluations and PK blood draws (see Schedule of Events below). 
Subjects will return to the clinic for PK and PD blood draws on Treatment Period 3, Days 
1, 7, 14 and 21 and Antibody blood draws on Treatment Period 3, Days 7, 14 and 21 and 
safety blood draws on Treatment Period 3, Day 14. 
Part B - Treatment Period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 4, 
Day 0 subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-037, subjects will receive fexofenadine 180 mg orally 1 hour 
prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 40 
mg (or equivalent drug) intravenously. Eligible subjects will receive a single IV infusion 
of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 mL of 
normal saline over 60 minutes by infusion pump. Subjects will remain in the clinic for 9 
hours after the start of the saline infusion for safety evaluations and PK blood draws 
(see Schedule of Events below). Subjects will return to the clinic for PK and PD blood 
draws on Treatment Period 4, Days 1, 7, 14 and 21 and Antibody blood draws on 
Treatment Period 4, Days 7, 14 and 21 and safety blood draws on Treatment Period 4, 
Day 14. 
Part B - Treatment Period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 5, 
Day 0 subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-037, subjects will receive fexofenadine 180 mg orally and 1 


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hour prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 
40 mg (or equivalent drug) intravenously. Eligible subjects will receive a single IV 
infusion of SEL-037 (0.2 mg/kg for Cohort 1 or 0.4 mg/kg for Cohort 2) diluted into 100 
mL of normal saline over 60 minutes by infusion pump. Subjects will remain in the clinic 
for 9 hours after the start of the saline infusion for safety evaluations and PK blood 
draws (see Schedule of Events below). Subjects will return to the clinic for PK and PD 
blood draws on Treatment Period 5, Days 1, 7, 14 and 21 and Antibody blood draws on 
Treatment Period 5, Days 7, 14 and 21 and safety blood draws on Treatment Period 5, 
Day 14. 
An End of Study visit will be performed on Treatment Period 5, Day 30 ± 1 day. Subjects 
who terminate participation early should have an End of Study visit assessments 
completed. 
Duration of Treatment for Cohort 3 (0.05 mg/kg SEL-110 + 0.2 mg/kg SEL-037), 
Cohort 4 (0.05 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 5 (0.08 mg/kg SEL-110 + 
0.2 mg/kg SEL-037), Cohort 6 (0.08 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 7 
(0.1 mg/kg SEL-110 + 0.2 mg/kg SEL-037), Cohort 8 (0.1 mg/kg SEL-110 + 0.4 mg/kg 
SEL-037), Cohort 10 (0.125 mg/kg SEL-110 + 0.4 mg/kg SEL-037), Cohort 11 (0.15 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), and Cohort 12 (0.15 mg/kg SEL-110 + 0.4 
mg/kg SEL-037) 
Note: Cohorts 9 is intentionally omitted from this protocol in order to maintain the 
cohort numbering convention of associating even numbered cohorts with the 0.4 
mg/kg SEL-037 dose. 
Part A - Treatment Period 1 
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when 
to start their premedication (date and medication, Day -7) for the prevention of gout 
flares. On the evening of Day -1 the subject will take their premedication of 
fexofenadine 180 mg orally. The day of initial dosing of study drug will be designated 
Day 0. On the morning of Day 0 subjects will report to the clinic for the dosing of study 
drug. 2 hours prior to the dosing of study drug SEL-110, the subject will receive 
fexofenadine 180 mg orally and 1 hour prior to the dosing of study drug SEL-037, 
subjects will receive methylprednisolone 40 mg (or equivalent drug) intravenously. 
Eligible subjects who have been assigned to Cohorts 3- 8, 10, and 12 will receive a 
single IV infusion of SEL-110 (dose based on a mg/kg basis administered with a syringe 
infusion pump. In cohorts receiving SEL-110 doses<0.10 mg/kg, SEL-110 will be infused 
at a single steady rate sufficient to deliver the dose volume over a period of 55 minutes 
concurrently with a 60 minute infusion of 125 mL of normal saline. In cohorts receiving 
SEL-110 >0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour for the first 30 


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minutes. and, then, will be increased to a steady rate sufficient to deliver the 
remainder of the dose volume for the additional 25 minutes, concurrently with a 60 
minute infusion of 125 mL of normal saline. This will be followed (± 3 minute) by an 
infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohorts 3 , 5 and 7; 0.4 
mg/kg for Cohorts 4, 6, 8, 10 and 12) diluted into 100mL of normal saline delivered over 
60 minutes (+/- 2 minutes). If necessary the infusion time may be extended in order to 
ensure the infusion of the study medication in entirety. Subjects will remain in the 
clinic for 9 hours after the start of the infusion of SEL-110 for safety evaluations and PK 
blood draws (see Schedule of Events below). Subjects will return for PK and PD blood 
draws on Treatment Period 1, Days 1, 7, 14, 21 and safety and Antibody blood draws on 
Treatment Period 1, Days 7, 14, 21. 
Part A - Treatment Period 2 
On the evening of Treatment Period 2, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 2, 
Day 0, subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 
hour prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 
40 mg (or equivalent drug) intravenously. Eligible subjects who have been assigned to 
Cohorts 3- 8, 10, and 12 will receive a single IV infusion of SEL-110 (dose based on a 
mg/kg basis) administered with a syringe infusion pump. In cohorts receiving SEL-110 
doses ≤0.10 mg/kg, SEL-110 will be infused at a single steady rate sufficient to deliver 
the dose volume over a period of 55 minutes concurrently with a 60 minute infusionof 
125 mL of normal saline In cohorts receiving SEL-110 >0.10 mg/kg, the rate of SEL-110 
infusion will be 5.5 mL/hour for the first 30 minutes. and, then, will be increased to a 
steady rate sufficient to deliver the remainder of the dose volume for the additional 25 
minutes, concurrently with a 60 minute infusion of 125 mL of normal saline. This will be 
followed (± 3 minute) by an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg 
for Cohorts 3, 5 and 7; 0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted to 100 mL of 
normal saline delivered over 60 minutes. Subjects will remain in the clinic for 9 hours 
after the start of the infusion of SEL-110 for safety evaluations and PK blood draws (see 
Schedule of Events below). Subjects will return for PK and PD on Treatment Period 2, 
Days 1, 7, 14 and 21 and safety and Antibody blood draws on Treatment Period 2, Days 
7, 14 and 21. 
Part A - Treatment Period 3 
On the evening of Treatment Period 3, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally the night before dosing. On the morning 
of Treatment Period 3, Day 0 subjects will report to the clinic for the dosing of study 
drug. 2 hours prior to the dosing of study drug SEL-110, subjects will receive 


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fexofenadine 180 mg orally and 1 hour prior to the dosing of study drug SEL-037, 
subjects will receive methylprednisolone 40 mg (or equivalent drug) intravenously. 
Eligible subjects who have been assigned to Cohorts 3- 8, 10, and 12 will receive a 
single IV infusion of SEL-110 (dose based on a mg/kg basis) administered with a syringe 
infusion pump at a single steady rate sufficient to deliver the dose volume over a period 
of 55 minutes concurrently with a 60 minute infusion of 125 mL of normal saline. In 
cohorts receiving SEL-110 >0.10 mg/kg, the rate of SEL-110 infusion will be 5.5 mL/hour 
for the first 30 minutes and, then, will be increased to a steady rate sufficient to 
deliver the remainder of the dose volume for the additional 25 minutes, concurrently 
with a 60 minute infusion of 125 mL of normal saline. This will be followed (± 3 minute) 
by an infusion delivered by infusion pump of SEL-037 (0.2 mg/kg for Cohorts 3, 5 and 7; 
0.4 mg/kg for Cohorts 4, 6, 8, 10, and 12) diluted into 100mL normal saline delivered 
over 60 minutes. Subjects will remain in the clinic for 9 hours after the start of the 
infusion of SEL-110 for safety evaluations and PK blood draws (see Schedule of Events 
below). Subjects will return for PK and PD blood draws on Treatment Period 3, Days 1, 
7, 14 and 21 and safety and Antibody blood draws on Treatment Period 3, Days 7, 14 
and 21. 
Part B - Treatment Period 4 
On the evening of Treatment Period 4, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg. On the morning of Treatment Period 4, Day 0 
subjects will report to the clinic for the dosing of study drug. 2 hours prior to the dosing 
of study drug SEL-110, subjects will receive fexofenadine 180 mg orally and 1 hour prior 
to the dosing of study drug SEL-037, subjects will receive methylprednisolone 40 mg (or 
equivalent drug) intravenously. Subjects will receive a single IV infusion of SEL-037 (0.2 
mg/kg for Cohorts 3, 5 and 7; 0.4 mg/kg for Cohorts 4, 6 , 8, 10, and 12) diluted into 
100 mL of normal saline over 60 minutes by infusion pump. Subjects will remain in the 
clinic for 9 hours after the start of the infusion of SEL-037 for safety evaluations and PK 
blood draws (see Schedule of Events below). Subjects will return for PK and PD blood 
draws on Treatment Period 4, Days 1, 7, 14 and 21 and safety and Antibody blood draws 
on Treatment Period 4, Days 7, 14 and 21. 
Part B - Treatment Period 5 
On the evening of Treatment Period 5, Day -1 (27 ± 1 days from prior dosing) subjects 
will self-administer fexofenadine 180 mg orally. On the morning of Treatment Period 5, 
Day 0 subjects will report to the clinic for the dosing of study drug. 2 hours prior to the 
dosing of study drug SEL-110, subjects will receive fexofenadine 180 mg orally and 1 
hour prior to the dosing of study drug SEL-037, subjects will receive methylprednisolone 
40 mg (or equivalent drug) intravenously. Subjects will receive a single IV infusion of 
SEL-037 (0.2 mg/kg for Cohorts 3, 5 and 7; 0.4 mg/kg for Cohorts 4, 6 , 8, 10, and 12) 
diluted into 100 mL of normal saline over 60 minutes by infusion pump. Subjects will 


