Clinical trial NCT04602390
Conditions: Multiple Sclerosis (MS) Relapsing Remitting Multiple Sclerosis
Keywords: Autoimmune Multiple Sclerosis (MS) Relapsing Remitting MS
Sponsor: Anokion SA
Start date: 2020-11-06; Completion date: 2024-04-23
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A safety study of ANK-700 in patients with relapsing remitting multiple sclerosis. The study has two parts:

Part A - first in human study in which patients receive a single dose of ANK-700 Part B - patients will receive three doses of either ANK-700 or placebo

Detailed description:
Study ANK-700-01 is a Phase 1, FIH study designed to evaluate the safety and tolerability of ANK-700 in patients with relapsing remitting multiple sclerosis (rrms).

An overview of the two parts and proposed dose groups is given below:

Part A (SAD): Patients will receive a single dose of ANK-700. Part B (MAD): Patients will receive three doses of either ANK-700 or placebo.

Arms: arm 1: All enrolled patients will receive one dose of 0.3 mg/kg ANK-700 arm 2: All enrolled patients will receive one dose of 1.0 mg/kg ANK-700 arm 3: All enrolled patients will receive one dose of 3.0 mg/kg ANK-700 arm 4: All enrolled patients will receive three doses of 0.3 mg/kg ANK-700 or placebo arm 5: All enrolled patients will receive three doses of 1.0 mg/kg ANK-700 or placebo
Interventions: intervention 1: ANK-700 intervention 2: Placebo
Intervention descriptions: intervention 1: Intravenous (IV) infusion intervention 2: Intravenous (IV) infusion

Protocol documents:
Prot_000.pdf: 
ANK-700 
Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
Page 1 of 68 
 
 
 
STUDY PROTOCOL 
ANK-700-01 
A Phase 1 Study of the Safety and Tolerability of Single and 
Multiple Doses of ANK-700 in Patients with Relapsing-Remitting 
Multiple Sclerosis 
 
Protocol Number: ANK-700-01 
Phase: 1 
Date of Protocol: 06 June 2022 
Version: Version 4  
IND: 22932 
Sponsor: Anokion US, Inc. 
50 Hampshire St., Suite 402 
Cambridge, MA 02139 
 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of 
Anokion US, Inc. The protocol is for use by the Principal Investigator and his or her designated 
representatives participating in this investigational study. This protocol may not be copied or 
made available for review by an unauthorized person or organization without the prior written 
authorization of Anokion US, Inc. 


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Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
Page 2 of 68 
 
INVESTIGATOR APPROVAL  
I have read both the latest version of the ANK-700 Investigator’s Brochure and Protocol 
ANK-700-01 and agree to the terms of this study protocol. I will conduct the study according to 
the procedures specified herein, and according to principles of Good Clinical Practice (GCP) and 
local regulations and requirements. 
 
Institution/Clinic:   
Principal Investigator 
Print Name:   
Signature:  
Date (dd/mmm/yyyy):  
 
 
 


ANK-700 
Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
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SPONSOR APPROVAL 
 
 






ANK-700 
Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
Page 6 of 68 
Methodology  
This is a 2-part, multicenter, Phase 1 study of ANK-700 in patients with RRMS. The 2 parts 
include: 
• Part A – First-in-human, single ascending dose (SAD) cohorts 
• Part B – Randomized, double-blind, PBO-controlled, multiple ascending dose (MAD) 
cohorts 
Part A and Part B will be conducted in adult patients (18 to 60 years inclusive, at screening), 
diagnosed with RRMS, and an EDSS score ≤ 6.5. Patients receiving a stable dose of a 
fumarate drug (i.e., dimethyl fumarate, diroximel fumarate) for ≥ 6 months will be allowed to 
remain on the fumarate drug throughout the study.  
A copy of the EDSS is available in Appendix 2. 
Part A – SAD 
The SAD part will include up to 3 cohorts of 3 patients each. Patients within each dose cohort 
will each receive 1 dose of ANK-700 intravenously (IV) and will be monitored for up to 
6 months. Patients will be dosed ≥ 14 days apart to monitor for acute and subacute reactions. 
Patients will arrive at the clinic on the morning of dosing (Day 1 [D1]) and will be monitored 
in the clinic for 8 hours after completion of the ANK-700 infusion for assessment of acute 
safety and PK blood sample collection. Patients will return to the clinic on D4±1, D15, D29±1, 
and at 3 and 6 months for follow-up.  In the event that patients are unable to return to the clinic 
for protocol-specified visits, alternative methods for safety assessments and data collection 
may be employed to ensure the safety of the patient where appropriate. 
Doses evaluated in Part A will include 0.3 mg/kg (Cohort 1), 1.0 mg/kg (Cohort 2), and 
3.0 mg/kg (Cohort 3). After all patients within a given dose cohort have been followed for 
≥ 14 days post-dose, a safety review will be performed by the Safety Monitoring Committee 
(SMC) to review all adverse events (AEs) and available laboratory test and PK data. Initiation 
of the next higher dose level will commence upon recommendation by the SMC and approval 
by the Sponsor. 
Please see Table 1 for the complete schedule of assessments for Part A. 
Part B - MAD 
The first MAD cohort (Cohort 4) will be initiated after the safety review of SAD Cohort 2, a 
recommendation to proceed by the SMC, and approval from the Sponsor. 
Patients in the MAD cohorts will be randomized 2:1 to either ANK-700 or PBO. Patients will 
be stratified based upon their use of fumarate medications at study entry within the interactive 
response technology system. A total of 12 patients will be enrolled per dose cohort (ANK-700, 
n = 8; PBO, n = 4). Patients will arrive at the clinic on the morning of dosing and will be 
monitored in-clinic for 8 hours after completion of their first infusion for assessment of acute 
safety and PK blood sample collection. A total of 3 doses (1 dose every 3 days) will be 