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remain in the clinic for 9 hours after the start of the infusion of SEL-037 for safety 
evaluations and PK blood draws (see Schedule of Events below). Subjects will return for 
PK and PD blood draws on Treatment Period 5, Days 1, 7, 14 and 21 and safety and 
Antibody blood draws on Treatment Period 5, Days 7, 14 and 21.  
An End of Study visit will be performed on Treatment Period 5, Day 30 ± 1 days. 
Subjects who terminate participation early should have an End of Study visit 
assessments completed. 
Duration of treatment for Cohort 13 (0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037) , 
Cohort 15 (induction dose of 0.15 mg/kg SEL-110 + 0.2 mg/kg SEL-037 THEN 0.1 
mg/kg SEL-110 + 0.2 mg/kg SEL-037), ), and Cohort 17 (0.10 mg/kg SEL-110 + 
0.2 mg/kg SEL 037)  
Note: Cohort 14 and 16 are intentionally omitted from this protocol in order to maintain 
the cohort numbering convention of associating odd numbered cohorts with the 0.2 
mg/kg SEL-037 dose.  
Part C – Treatment period 1  
Subjects will be screened within 45 days of dosing. Once they meet inclusion/exclusion 
criteria and all assessments are considered acceptable they will be instructed on when 
to start their premedication (date and medication, Day -7) for the prevention of gout 
flares. On the evening of Day -1 the subject will take their premedication of 
fexofenadine 180 mg orally.  
The day of initial dosing of study drug will be designated Day 0. On the morning of Day 0 
subjects will report to the clinic for the dosing of study drug. 2 hours prior to the dosing 
of study drug SEL-110, the subject will receive fexofenadine 180 mg orally and 1 hour 
prior to the dosing of study drug SEL-110, subjects will receive methylprednisolone 40 
mg (or equivalent drug) intravenously. Eligible subjects assigned to Cohort 13, 15 and 17 
will receive a single IV infusion of SEL-110 (dose based on a mg/kg basis) administered 
with a syringe infusion pump. The rate of SEL-110 infusion will be 5.5 mL/hour for the 
first 30 minutes and, then, will be changed to a steady rate sufficient to deliver the 
remainder of the dose volume for the additional 25 minutes, concurrently with a 60 
minute infusion of 125 mL of normal saline. This will be followed (± 3 minutes) by an 
infusion delivered by infusion pump of 0.2 mg/kg SEL-037 diluted into 100 mL of normal 
saline delivered over 60 minutes (+/- 2 minutes). If necessary the infusion time may be 
extended in order to ensure the infusion of the study medication in entirety. Subjects 
will remain in the clinic for 9 hours after the start of the infusion of SEL-110 for safety 
evaluations and PK blood draws (see Schedule of Events below). Subjects will return for 
PK and PD blood draws on Treatment Period 1, Days 1, 7, 14, 21 and safety and 
Antibody blood draws on Treatment Period 1, Days 7, 14, 21.  


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Part C – Treatment periods 2, 3, 4, and 5  
On the evening of each of Treatment Periods 2-5, Day -1 (27 ± 1 days from prior dosing) 
subjects will self-administer fexofenadine 180 mg orally. On the morning of Treatment 
Period 2, Day 0, subjects will report to the clinic for the dosing of study drug. 2 hours 
prior to the dosing of study drug SEL-110, the subject will receive fexofenadine 180 mg 
orally and 1 hour prior to the dosing of study drug SEL-110, subjects will receive 
methylprednisolone 40 mg (or equivalent drug) intravenously. Eligible subjects who 
have been assigned to Cohorts 13, 15 and 17 will receive a single IV infusion of SEL-110 
(dose based on a mg/kg basis) administered with a syringe infusion pump. The rate of 
SEL-110 infusion will be 5.5 mL/hour for the first 30 minutes and, then, will be changed 
to a steady rate sufficient to deliver the remainder of the dose volume for the 
additional 25 minutes, concurrently with a 60 minute infusion of 125 mL of normal 
saline. This will be followed (± 3 minutes) by an infusion delivered by infusion pump of 
0.2 mg/kg SEL-037 diluted into 100 mL of normal saline delivered over 60 minutes (+/- 2 
minutes). If necessary the infusion time may be extended in order to ensure the infusion 
of the study medication in entirety. Subjects will remain in the clinic for 9 hours after 
the start of the infusion of SEL-110 for safety evaluations and PK blood draws (see 
Schedule of Events below). Subjects will return for PK and PD on Days 1, 7, 14 and 21 of 
each treatment period and will return for safety and Antibody blood draws on Days 7, 14 
and 21 of each treatment period.  


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3.9. 
STUDY PROCEDURES AND FLOWCHART 
 
 


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Note: Cohorts 9 is intentionally omitted from the protocol in order to maintain the cohort numbering 
convention of associating even numbered cohorts with the 0.4 mg/kg SEL-037 dose.  
 


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Note: Cohorts 9 is intentionally omitted from the protocol in order to maintain the cohort numbering 
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Table 5: Schedule of Events, Cohorts 13, 15, and 17 Part C - Treatment Periods 1-5 
 
 
Note: Cohorts 14 and 16 are intentionally omitted from the protocol in order to maintain the cohort 
numbering convention of associating odd numbered cohorts with the 0.2 mg/kg SEL-037 dose.  


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4. 
ENDPOINTS 
4.1. 
PHARMACOKINETIC ENDPOINTS 
The following PK parameters will be calculated on SEL-037 and SEL-110 (rapamycin) PK 
concentration as well as uricase activity separately for each analyte and type of PK 
assessment using noncompartmental intravascular infusion log-linear model for each 
Cohort and Treatment Period where possible and summarized statistically: 
Cmax 
Maximum observed PK concentration or activity 
Tmax 
Time of maximum observed PK concentration or activity 
Clast 
Last observed PK concentration or activity 
Tllast 
Time of last observed PK concentration or activity 
AUC0-last 
Area under the serum concentration-time curve from time zero to 
the time of the last quantifiable PK concentration or activity 
AUC0-inf 
Area under the PK concentration or activity-time curve from time 
zero extrapolated to infinity 
t1/2 
Terminal elimination half-life 
λz 
Terminal elimination rate constant 
CL 
Clearance of drug 
Vd 
Terminal volume of distribution  
Additional PK parameters may be calculated as needed. Change from baseline in uricase 
activity may be used for derivation of PK parameters in addition to actual measured 
activity. 
Multiple dose parameters will be also derived where possible: 
Cmin 
Min observed trough PK concentration or activity  
Tmin 
Time of min observed PK concentration or activity 
Cave 
Average observed PK concentration or activity 
AUCtau 
Area under the PK concentration or activity from time 0 to the end 
of dosing interval 
% Fluctuation 
Difference between Cmax and Cmin normalized by average 
concentration 
RAUCtau 
Accumulation ratio based on comparison of AUCtau between last 
and first dose 
RCmax 
Accumulation ratio based on comparison of Cmax between last and 
first dose 
RCmin 
Accumulation ratio based on comparison of Cmin between last and 
first dose 
CLss 
Steady state clearance (if steady state is achieved) 
 


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4.2. 
PHARMACODYNAMIC ENDPOINTS  
The following PD parameters will be calculated on PD uric acid for each Cohort and 
Treatment period and Overall where possible. The parameters will be derived for actual 
measurements of uric acid as well as for % change from baseline: 
Cmin 
Minimal observed serum concentration 
Tmin 
Time of minimal observed serum concentration 
CFBmin 
Minimum observed change from baseline in serum concentration 
AUECFBlast 
Absolute value for Area under the change from baseline in effect-
time curve from time zero to the time of the last quantifiable 
concentration (effect – uric concentration) 
TA_AUECFBlast 
Time adjusted area under the absolute value for effect-time curve 
from time zero to the time of last quantifiable concentration 
(effect – uric concentration) 
Tonset 
Time of onset of effect – first time point of reduction uric acid 
concentration >10% of baseline 
Tresolve 
Time of resolution of effect – first time point of return of uric acid 
concentration to baseline defined as <10% difference from pre-dose 
baseline 
Tduration 
Time of duration of effect, calculated as Tresolve - Tonset 
4.3. 
SAFETY ENDPOINTS  
The primary objective of this study is to assess the safety and tolerability of multiple IV 
infusions of SEL-212. Safety assessments will be based on medical review of adverse 
event (AE) reports and the results of vital sign measurements, electrocardiograms 
(ECGs), physical examinations, and clinical laboratory tests. These endpoints will be 
measured at the time points specified in the protocol in Section 1.1, Schedules of 
Events. The primary endpoints are frequencies of AEs, serious AEs (SAEs), AEs leading to 
discontinuation, and ECG and laboratory abnormalities occurring up to 30 days after the 
last dose of study medication. 
4.4. 
IMMUNOGENICITY ENDPOINTS 
Immunogenicity endpoints include occurrence of anti-PEG, anti-pegsiticase, and anti-
uricase specific antibodies based on screening assay; and the titer for the 
anti-pegsiticase antibodies, where the confirmation assay is also available. Frequency of 
occurrence of antibodies by study day and overall by cohort, time of onset 
immunogenicity, and time of resolution of immunogenicity will be calculated and 
summarized by treatment in summary tables. Time of onset is defined as the first time 
point with positive ADA (anti-drug antibodies) result; time of resolution is defined as the 


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first time point when a previously observed positive ADA result returns to baseline. 
Titers of antibodies against PEG, uricase and pegsiticase will be listed. 


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5. 
 ANALYSIS SET 
5.1. 
SCREENED/RANDOMIZED SUBJECTS 
• 
Screened subjects are defined as all subjects who signed an informed consent; 
Screen Failure Subjects are defined as all subjects who were screened but not dosed. 
• 
Randomized subjects are defined as all subjects who are assigned a 
randomization number. 
5.2. 
SAFETY ANALYSIS SET 
The safety analysis set will include all subjects who are randomized and have drug 
exposure. The safety analysis set will be used for all analyses of safety endpoints. 
5.3. 
PHARMACOKINETIC ANALYSIS SET 
The PK analysis set will include all subjects who are randomized, dosed with any 
amount of study drug, and for whom PK data are available with no significant protocol 
violations or deviations that would significantly affect the PK evaluation of the drug. 
Factors that may influence serum SEL-037 concentrations and/or the whole blood 
rapamycin concentrations (e.g., interruptions in the infusion or changes in the infusion 
rate) will be reviewed. If an influencing factor is present, a decision will be made by 
the responsible pharmacokineticist, whether to include or exclude the specific sample 
or subject. If a whole blood rapamycin concentration sample or a serum SEL-037 
concentration sample is the subject of an ongoing investigation at the time of 
databased lock, the corresponding tables, figures and listings involving that sample may 
be calculated additionally with the exclusion of the sample in question. All subjects and 
samples excluded from the analysis will be clearly documented in the study report. 
5.4. 
PHARMACODYNAMIC ANALYSIS SET 
The PD analysis set will include will include all subjects who are randomized, receive 
any amount of study drug, and have at least one post-baseline assessment of sUA is 
available. Uric acid concentrations will be listed for all subjects in PD analysis set. 
All available PD data will be included in the listings; the PD data will be evaluated for 
protocol violations or deviations that would significantly affect the PD evaluation of the 
drug. Profiles or individual time points with such violations or deviations will be flagged 
and may be excluded from summary statistics and the derivation of PD parameters. 
Examples to treat as the deviations will be but not limited to: 


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1) 
 Dose interruptions in their SEL-037 dose such that only partial doses were 
delivered – PD profiles may be excluded from summaries and may be used in analyses 
with actual dose of SEL-037 used if possible 
2) 
 Dose interruptions in their SEL-110 dose such that only a partial dose of SEL-110 
and/or NO DOSE of SEL-037 was administered (since only SEL-037 will cause sUA to be 
reduced) – the profiles for the treatment period with deviation will be excluded from 
summaries and may be used for additional analyses without SEL-037 if needed; the data 
for prior periods will be included  
3) 
 Subjects who have a dose interruption during SEL-110 administration in the 1st 
treatment period and so do not ever receive SEL-037 but do have measured sUA values – 
as above, may be used for additional analyses without SEL-037 if needed post-hoc.  
5.5. 
PROTOCOL DEVIATIONS 
All protocol deviations related to study inclusion or exclusion criteria, conduct of the 
trial, subject management, dosing, and sampling procedures or subject assessment will 
be listed. The list of protocol deviations will be reviewed by the Sponsor, the medical 
director at Syneos Health , the study statistician and the study pharmacokineticist and 
finalized before database lock.  
 


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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
SAS® version 9.3 will be used for all statistical analyses and tabulations. 
In general, summaries will present data by treatment/cohort and assessment time 
where appropriate. Unless stated otherwise, descriptive summaries will include n, 
mean, standard deviation, median, minimum, and maximum for continuous variables, 
and n and percent for categorical variables. If there are multiple assessments collected 
on the same scheduled time within the windows, the average of these assessments will 
be used. For tabulated safety summaries, only the scheduled assessments will be 
included in the summary tables. 
Data collected at unscheduled visits will be included in the data listings but will not be 
included in the analyses. The data for the EOS visit at day 140 will be separated from 
the Early Termination visit data and will be summarized for all the subjects within the 
defined population who reached this visit. An additional observational visit for subjects 
with <6 mg/dL uric acid concentration on day 140 (approx. 30 days after last dose) were 
scheduled at approx. 170 days from 1st dose. The data for the observational visit will be 
reported and summarized for all subjects participating in this visit. Data for Early 
Termination visits will be listed with actual day from dose included and will not be 
summarized. The last result for repeat test at screening visit will be considered as final 
and will be included in summaries. Previous results will be listed but not summarized.  
Adverse events and medical history will be coded according to the most recent Medical 
Dictionary for Regulatory Activities (MedDRA) version. Prior and concomitant 
medications will be coded using the most recent WHO Drug Dictionary version. 
Derivation of PK parameters will be performed using Phoenix WinNonLin 6.4 or higher on 
a Windows 7 platform or higher. 
6.2. 
KEY DEFINITIONS 
The last non-missing value prior to the start of infusion of any study drug in Period 1 will 
be used as baseline.  
6.3. 
MISSING DATA 
The handling of missing PK data is detailed in SAP section 8.2.1. 
The handling of missing PD data is detailed in SAP section 9.3.1. 


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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition will be listed. Summary tables reflecting the number of subjects for 
the following will be presented: 
- 
Screened subjects 
- 
Randomized subjects 
- 
Safety analysis set 
- 
PK analysis set 
- 
PD analysis set 
- 
Subjects who complete the study 
- 
Subjects who early terminate the study and reasons for early termination  
Screen Failure subjects will be listed. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic characteristics such as sex, age, race, and ethnicity will be summarized 
for Safety Analysis Set, by treatment and overall. Demographic characteristics will be 
also listed for Safety Analysis Set. 
7.3. 
MEDICAL HISTORY AND CONCOMITANT DISEASES 
Medical history will be listed by treatment and subject. Summaries will be provided. 
Medical history will be coded by using the most recent (MedDRA®) version. 
7.4. 
MEDICATION 
Concomitant therapy includes any medication (eg, prescription drugs, over-the-counter 
drugs, vaccines, topical medications, herbal or homeopathic remedies, nutritional 
supplements) used by a subject from 3 months prior to screening to the last study visit. 
All such medications should be reported to the investigator and recorded on the 
Concomitant Medications electronic case report form (eCRF). The reported medications 
will be reviewed and evaluated by the investigator or designee to determine if they 
affect a subject’s eligibility to participate or continue to participate in the study.  


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The original verbatim terms collected in the eCRF for concomitant medications will be 
coded using the World Health Organization Drug Dictionary (WHO-DD September 2015 
version) into drug class (Anatomical Therapeutic Classification [ATC] level 4) and 
preferred term. 
Concomitant medication will be listed and summarized. 
 


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8. 
ANALYSIS OF PHARMACOKINETICS 
The PK analysis set will be used to calculate PK parameters, graphical displays of 
individual data, and the listings of PK concentrations and parameters, and for all PK 
summaries. Subjects with missing PK parameters due to unreliable or missing data will 
be flagged and excluded from summarization. 
Concentrations of pegsiticase and uricase activity in serum at different time points will 
be used as measures of the PK of SEL-037. Concentrations of rapamycin in whole blood 
will be used to characterize the PK of SEL-110. 
The Parts A/B (Treatment periods 1-3 and 4-5 for cohorts 1-8, 10-12 respectively) will 
be presented together, Part C (cohorts 13 and 15) will be presented separately unless 
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8.1. 
COLLECTION SCHEDULE 
Cohorts 1-2 
Period 
Day 
Time from start of 
dose for saline, h  
Time from start of dose for SEL-037, h 
SEL-037 PK concentration 
Uricase activity 
1-3 
0 
0 
-1 (0) 
-1 (0) 
 
 
1.5 
 
0.5 
 
 
2 
 
1 
 
 
3 
 
2 
 
 
6 
 
5 
 
 
9 
 
8 
 
1 
24 
23 
23 
 
7 
168 
167 
167 
 
14 
336 
335 
335 
 
21 
504 
503 
503 
 
28* 
672 
671 
671 
4-5 
0 
 
0 
0 
 
 
 
0.5 
0.5 
 
 
 
1 
1 
 
 
 
1.5 
1.5 
 
 
 
2 
2 
 
 
 
3 
3 
 
 
 
6 
6 
 
1 
 
24 
24 
 
7 
 
168 
168 
 
14 
 
336 
336 
 
21 
 
504 
504 
 
28** 
 
672 
672 
 
30*** 
 
720 
720 
* - pre-dose for next Treatment period 
** - PK point for Treatment period 4 as pre-dose for Treatment period 5 
*** - last point for Treatment period 5 only 
Repeat the same for other periods 
 
 
 
 


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Cohorts 3-8, 10, 11, 12 
Period 
Day 
Time from start of 
dose for SEL-110, h  
Time from start of dose for SEL-037, h  
SEL-110 
concentration 
SEL-037 PK 
concentration 
Uricase activity 
1-3 
0 
0 
-1 (0) 
-1 (0) 
 
 
0.25 
 
 
 
 
0.5 
 
 
 
 
0.75 
 
 
 
 
1.5 
0.5 
 
 
 
2 
1 
 
 
 
3 
2 
 
 
 
6 
5 
 
 
 
9 
8 
 
 
1 
24 
23 
23 
 
7 
168 
167 
167 
 
14 
336 
335 
335 
 
21 
504 
503 
503 
 
28* 
672 
671 
671 
4-5 
0 
 
0 
 
 
 
 
0.5 
 
 
 
 
1 
 
 
 
 
1.5 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
6 
 
 
1 
 
24 
24 
 
7 
 
168 
168 
 
14 
 
336 
336 
 
21 
 
504 
504 
 
28** 
 
672 
672 
 
30*** 
 
720 
720 
* - pre-dose for next Treatment period 
** - PK point for Treatment period 4 as pre-dose for Treatment period 5 
*** - last point for Treatment period 5 only 
 
 
 


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Cohorts 13, 15, 17 
Period 
Day 
Time from start of 
dose for SEL-110, h  
Time from start of dose for SEL-037, h  
SEL-110 
concentration 
SEL-037 PK 
concentration 
Uricase activity 
1-5 
0 
0 
-1 (0) 
-1 (0) 
 
 
0.25 
 
 
 
 
0.5 
 
 
 
 
0.75 
 
 
 
 
1.5 
0.5 
 
 
 
2 
1 
 
 
 
3 
2 
 
 
 
6 
5 
 
 
 