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Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
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administered in Part B, a regimen that was effective in animal models of multiple sclerosis 
(MS). Patients will return to the clinic on D22, D43, and at 3, 6, and 12 months for follow-up. 
In the event that patients are unable to return to the clinic for protocol-specified visits, 
alternative methods for safety assessments and data collection may be employed to ensure the 
safety of the patient where appropriate. 
Doses planned for evaluation in Part B include 0.3 mg/kg (Cohort 4) and 1.0 mg/kg 
(Cohort 5). Both Part B cohorts will employ sentinel dosing to monitor for the acute and 
subacute safety of multiple doses of ANK-700. In this design, the first 2 patients in a cohort 
(1 ANK-700 and 1 PBO) will complete all 3 doses and then complete an additional 14 days of 
safety monitoring (through D22) before dosing can be initiated in any further patients.   
Cohort 5 will only commence after review of the safety, tolerability, and available PK data of 
all the SAD cohorts (Cohorts 1 to 3) and Cohort 4, recommendation by the SMC, and approval 
by the Sponsor.  
Please see Table 2 for the complete schedule of assessments for Part B. 
Number of Patients (Planned) 
It is anticipated that the study will enroll approximately 33 to 42 patients across 5 dose 
cohorts.  
Part A (SAD) will enroll approximately 9 to 18 patients across 3 dose cohorts using a 
3+3 dose escalation design without intra-patient dose escalation. In Part A, patients may be 
replaced if they do not receive the full dose of study drug or do not complete the D15 visit, as 
long as they did not discontinue the study because of dose-limiting toxicity (DLT). No patient 
with a DLT will be replaced. 
Part B (MAD) will enroll approximately 24 patients across 2 dose cohorts. Sixteen patients 
will receive ANK-700 and 8 patients will receive PBO. In Part B, patients may be replaced if 
they do not receive all 3 doses and complete the D22 visit, as long as they did not discontinue 
the study because of a DLT. No patient with a DLT will be replaced. 
Starting Dose and Dose Escalation 
The starting dose of ANK-700 will be 0.3 mg/kg based on findings from Good Laboratory 
Practice (GLP) toxicology studies and animal models in MS, which identified the 
pharmacologically active doses.  
Part A will employ a 3+3 design to evaluate single ascending doses of ANK-700. At any dose 
level, if none of the first 3 patients dosed experience a DLT within 14 days of treatment, then 
escalation to the next dose level may proceed if recommended by the SMC and approved by 
the Sponsor. If 1 of the first 3 patients in the cohort experiences a DLT within 14 days of 
treatment (D1 to D15), the dose level may expand to a maximum of 6 patients. If no DLT 
occurs among the additional patients enrolled at that dose level, then escalation to the next 
dose level may proceed if recommended by the SMC and approved by the Sponsor. The first 