9 
8 
 
 
1 
24 
23 
23 
 
7 
168 
167 
167 
 
14 
336 
335 
335 
 
21 
504 
503 
503 
 
28* 
672 
671 
671 
 
30** 
 
720 
720 
* - pre-dose for next Treatment period 
** - last point for Treatment period 5 only 
8.2. 
PHARMACOKINETIC PARAMETERS 
The following PK parameters will be calculated on SEL-037 and SEL-110 (rapamycin) PK 
concentration as well as uricase activity using noncompartmental intravascular infusion 
log-linear model for each Cohort and Treatment Period where possible and summarized 
statistically: 
Cmax 
Maximum observed PK concentration or activity 
Tmax 
Time of maximum observed PK concentration or activity 
Clast 
Last observed PK concentration or activity 
Tlast 
Time of last observed PK concentration or activity 
AUC0-last 
Area under the serum concentration-time curve from time zero to 
the time of the last quantifiable PK concentration or activity 
AUC0-inf 
Area under the PK concentration or activity-time curve from time 
zero extrapolated to infinity 
t1/2 
Terminal elimination half-life 
λz 
Terminal elimination rate constant 
CL 
Clearance of drug 
Vd 
Terminal volume of distribution  


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Additional PK parameters may be calculated as needed.  
Multiple dose parameters will be also derived where possible: 
Cmin 
Min observed trough PK concentration or activity  
Tmin 
Time of min observed PK concentration or activity 
Cave 
Average observed PK concentration or activity 
AUCtau 
Area under the PK concentration or activity from time 0 to the end 
of dosing interval 
% Fluctuation 
Difference between Cmax and Cmin normalized by average 
concentration 
RAUCtau 
Accumulation ratio based on comparison of AUCtau between last 
and first dose 
RCmax 
Accumulation ratio based on comparison of Cmax between last and 
first dose 
RCmin 
Accumulation ratio based on comparison of Cmin between last and 
first dose 
CLss 
Steady state clearance (if steady state is achieved) 
Dose dependent parameters for SEL-110 (Cmax, AUC0-last, AUC0-inf) will be dose normalized 
for comparison between treatments involving different doses of SEL-037. 
The PK parameters will be estimated as follows: 
The apparent Cmax and the corresponding Tmax will be read directly from the 
concentration-time plot (observed data, not predicted data by the program); 
AUCs will be calculated using the linear-log trapezoidal rule; 
The terminal elimination rate constant (λz) will be determined by log linear regression 
obtained on at least the 3 last quantifiable concentrations and will not include Cmax. The 
adjusted square of the correlation coefficient (Rsquare adjusted) for the goodness of fit 
of the regression line through the data points must be at least 0.8500 for the λz value to 
be considered reliable; 
t1/2 is calculated by the program as ln2/λz; 
If the time interval between the lower and upper time points used for the regression 
spans less than the derived half-life itself then λz and the associated t1/2 will be 
considered unreliable; 
The AUC from 0 to infinity is calculated by the program as: 
 
AUCinf = AUClast + AUClast-inf where last is the sampling time point of the last measurable 
concentration (tlast). AUClast-inf is calculated by the program as: Clast/λz, where Clast is the 


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observed concentration at time tlast and λz is the elimination rate constant during the 
apparent terminal elimination phase; AUCinf will only be presented for subjects with a 
reliable λz; 
The AUC extrapolation to infinity must be ≤20% of the total area for AUCinf to be 
considered reliable; 
CL is calculated by program as (dose/AUCinf) 
Vd is calculated by the program as (dose/AUCinf)/ λz. 
For subjects with unreliable λz (ie, Rsquare adjusted <0.8500, interval for λz calculation 
shorter than t1/2, number of points to calculate λz <3), λz, t1/2, AUCinf, CL and Vd will be 
flagged in the individual data. 
For subjects with unreliable AUCinf (because of extrapolation >20%), AUCinf, CL and Vd 
will be flagged in the individual data. 
Flagged PK parameters will be excluded from summarization and statistical analyses. 
 
8.2.1. 
Handling of Dropouts, Missing Data or Data Below the Lower Limit 
of Quantification 
Missing concentration data for all subjects who are administered scheduled study 
treatments will be considered as non-informative missing and will not be imputed for 
each treatment period individually. The missing data will not affect analyses for the 
previous treatment periods where complete dose were administered and PK profiles 
available. No concentration estimates will be provided for missing sample values. 
For the derivation of PK parameters, the following rules will apply: 
Concentration values below the assay’s lower limit of quantification (BLQ) in pre-dose 
samples and in samples taken before the time of the first quantifiable concentration 
will be treated as zero.  
The sampling time of pre-dose samples relative to dosing will also be treated as zero. 
Post-dose BLQ values after the first quantifiable time point will be set to missing. 
If the actual time of sampling is missing, the planned time may be used. 


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Samples taken outside the sampling windows may be excluded from by-time point 
summary statistics. This will be determined prior start of analyses around timing for 
database lock. 
For serum or whole blood concentration summary, individual concentration versus time 
curves and mean concentration versus time graphs, the following rules will apply: 
 
Serum or whole blood concentrations BLQ in pre-dose samples and in samples 
taken before the time of the first quantifiable value will be set to zero 
 
The serum or whole blood concentrations BLQ after quantifiable concentration 
will be set to zero 
No further imputation will be applied to any missing values. 
8.3. 
DATA SUMMARIZATION 
PK parameters and serum (SEL-037) or whole blood (SEL-110) concentration data will be 
summarized by treatment using the following descriptive statistics: 
Variable 
Summarized with: 
Serum or whole blood 
concentration at each 
nominal time point 
n, number and % BLQ, arithmetic mean, SD, 
coefficient of variance (CV) %, minimum, median and 
maximum 
AUC, Cmax, CL and Vd 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV%  
t1/2, and λZ  
n, arithmetic mean, SD, CV%, minimum, median, 
maximum 
Tmax (actual time) 
n, minimum,Q1, median, Q3 and maximum 
Note: CV% = SD/mean in %.  
%BLQ = 100 * (total number of subjects who have BLQ values/total number of subjects within each cohort at 
each time point) 
Mean concentrations will not be presented if 30% or more of the actual values for PK 
analysis set at any one time point in the terminal phase are BLQ or missing. 
Samples taken outside the allowed time windows may be excluded from summarization. 
This will be determined prior to database lock. 
The following conventions will be used for the presentation of the descriptive statistics 
of PK parameters and of serum or whole blood concentrations: 


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PK Reporting Precision 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant digits or as needed based on 
actual measured values (for example PK 
concentrations) 
Mean (arithmetic and geometric), 
Median 
4 significant digits or as needed based on 
actual measured values (for example PK 
concentrations) 
Standard deviation 
5 significant digits or as needed based on 
actual measured values (for example PK 
concentrations) 
CV% and Geometric CV% 
1 decimal point or as needed based on 
actual measured values (for example PK 
concentrations) 
 
8.4. 
 DATA PRESENTATION FOR SEL-110 AND SEL-037  
The actual sampling time of PK blood sample collection will be listed for each cohort 
and will include the deviation in time from the protocol scheduled time, if applicable. 
Individual subject serum (SEL-037) or whole blood (SEL-110) concentration data will be 
listed by subject, time point and treatment (in relevant concentration units) and will be 
summarized at each time point by cohort. Individual subject PK parameters will be 
listed for the PK analysis set in a table by subject and will be summarized, by treatment 
group/cohort. Unreliable PK parameters will be listed but flagged and excluded from 
the summary. 
PK parameters of secondary interest, namely Rsquare adjusted, the number of data 
points used for estimating Z, the upper and lower time point used for estimation of Z, 
and the % AUC extrapolation from tlast to infinity will be listed by subject and dose 
level/cohort to enable verification of the exclusions, if any, of data from the summary 
statistics of the PK parameters of primary interest. 
The following figures will be produced for SEL-110: 
Mean ± SD whole blood concentration-time profiles will be presented, combining the 
curves for all treatment periods within the same figure for each cohort separately. 
Individual whole blood concentration-time profiles will be presented, for each cohort 
with all subjects in the same figure on linear and log-linear scales – 3 curves on the plot 


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for 3 treatment periods for Part A (cohorts 1-8, 10-12, treatment periods 1-3). For Part 
C of the study (cohorts 13, 15) the presentation will include 5 curves for treatment 
periods 1-5 on the same plot. 
Additional mean ± SD whole blood concentration-time profiles will be presented, 
combining the curves for all dose levels of SEL-110 separately in Part A for cohorts with 
0.2 mg/kg SEL-037 (cohorts 3, 5, 7, 11) and 0.4 mg/kg SEL-037 (cohorts, 4, 6, 8, 10, 12) 
within the same figure for each of the three treatment periods 1-3 on a separate plot – 
4 and 5 curves respectively, 6 plots total for 3 treatment periods. 
The following figures will be produced for SEL-037: 
Mean ± SD serum concentration-time profiles will be presented on linear and log-linear 
scales for all Treatment periods within the same figure for each cohort separately. PK 
concentrations of SEL-037 and uricase activity will be also presented on the same plot 
with double Y axes for each Cohort and Treatment period separately. 
Additionally mean ± SD serum concentration-time profiles will be presented on linear 
and log-linear scales for all cohorts in Parts A/B with 0.2 mg/kg SEL-037 (cohorts 1, 3, 5, 
7, 11) or 0.4 mg/kg dose levels (cohorts 2, 4, 6, 8, 10, 12) within the same figure for 
each treatment period separately. Cohorts 13, 15 in Part C of the study will be 
presented separately. 
Individual serum concentration-time profiles will be presented, for each Cohort and 
Treatment period with all subjects in the same figure on linear and log-linear scales. 
Regression/scatter plots for SEL-037 PK parameters (Cmax, AUC0-last, AUC0-inf) for dose 
levels 0.2 and 0.4 mg/kg separately versus dose of SEL-110 (for cohorts 1 and 2, the 
SEL-110 dose level will be set to 0) on the same plot for each parameter individually. 
The plots will be produced for all treatment periods in Part A of the study separately 
and can be combined for treatment periods 1-3 with Part C data cohorts 13, 15 as 
additional plot.   
8.5. 
ASSESSMENT OF DOSE PROPORTIONALITY FOR SEL-110  
Exploratory dose proportionality will be analyzed with the method originally described 
by Gough et al. (1995)1 and modified as described by Smith et al. (2000)2 and further 
adapted by Hummel et al. (2009)3. Hereby Analyses of Variance model (ANOVA) method 
will be performed on the logarithm e transformed PK parameter endpoints: Cmax, AUC0-
last and AUC0-inf, Cmin and AUCtau for all treatment periods 1-3 in Part A of the study. 
Additional analysis may combine Part A data with the data from Part C treatment 
periods 1-3. The model will include log e-transformed SEL-110 dose level as 
independent variable. This model will be used to investigate the null hypothesis (H0: 


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ß=1). Dose-proportionality will be rejected if the 90% confidence interval (CI) of the 
estimated slope falls outside the critical interval. The linear form of the model will be 
as following: 
Yij =α + β * Xi + εij 
Where: 
 
Yij = logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …m, j = 1, 2, …, n 
 
α = intercept parameter 
 
β = slope parameter 
 
Xi = logarithm of dose i 
 
εij = random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed). 
An example SAS code will be: 
PROC MIXED DATA=xx ALPHA = .1; 
MODEL loge(PK parameter) = loge(dose of SEL-110) / CL; 
RUN; 
 
The 
critical 
interval 
will 
be 
calculated 
as 
follows:  
First the ratio (r) of the highest dose level to the lowest dose level will be calculated. 
The lower limit of the critical interval will be calculated as: Ln (0.5)/ln(r) + 1. 
The upper limit of the critical interval will be calculated as: Ln (2.0)/ln(r) + 1. 
r value is based on the ratio between highest and lower dose levels of SEL-110 and 
equals to 0.15 / 0.05 mg/kg = 3 
Thus critical interval to declare dose linearity will be 0.37 to 1.63 for 90% confidence 
interval of the slope estimate. 
The effect of SEL-037 doses may be explored by including them as fixed covariate effect 
in the model. p-value for SEL-037 dose will be presented. 
Additionally PK parameters Cmax, AUC0-last and AUC0-inf, Cmin, AUCtau with total dose and 
body weight adjusted dose will be investigated using Pearson correlation analysis to 
estimate which type of dosing has an effect on pharmacokinetics of SEL-110. The 
correlations for combination with 0.2 and 0.4 mg/kg SEL-037 will be explored separately 
and overall. The data for Parts A and C (treatment periods 1-3 only) will also be 
combined in the separate table. 


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The FISHER option in the PROC CORR statement will be used to estimate confidence 
limits and p-values for Pearson correlation coefficients based on Fisher’s z 
transformation. Alpha value and a null hypothesis value will be specified for 95% two-
sided confidence interval. 
Dose proportionality analysis for both Hummel power analysis and Pearson correlation 
analysis will be also presented graphically as described in Section 8.4 of the SAP. Dose 
proportionality plots will be presented for SEL-110 Cmax and AUC0-inf and AUC0-last for Part 
A only and for combined data from Parts A and C treatment periods 1-3.  
8.6. 
ASSESSMENT OF DOSE PROPORTIONALITY FOR SEL-037 
Single and multiple dose PK parameters for SEL-037 PK concentrations or uricase 
activity Cmax, Cmin, AUC0-last, AUCtau normalized by dose of SEL-037 will be compared 
between cohorts 1, 3, 5, 7, 11 with 0.2 mg/kg and 2, 4, 6, 8, 10, 12 with 0.4 mg/kg 
doses of SEL-037 using ANOVA model separately for Parts A and B and each treatment 
period and combined data for Parts A and C (treatment periods 1-3 only). 
For Part A of each cohort, the dose of SEL-110 will be included as fixed effect in this 
comparison. 
The dose normalized PK parameters for SEL-037 will be presented on box plots for each 
treatment and part separately and overall for all cohorts with the same dose level for 
comparison for Parts A and B and separately for combined data Parts A and C 
(treatment periods 1-3). 
8.7. 
ASEESSMENT OF EFFECT OF VARIOUS DOSES OF SEL-110 ON 
PHARMACOKINETICS OF SEL-037 
Effect of co-administration of various doses of SEL-110 on pharmacokinetics of SEL-037 
PK parameters for serum concentrations or uricase activity for cohorts 1, 3, 5, 7, 11 
(SEL-037 dose 0.2 mg/kg) and 2, 4, 6, 8, 10, 12 (SEL-037 dose 0.4 mg/kg) separately 
(SEL-110 dose in cohorts 1 and 2 will be set to 0) will be performed by a linear mixed-
effect model: 
𝑃𝐾𝑝𝑎𝑟𝑎𝑚(𝑆𝐸𝐿−037) = 𝛼+ 𝑠𝑖+ 𝛽× 𝐷𝑜𝑠𝑒(𝑆𝐸𝐿−110) + 𝑒𝑖 
𝛼: population mean intercept  
𝛽: population mean slope 
𝑠𝑖: random effect of subject i on the intercept, iid N(0, 𝜎𝑠2) 
ei: residual, iid N(0, бe) for subject i 


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the PK parameters and dose of SEL-110 will not be log-transformed to allow inclusion of 
0 dose of SEL-110 into the model 
P value will be calculated for slope and intercept. If the p-value of the slope is less than 
0.05, a direct relationship is declared. If p value for slope will be >0.05 the result will 
be interpreted as lack of effect of SEL-110 on pharmacokinetics of SEL-037.  
SEL-110 co-administration effect will also be explored graphically with scatter plots of 
Cmax, AUC0-last and AUC0-inf for SEL-037 serum concentrations or uricase activity vs dose 
levels of co-administered SEL-110 including 0 dose for placebo. 
The example SAS code will be: 
PROC MIXED DATA=data_set_name; 
CLASS treatment; 
MODEL PK Parameter = dose /DDFM=KR; 
LSMEANS dose / CL; 
RUN; 
Additionally the effect of SEL-110 on PK of SEL-037 will be performed by comparison of 
data from Parts B vs Part C for treatment periods 4-5 using ANOVA model as described 
in the Section 8.6 of the SAP. 
The contrasts will include:  
Cohort 13 treatment period 4 vs Cohort 11 treatment period 4 
Cohort 13 treatment period 5 vs Cohort 11 treatment period 5 
Cohort 15 treatment period 4 vs Cohort 11 treatment period 4 
Cohort 15 treatment period 5 vs Cohort 11 treatment period 5 
Cohort 15 treatment period 4 vs Cohort 13 treatment period 4 
Cohort 15 treatment period 5 vs Cohort 13 treatment period 5 
Graphic presentation in the form of box plots will be also added to the exploratory 
analysis. 


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9. 
ANALYSIS OF PHARMACODYNAMICS 
9.1. 
MEASUREMENTS 
Concentration of uric acid in serum will be used as measure of PD for both drugs. The 
concentration-time profile of uric acid is used to determine PD parameters as described 
in section 9.3. PD parameters will be derived based on actual measurements and %CFB 
(%CFB = value of change from baseline at each time point / value of measurement at 
baseline * 100%) for each cohort and treatment period and overall where applicable. 
The Parts A/B (Treatment periods 1-3 and 4-5 for cohorts 1-8, 10-12 respectively) will 
be presented together, Part C (cohorts 13 and 15) will be presented separately unless 
necessary for comparative analysis. 
9.2. 
 COLLECTION SCHEDULE 
Venous blood samples with corresponding time post-dose for uric acid are shown in 
table below: 
Cohorts 1-2 
Period 
Day 
Time from start of dose for saline, h  
Time from start of dose for SEL-037, 
h  
1-3 
0 
0 
-1 (0) 
 
 
1.5 
0.5 
 
 
2 
1 
 
 
3 
2 
 
 
6 
5 
 
 
9 
8 
 
1 
24 
23 
 
7 
168 
167 
 
14 
336 
335 
 
21 
504 
503 
 
28* 
672 
671 
4-5 
0 
 
0 
 
 
 
0.5 
 
 
 
1 
 
 
 
1.5 
 
 
 
2 
 
 
 
3 
 
 
 
6 
 
1 
 
24 
 
7 
 
168 


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Period 
Day 
Time from start of dose for saline, h  
Time from start of dose for SEL-037, 
h  
 
14 
 
336 
 
21 
 
504 
 
28** 
 
672 
 
30*** 
 
720 
* - pre-dose for next Treatment period 
** - PD point for Treatment periods 4 as pre-dose for Treatment period6 
*** - last point for Treatment period 5 only 
Cohorts 3-8, 10, 11, 12 
Period 
Day 
Time from start of dose for saline, h  
Time from start of dose for SEL-037, 
h  
1-3 
0 
0 
-1 (0) 
 
 
1 
0 
 
 
1.5 
0.5 
 
 
2 
1 
 
 
3 
2 
 
 
6 
5 
 
 
9 
8 
 
1 
24 
23 
 
7 
168 
167 
 
14 
336 
335 
 
21 
504 
503 
 
28* 
672 
671 
4-5 
0 
 
0 
 
 
 
0.5 
 
 
 
1 
 
 
 
1.5 
 
 
 
2 
 
 
 
3 
 
 
 
6 
 
1 
 
24 
 
7 
 
168 
 
14 
 
336 
 
21 
 
504 
 
28** 
 
672 
 
30*** 
 
720 
* - pre-dose for next Treatment period 
** - PD point for Treatment periods 4 as pre-dose for Treatment period6 
*** - last point for Treatment period 5 only 


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Cohorts 13, 15 
Period 
Day 
Time from start of dose for saline, h  
Time from start of dose for SEL-037, 
h  
1-5 
0 
0 
-1 (0) 
 
 
1 
0 
 
 
1.5 
0.5 
 
 
2 
1 
 
 
3 
2 
 
 
6 
5 
 
 
9 
8 
 
1 
24 
23 
 
7 
168 
167 
 
14 
336 
335 
 
21 
504 
503 
 
28* 
672 
671 
 
30** 
 
720 
* - pre-dose for next Treatment period 
** - last point for Treatment period 5 only 
9.3. 
PHARMACODYNAMICS PARAMETERS 
The following PD parameters will be calculated based on actual measurements of PD 
uric acid for each Cohort and Treatment period and Overall where possible: 
Cmin 
Minimal observed serum concentration 
Tmin 
Time of minimal observed serum concentration 
CFBmin 
Minimum observed change from baseline in serum concentration 
AUECFBlast 
Absolute value for Area under the change from baseline in effect-
time curve from time zero to the time of the last quantifiable 
concentration (effect – uric concentration) 
TA_AUECFBlast 
Time adjusted area under the absolute value for effect-time curve 
from time zero to the time of last quantifiable concentration 
(effect – uric concentration) 
Tonset 
Time of onset of effect – first time point of reduction uric acid 
concentration >10% of baseline 
Tresolve 
Time of resolution of effect – first time point of return of uric acid 
concentration to baseline defined as <10% difference from pre-dose 
baseline 
Tduration 
Time of duration of effect, calculated as Tresolve - Tonset 
The following PD parameters will be calculated based on %CFB of PD uric acid for 
each Cohort and Treatment period and Overall where possible 
 


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%CFBmin 
Minimum %CFB in serum concentration 
AUE%CFBlast 
Absolute value for Area under the %CFB in effect-time curve from 
time zero to the time of the last quantifiable concentration (effect 
– uric concentration) 
TA_AUE%CFBlast 
Time adjusted area under the %CFB for effect-time curve from 
time zero to the time of last quantifiable concentration (effect – 
uric concentration) 
# and % of 
patients with 
SUA<6 in TP3  
The number  and % of patients maintaining sUA concentrations 
below 6 mg/dL at the end of treatment period 3 
# and % of 
patients with 
SUA<6 in TP5  
The number  and % of patients maintaining sUA concentrations 
below 6 mg/dL at the end of treatment period 5 
9.3.1. 
Handling of Dropouts, Missing Data or Data Below the Lower Limit of 
Quantification  
Missing concentration data for all subjects who are administered scheduled study 
treatments will be considered as non-informative missing and will not be imputed. No 
concentration estimates will be provided for missing sample values. 
For the derivation of PD parameters, serum concentration summary, individual 
serum concentration versus time curves and mean concentration versus time graphs 
the following rules will apply: 
 
Concentration values below the assay’s lower limit of quantification (BLQ) for all 
time points will be treated as zero 
 
The sampling time of pre-dose samples relative to dosing will also be treated as 
zero 
 
If the actual time of sampling is missing, the planned time may be used 
 
In case of discrepancy between the nominal time and time stamp on the sample 
concentration data, which affects the temporal order of PD samples and is not 
related to documented protocol deviations, the nominal (planned) time will be 
used only for the pre-dose samples before treatment period 1. All other data 
with such time discrepancy will be removed from PD parameter derivations and 
summaries. The profiles for subjects with the single PD points removed due to 
this type of discrepancy can still be used for derivation of PD parameters and 
any summaries or models for other PD time points. 


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Samples taken outside the sampling windows may be excluded from by-time point 
summary statistics. This will be determined prior to the start of analyses around 
database lock. 
No further imputation will be applied to any missing values. 
9.4. 
DATA SUMMARIZATION 
PD parameters and serum concentration data will be summarized by Treatment period 
and Cohort using the following descriptive statistics: 
PD Summary Statistics: 
Variable 
Summarized with: 
Serum concentration at 
each nominal time point 
n, number and % BLQ, arithmetic mean, SD, CV%, 
minimum, median and maximum 
CFBmin, %CFBmin, AUECFBlast, 
AUE%CFBlast and TA_AUECFBlast, 
TA_AUE%CFBlast 
n, arithmetic mean, SD, CV%, minimum, median, 
maximum, geometric mean and geometric CV%  
Tonset, Tresolve, Tduration, and 
Tmin (actual time) 
n, minimum, Q1, median, Q3 and maximum 
Mean concentrations will not be presented if 50% or more of the available observations 
relative to total number of subjects within the treatment at any time point are missing. 
BLQ values for uric acid concentration will be summarized as 0 (zero) for all time 
points.  
Samples taken outside the allowed time windows may be excluded from summarization. 
This will be determined prior to database lock. 
The following conventions will be used for the presentation of the descriptive statistics 
of PD parameters and serum concentrations for uric acid: 


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PD Reporting Precision: 
Statistics 
Degree of Precision 
Minimum, Maximum 
3 significant digits or as needed based on 
actual measured values (for example PD 
concentrations) 
Mean (arithmetic and geometric), 
Median 
4 significant digits or as needed based on 
actual measured values (for example PD 
concentrations) 
Standard deviation 
5 significant digits or as needed based on 
actual measured values (for example PD 
concentrations) 
CV, Geometric CV 
1 decimal point or as needed based on 
actual measured values (for example PD 
concentrations) 
9.5. 
DATA PRESENTATION FOR DUAL ENERGY COMPUTED TOMOGRAPHY 
(DECT) SCANS 
Dual energy computed tomography (CT) scans will be performed as an exploratory 
measure for at least 2 subjects in Cohorts 10, 11, and 12 during the screening interval, 
between Days 21-28 of Treatment Period 3 (Visit 20-Visit 21), and between Days 21-30 
(inclusive) of Treatment Period 5 (Visit 32) or at Early Termination to investigate 
changes to uric acid deposits. In addition, in any cohorts reopened for enrollment, at 
least 2 newly enrolled subjects per cohort will undergo DECT during the screening 
interval, between Days 21-28 of Treatment Period 3 (Visit 20-Visit 21), and between 
Days 21-30 (inclusive) of Treatment Period 5 (Visit 32) or at Early Termination to 
investigate changes to uric acid deposits.  


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In Part C, dual energy CT scans will be performed for Cohorts 13, 15, and 17 as 
described above. 
The summary statistics at baseline, and both the changes from baseline and percent 
change from baseline at the specified post-baseline time points in total urate volume 
(mL), knee volume (mL), hand/wrist volume (mL) and foot/ankle volume (mL). In 
addition, line plot of individual patients for total urate volume (mL), knee volume (mL), 
hand/wrist volume (mL) and foot/ankle volume (mL) over post-infusion days will be 
provided. 
9.6. 
DATA PRESENTATION FOR URIC ACID 
The actual sampling time of uric acid blood sample collection will be listed for each 
cohort and will include the deviation in time from the protocol scheduled time, if 
applicable. 
Individual subject serum concentration data and %CFB will be listed by subject, time 
point, and treatment group (combined placebo or dose group in relevant concentration 
units) and will be summarized at each time point by cohort. Baseline is defined as the 
last concentration of uric acid measured before dose for the 1st Treatment period and 
Cohort separately. 
Individual subject PD parameters derived using actual measurements and %CFB will be 
listed for the PD analysis set in a table by subject and will be summarized, by treatment 
group (combined placebo or dose group) and cohort. 
The table summarizing the number and % of the subjects maintaining sUA levels below 6 
mg/dL at the end of treatment period 3 (week 12, visit 22) and at the end of treatment 
period 5 (Week 20, visit 32)will be produced. 
Additionally the sUA concentrations for the week 12, visit 22 will be summarized in 
separate table including frequency of the subjects with sUA levels <6 mg/dL at this visit 
for a subset of population meeting the following eligibility criteria; 
1. Patients received entire 1st doses (without drug discontinuation) 
2. Patients did NOT discontinue due to a withdrawal of consent during Treatment 
Period 1 or TP2 
3. Patients did NOT discontinue due to a protocol deviation during Treatment Period 
1 or TP2 
4. Patients did NOT discontinue due to NON-study drug related (OR unlikely to be 
study drug related) SAE during TP1 or TP2 


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Additionally the sUA concentrations for the week 20, visit 32 will be summarized in 
separate table including frequency of the subjects with sUA levels <6 mg/dL at this visit 
for a subset of population meeting the following eligibility criteria; 
1. Patients received entire 1st doses (without drug discontinuation) 
2. Patients did NOT discontinue due to a withdrawal of consent during Treatment 
Period 1, TP2, TP3 or TP4 
3. Patients did NOT discontinue due to a protocol deviation during Treatment Period 
1 or TP2 
4. Patients did NOT discontinue due to NON-study drug related (OR unlikely to be 
study drug related) SAE during TP1 or TP2 
 
The following figures will be produced for Uric Acid: 
Mean time response profiles for uric acid concentration raw values and %CFB at each 
time point for each Treatment period and cohort plotted against time for each Cohort 
separately with curves for all Treatment periods overlaid on one plot. BLQ values for 
uric acid concentration will be assigned 0 values for linear scales and 1/10 of LLOQ 
values for all time points for the graphic representation on log-linear scales only. Actual 
measured concentrations will be presented on both linear and log-linear scales 
while %CFB profiles will be presented on linear scale only.  
Box plots for each derived PD parameter based on actual measurements and %CFB: 
CFBmin, AUECFBlast, TA_AUECFBlast will also be plotted by treatment.  
Individual profiles for uric acid concentration absolute values and %CFB will be plotted 
for each Treatment period and cohort on a separate plot. 
9.7. 
ASSESSMENT OF THE EFFECTS OF SEL-110 (RAPAMYCIN) AND SEL-037 
(PEGSITICASE) ON PD PARAMETERS OF URIC ACID 
Assessments done outside the assessment windows may be excluded from 
summarization. This will be determined prior to database lock. 
The key PD parameters based on measured values and %CFB %CFBmin, AUE%CFBlast, and 
TA_AUE%CFBlast as well as uric acid concentration and %CFB on day 21 of each treatment 
period will be analyzed using linear mixed model for the response to SEL-110 dose levels 
co-administered with either 0.2 or 0.4 mg/kg of SEL-037 (the dose level of SEL-110 for 
Cohorts 1 and 2 will be assigned as 0). Additionally contribution of SEL-110 to the PD 
effect of SEL-037 will be tested to compare the following (test – reference). For PD 


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parameters based on actual measured values baseline concentration of uric acid will be 
incorporated in the model as covariate. 
For Parts A and B following contrasts will be tested: 
Cohort 3 Part A vs Cohort 1 Part A 
Cohort 5 Part A vs Cohort 1 Part A 
Cohort 7 Part A vs Cohort 1 Part A 
Cohort 4 Part A vs Cohort 2 Part A 
Cohort 6 Part A vs Cohort 2 Part A 
Cohort 8 Part A vs Cohort 2 Part A 
Cohort 10 Part A vs Cohort 2 Part A 
Cohort 12 Part A vs Cohort 2 Part A 
Cohort 1 Part A vs Cohort 2 Part A 
Cohort 3 Part A vs Part B 
Cohort 5 Part A vs Part B 
Cohort 7 Part A vs Part B 
Cohort 4 Part A vs Part B  
Cohort 6 Part A vs Part B 
Cohort 8 Part A vs Part B 
Cohort 10 Part A vs Part B 
Cohort 12 Part A vs Part B 
For Part C (cohorts 13, 15, 17) additional contrasts will be: 
Cohort 13 treatment period 4 vs Cohort 11 treatment period 4 
Cohort 13 treatment period 5 vs Cohort 11 treatment period 5 
Cohort 15 treatment period 4 vs Cohort 11 treatment period 4 
Cohort 15 treatment period 5 vs Cohort 11 treatment period 5 
Cohort 15 treatment period 4 vs Cohort 13 treatment period 4 
Cohort 15 treatment period 5 vs Cohort 13 treatment period 5 
Cohort 17 treatment period 4 vs Cohort 11 treatment period 4 
Cohort 17 treatment period 5 vs Cohort 11 treatment period 5 
Cohort 17 treatment period 4 vs Cohort 13 treatment period 4 
Cohort 17 treatment period 5 vs Cohort 13 treatment period 5 
Cohort 17 treatment period 4 vs Cohort 15 treatment period 4 
Cohort 17 treatment period 5 vs Cohort 15 treatment period 5 


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Unstructured variance-covariance matrix will be used. If the model cannot converge or 
unable to make hessian positive definite, compound symmetry or other variance-
covariance matrices will be explored and used. 
Example SAS code will be: 
PROC MIXED DATA=data_set_name; 
CLASS subject_id treatment; 
MODEL loge(PD Parameter) = treatment /DDFM=KR; 
RANDOM subject_id / TYPE=UN; 
LSMEANS treatment / DIFFS CL; 
RUN; 
1. The following hypotheses will be tested: 
 
H01: µT/µR ≤ 80% vs. HA1: µT/µR > 80% 
and 
 
H02: µT/µR ≥ 125% vs. HA2: µT/µR < 125% 
If the 90% confidence interval (CI) for the geometric mean ratio (GMR) is within (80% – 
125%) for any of the contrasts for Cmax, AUC0-t and AUC0-inf, the null hypotheses, that is 
H01 and H02, will be rejected and we will conclude that the Test (T) is equivalent to the 
Reference (R). 
2. If bioequivalence cannot be established in step 1 above, the following hypothesis 
will be tested to explore noninferiority (1-sided test): 
 
H01: µT/µR ≤ 80% vs. HA1: µT/µR > 80% 
If the lower 90% CI bound for the GMR is greater than 80% for Cmax, AUC0-t and AUC0-inf, 
H01 will be rejected and we will conclude that the new therapy (T=Test) is no worse 
than the old therapy (R=Reference). 
The formula for calculation of the estimated ratio between the test and reference and 
the (1­2*α)*100 % CI of the ratio is given below. 
Difference = Estimate of difference between test and reference least square means 


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(1-2*α)*100% CIs for the Ratio: 
 
 
GMR ratio outside equivalence criteria 80-125% will demonstrate (1) dose effect SEL-
110; (2) synergy or additive effect of SEL-110 administration on PD by SEL-037. P-values 
will be generated for all contrasts. Values of p<0.05 will indicate statistical significance 
of the effect. 
The results of the comparisons will be graphically illustrated using box plots for Part A/B 
and comparison between Part C and B separately. 
Correlations between PD endpoints (Cmin, CFBmin, AUECFBlast, and TA_AUECFBlast) and PK 
parameters (Cmax, AUC0-last and AUC0-inf) for both SEL-110 and SEL-037 will be explored 
using Spearman correlation analysis. The correlations for Part C treatment periods will 
be presented in the separate table. 
The correlation between each of these PK (Cmax, AUC0-last and AUC0-inf) and PD (Cmin, 
CFBmin, AUECFBlast, and TA_AUECFBlast) parameters will also be explored and presented in a 
scatter plot with a regression line on it using simple linear regression which will have PK 
parameter as dependent variable and PD parameter as independent variable. The 
additional plots will be created for the Part C. 
Example SAS code will be: 
PROC GLM DATA=PKPDDATA; 
MODEL PD_parameter = PK_parameter; 
RUN; 
 
Difference
e
Ratio

100
)
%
)
*
2
-
(1
(
100
Difference
the
for
CIs
d
Boun
Lower
e
Lower



)
%
)
*
2
-
(1
(
100
Difference
the
for
CIs
d
Boun
Upper
e
Upper





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10. 
ANALYSIS OF IMMUNOGENICITY 
Immunogenicity endpoints include screening and confirmation results for IgG antibodies 
to pegsiticase, uricase, and IgM anti-PEG antibody. The titer for the antipegsiticase IgG 
antibodies will be determined during confirmation assay. The titer for the anti-uricase 
IgGs will be reported for positive samples. Preliminary concentration for anti-PEG IgM 
will be estimated in screening assay and confirmed in confirmation assay using multiple 
dilutions. 
The Parts A/B (Treatment periods 1-3 and 4-5 for cohorts 1-8, 10-12 respectively) will 
be presented together separately from Part C (cohorts 13, 15) unless necessary for 
comparative analysis. 
10.1. COLLECTION SCHEDULE 
Cohorts 1-8, 10, 11, 12 
Period 
Day 
Time from start of dose for 
saline, h  
Time from start of dose for SEL-037, 
h 
1-3 
0 
0 
-1 (0) 
 
7 
168 
167 
 
14 
336 
335 
 
21 
504 
503 
 
28* 
672 
671 
4-5 
0 
 
0 
 
7 
 
168 
 
14 
 
336 
 
21 
 
504 
 
28** 
 
672 
 
30*** 
 
720 
* - pre-dose for next Treatment period 
** - immunogenicity point for Treatment period 4 as pre-dose for Treatment period 5 
*** - last point for Treatment period 5 only 
Cohorts 13, 15 
Period 
Day 
Time from start of dose for 
saline, h  
Time from start of dose for SEL-037, 
h 
1-5 
0 
0 
-1 (0) 
 
7 
168 
167 
 
14 
336 
335 
 
21 
504 
503 
 
28* 
672 
671 
 
30** 
 
720 


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* - pre-dose for next Treatment period 
** - last point for Treatment period 5 only 
 
10.2. DERIVED AND IMPUTED DATA 
No imputation of missing immunogenicity data will be performed. 
 
10.3. DATA SUMMARIZATION 
Tables summarizing the frequency of the occurrence of ADAs by dose and by time point 
with overall summary per treatment will be produced for all cohorts separately and 
combined. The time of onset of immunogenicity, duration and number of resolved ADA 
cases will be summarized. 
10.4. DATA PRESENTATION FOR IMMUNOGENICITY 
Immunogenicity sampling times and results will be listed for safety analysis set outlined 
in Section 5.2 in this SAP. Immunogenicity endpoints include occurrence of anti-PEG, 
anti-pegsiticase, and anti-uricase specific antibodies based on screening assay and the 
titer for the anti-drug antibodies as identified in the confirmation assay.  
Frequency of occurrence of antibodies by study day and overall by cohort, time of onset 
immunogenicity and time of resolution of immunogenicity will be calculated and 
summarized by treatment in summary tables. Time of onset is defined as 1st time point 
with positive ADA result; time of resolution is defined as 1st time point when previously 
observed positive ADA result returns to baseline. Titer of antibodies against PEG, 
uricase and pegsiticase will be listed. The effect of possible antibody responses on PK 
and PD parameters will be evaluated descriptively.  
Cumulative positive ADA result for subject will be defined for each treatment period 
separately as at least one positive antibody post-dose time point for each Treatment 
period and Overall. The ADA positive subjects will be also stratified by the titer values 
for anti-pegsiticase and anti-uricase. The limits for titer values for low, moderate and 
high range will be identified based on percentiles after review of actual data (for 
example ≤30 percentile - low, 31-70 percentile - moderate, 71-100 percentile – high). 
Cumulative negative result will be defined as negative ADA result at all time points for a 
subject during each Treatment period.  
Following tables will be produced to evaluate effect of immunogenicity on PK: 


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 
Descriptive statistics of the key PD parameters based on measured values and 
%CFB %CFBmin, AUE%CFBlast, and TA_AUE%CFBlast as well as uric acid concentration and 
%CFB on day 21 of each treatment period for ADA positive and negative, ADA low, 
moderate and high titer groups including Q1, Q3, 5, 10, 90 and 95 percentiles. 
The data will be presented by cohort and overall. 
 
Descriptive statistics of the key PK parameters based on measured values and 
Cmax, Tmax, AUC0-last, and AUC0-inf for ADA positive and negative, ADA low, 
moderate and high titer groups including Q1, Q3, 5, 10, 90 and 95 percentiles. 
The data will be presented by cohort and overall. 
 
Frequency summary of subjects for ADA positive and negative results on day 21 
as well as titer groups stratified by stopping rule from the protocol – subjects 
who had serum uric acid (sUA) value less than or equal to 1.0 mg/dL at any of 
the Day 21 visits and were eligible for the next dosing of SEL-212 (or SEL-037) vs 
subjects who had > 1mg/dL sUA at this time point. The results for the treatment 
periods will be time-matched between immunogenicity testing and sUA 
concentration measurement. The data will be presented by cohort and overall. 
 
 
Additionally model for the evaluation of the dose effect of SEL-110 and SEL-037 
on PD results described in the section 9.6 of the SAP may be repeated with 
additional covariate for immunogenicity (cumulative positive, negative, positive 
low, high and moderate titer) to evaluate if immunogenicity had an additive or 
individual effect on the sUA as compared to the dose effect. 
 
Following plots will be presented for immunogenicity and PK parameters: 
Box and whiskers plot for comparison of CL values for SEL-037 (pegsiticase), Cmax, Tmax, 
AUC0-last, and AUC0-inf derived using both PK concentrations and uricase activity between 
subjects with cumulative positive and negative immunogenicity results for each antigen 
separately (PEG, uricase or pegsiticase) by Cohort with varying doses of SEL-110 and 
overall. The additional plots will be created for the Part C. 
Following plots will be presented for immunogenicity and PD parameters: 
Box and whiskers plot for comparison of Cmin, CFBmin, AUECFBlast and TA_AUECFBlast, 
%CFBmin, AUE%CFBlast and TA_AUE%CFBlast values for uric acid between subjects with 
cumulative positive and negative immunogenicity results for each antigen separately 
(PEG, uricase or pegsiticase) by cohort and overall. 


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10.5. ASSESSMENT OF THE EFFECTS OF IMMUNOGENICTY OF 
PHARMACOKINETICS OF SEL-037(PEGSITICASE) AND ON PD PARAMETERS OF 
URIC ACID 
The effect of possible antibody responses on PK parameters will be evaluated 
descriptively. 
Immunogenicity results will be compared descriptively between treatments using 
frequency of each type of ADA as main parameter as well as the time of onset of 
immunogenicity. 
The CL for SEL-037 (pegsiticase), Cmax, Tmax, AUC0-last, and AUC0-inf derived using both PK 
concentrations and uricase activity will be compared between subjects with cumulative 
negative and cumulative positive ADA results by Treatment period and cohort and 
overall for each cohort individually in the descriptive statistics table. 
Similarly, PD parameters Cmin, CFBmin, AUECFBlast, TA_AUECFBlast, %CFBmin, AUE%CFBlast and 
TA_AUE%CFBlast will be compared between subjects with cumulative negative and 
cumulative positive ADA results by Treatment period and cohort and overall for each 
cohort individually in the descriptive statistics table. 
No statistical inferences will be done for the comparisons. 


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11. 
SAFETY 
Safety analysis set will be used for safety analyses. Safety will be assessed on the basis 
of AE reports, clinical laboratory data, ECG parameters, physical examinations, and 
vital signs. 
11.1. 
EXTENT OF EXPOSURE 
Study drug administration and randomization schedule will be documented as per 
subject listings. Frequency counts of number of subjects who received all doses and 
descriptive statistics of doses and total cumulative doses by treatment group will be 
presented. 
11.2. 
TREATMENT COMPLIANCE  
Treatment compliance is defined as subjects receiving study drug as planned.  
Direct observation of the administration of the study drug by study staff will ensure 
compliance. The date and time of the start and stop of drug administration and volume 
infused will be listed. 
11.3. 
ADVERSE EVENTS 
All AEs will be coded and grouped into Preferred Terms (PT) by System Organ Class 
(SOC), using the most recent MedDRA Version. All AEs will be summarized by SOCs and 
PTs.  
By definition, the study only collects treatment-emergent adverse events (TEAEs) so all 
AEs are TEAEs. The percentage of subjects with specific TEAEs will be summarized for 
each cohort and part (Part A and Part B and Part C).  
All AEs will be listed by treatment, subject, SOC, and PT. 
TEAEs will be summarized (number of events, number and % of subjects having 
experienced at least one event) by treatment, SOC, and PT. TEAEs will be also be 
summarized by intensity and causality. SAEs will be listed and summarized by causality.  
Clinical study report narratives will be prepared for deaths, other serious adverse 
events, and withdrawals due to adverse events. 
11.4. 
LABORATORY EVALUATIONS 
Laboratory data will be summarized by the type of laboratory test. Normal reference 


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ranges and markedly abnormal results will be used in the summary of laboratory data. 
Data will be flagged according to the reference limits (High or Low), if applicable. 
Descriptive statistics will be calculated for each laboratory analyte at baseline and at 
each scheduled time point for each dose and treatment. Changes from baseline results 
will be presented descriptively as well as in pre- versus post-treatment cross tabulations 
(with classes for below, within, and above normal ranges). A listing of subjects with any 
laboratory results outside the reference ranges will be provided. 
11.5. 
VITAL SIGNS  
Pulse, temperature, respiration rate, and systolic and diastolic blood pressure will be 
analyzed. Data will be flagged according to the reference limits (High or Low), if 
applicable. Descriptive statistics on actual values and changes from baseline by dose 
will be computed at each scheduled time point. Plots (mean ± standard error of the 
mean [SEM]) on changes from baseline over time will be given as appropriate. 
Vital sign data will also be listed. 
11.6. 
ELECTROCARDIOGRAM  
The ECG variables that will be analyzed are heart rate, RR interval, PR interval, QRS 
interval, QT interval, QTcB, and QTcF. The ECG measurements will be summarized at 
each time point of measurement. The change from baseline will be summarized. 
Descriptive statistics on actual values and changes from baseline by dose and time will 
be computed. Plots (mean ± SEM) on changes from baseline over time will be provided. 
A listing of abnormal clinically significant evaluations as well as a listing of subjects 
with abnormal QTcF/QTcB values (>450, >480 and >500 ms) and of subjects with 
abnormal QTcF/QTcB changes from baseline (≥ 30 but <60; ≥ 60) will be provided. 
All important abnormalities from the ECG readings, including changes in T wave 
morphology and/or the occurrence of U waves versus baseline recordings, will be 
included in the AE listing.   
11.7. 
PHYSICAL EXAMINATION 
Physical examination will be performed at Screening and early termination. 
Physical examination data will be listed. 
 
 


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12. 
INTERIM ANALYSES 
No interim analysis is planned for this study. 


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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
No changes from the analysis planned in the protocol have been made.  
 
 


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14. 
REFERENCE LIST 
1. Gough K, Hutchinson M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. 
Assessment of Dose Proportionality: Report from the Statisticians in The 
Pharmaceutical Industry/Pharmacokinetics UK joint working party. Drug Inf J. 
1995; 29:1039-1048. 
2. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, 
Forgue ST. Confidence interval criteria for assessment of dose proportionality, 
Pharmaceutical Research, Volume 17, Number 10, October 2000. 
3. Hummel J, McKendrick S, Brindley C and French, R. Exploratory assessment of 
dose proportionality: review of current approaches and proposal for a practical 
criterion. Pharmaceut. Statist. 2009; 8: 38-49. 
4. Maganti L, Panebianco DL, Maes AL. Evaluation of Methods for Estimating Time to 
Steady State with Examples from Phase 1 Studies. The AAPS Journal. 2008; 
10(1):141-147. 
5. Kenward, M. G. and J. H. Roger Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics, 1997, 53(3), 983–997. 
 
 


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15. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications.  
15.1. 
GENERAL CONSIDERATIONS 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Rich Text Format. 
 
Numbering of TFLs will follow ICH E3 guidance 
15.2. 
TABLE, LISTING, AND FIGURE FORMAT 
15.2.1. General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8  
 
The data displays for all TLFs will have a minimum 1-inch margin on all 4 sides. 
 
Headers and footers for figures will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no color), unless otherwise specified 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used (see below). 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display math symbols (e.g., μ). Certain subscripts and 
superscripts (e.g., cm2, Cmax) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 


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15.2.2. Headers 
 
All output should have the following header at the top left of each page: 
SELECTA Biosciences 
Protocol SEL–212/201    
      
 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the table). 
 
All output should have date of data (Data as of DDMMMYYYY) on bottom of each 
page.  
 
The date output was generated should appear along with the program name as a 
footer on each page. 
15.2.3. Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
ICH E3 numbering is strongly recommended but sponsor preferences should be 
obtained prior to final determination. A decimal system (x.y and x.y.z) should be 
used to identify TLFs with related contents. The title is centered. The analysis set 
should be identified on the line immediately following the title. The title and table 
designation are single spaced. A solid line spanning the margins will separate the 
display titles from the column headers. There will be 1 blank line between the last 
title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
Safety Set 
15.2.4. Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  


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 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
 
The order of treatments in the tables and listings will be Placebo first in the case of 
placebo controlled studies and Active comparators first in the case of active 
comparator trials, followed by a total column (if applicable). 
15.2.5. Body of the Data Display 
15.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
• 
alphanumeric values are left-justified; 
• 
whole numbers (e.g., counts) are right-justified; and 
• 
numbers containing fractional portions are decimal aligned. 
15.2.5.2. Table Conventions 
 
Units will be included where available 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 


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moderate 
8 
mild 
3 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
XX 
Mean (SD) 
XX.X (XX.XX) 
Median (Min, Max) 
XX.X(XX.X, XX.X) 
95% CI 
(XX,XX, XX,XX) 
 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999 
 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0. A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  


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 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page. The overall summary statistics for the subheading should only be 
output on the first relevant page. 
15.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 


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 
Units will be included where available 
15.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
15.2.6. Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas  Listing source: 16.x.y.z’). 


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 Syneos Health © LLC 
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16. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. Syneos Health SOP 
03.010.00 and 03.013.00 provide an overview of the development of such SAS programs. 
Syneos Health SOP 03.009.00 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output.