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Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
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MAD cohort (Cohort 4) will be initiated after the safety review of SAD Cohort 2 (Part A), a 
recommendation to proceed by the SMC, and approval by the Sponsor. Cohort 5 will only 
commence after review of the safety, tolerability, and available PK data of all the SAD cohorts 
(Cohorts 1 to 3) and Cohort 4, recommendation by the SMC, and approval by the Sponsor.  
DLTs include any Grade 2 AE not resolving within 14 days or any ≥ Grade 3 AE occurring 
during the dose-escalation safety monitoring period (D1 to D15 in Part A; D1 to D22 in 
Part B).  
Any ≥ Grade 4 AE will result in notification to the Food and Drug Administration (FDA) in 
parallel with the SMC; all study dosing and enrollment will be paused pending review by the 
FDA.    
The non-tolerated dose (NTD) is the dose level at which > 1 patient experiences a DLT during 
the dose-escalation safety monitoring period (D1 to D15 in Part A; D1 to D22 in Part B). The 
maximum tolerated dose (MTD) will be defined as the proximal dose level below the NTD 
administered during the study. Of note, dose escalation may not identify an NTD or MTD.  
Safety Monitoring Committee 
This study will utilize an independent SMC that will meet regularly during dose escalation to 
review all available data, including safety and PK. The SMC will make recommendations 
concerning dose escalation and/or any changes to the dosing paradigm based on review of the 
received data. The SMC will also make recommendations about the dose(s) selected for 
Part B. The final decisions related to dose escalation or the dosing paradigm will be made by 
the Sponsor. 
Inclusion Criteria  
Key Inclusion Criteria 
1. Male or female adults aged 18 to 60 years inclusive at screening 
2. Diagnosed with RRMS per revised McDonald criteria (2017) with an EDSS 
score ≤ 6.5 at screening 
3. Neurologically stable with no evidence of relapse within the 28 days before signing the 
informed consent form (ICF)  
Note: Patients who experienced relapse during the screening period (i.e., after signing 
the ICF but before dosing) may be rescreened after 28 days 
4. Either not currently receiving disease modifying MS therapy, or currently using 
fumarate drugs (i.e. dimethyl fumarate, diroximel fumarate)   
Note: Patients on fumarate drugs are only eligible if they have been on a stable dose 
≥ 6 months before administration of study drug 
5. Patients must use a highly effective method of birth control or are sterile or 
postmenopausal as confirmed by study Investigator for the first 3 months (through 
D90) of the study 


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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
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6. Patient has signed and understands the ICF 
Key Exclusion Criteria 
1. Diagnosis of primary progressive MS or secondary progressive MS  
2. Uncontrolled or significant medical conditions (including active infection, chronic 
hepatitis, or Neuromyelitis Optica Spectrum Disorder) which, in the opinion of the 
Investigator, preclude participation 
3. Has any of the following laboratory parameters at screening: 
a. Hemoglobin < 10 g/dL 
b. Platelet count < 100 × 109/L 
c. White blood cell count outside the normal range and assessed as clinically 
significant by the Investigator 
d. Alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase 
> 1.5 × the upper limit of normal 
e. Estimated glomerular filtration rate < 60 mL/min/1.73 m2 based on the 
Cockcroft-Gault equation during screening 
4. Positive for HIV, hepatitis B virus, or hepatitis C virus 
5. Patients treated with glatiramer acetate, parenteral steroids or adrenocorticotropic 
hormone, β-interferon, or plasma exchange within the 3 months prior to first dose 
6. Patients treated with sphingosine-1-phospate receptor modulators such as fingolimod, 
ozanimod, or siponimod within 6 months prior to first dose 
7. Patients treated with cytotoxic agents (including, but not limited to, cladribine, 
mitoxantrone, cyclophosphamide, azathioprine, and methotrexate), laquinimod, 
teriflunomide, or IV gamma globulin within 12 months prior to first dose  
8. Patients treated with monoclonal antibody therapy (including natalizumab, daclizumab, 
rituximab, ofatumumab, and ocrelizumab) within 24 months prior to first dose except 
anti-severe acute respiratory syndrome coronavirus 2 monoclonal antibodies 
9. Patients previously treated with alemtuzumab, total lymphoid irradiation, mesenchymal 
stem cell or hematopoietic stem cell transplantation, or tolerance-inducing therapies for 
MS 
10. Patients receiving any vaccination within 28 days prior to first dose 
11. Patients with clinical signs and symptoms consistent with suspected COVID-19 or 
confirmed COVID-19 infection by appropriate laboratory test within the last 4 weeks 
prior to screening or on admission  
Note: Patients who experienced symptoms consistent with COVID-19 or confirmed 
infection during the screening period (i.e., after signing the ICF but before dosing) may 
be rescreened after 4 weeks  
12. Patients with a prior severe course of COVID-19 requiring extracorporeal membrane 
oxygenation (ECMO) or mechanical ventilation  


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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
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13. Patient does not agree to limit alcohol intake to 2 drink equivalents or less per day 
during the study 
14. Contraindication to or inability to undergo gadolinium-enhanced magnetic resonance 
imaging (MRI) scan 
15. Use of any investigational drug or experimental procedure within previous 6 months 
that would interfere with the assessment of ANK-700 
16. Patients who are pregnant or breastfeeding 
Investigational Product, Dosage, and Mode of Administration  
 
 Administration of ANK-700 
 will be by 
IV infusion over approximately 30 minutes. For Part A, patients will receive a single 
IV infusion of ANK-700. For Part B, patients will receive a total of 3 IV infusions, 
administered 3 days apart, of either ANK-700 or PBO. 
Study Duration per Patient  
The maximum duration of study participation for patients in Part A is approximately 210 days, 
which includes a screening period of up to 28 days, followed by a single dose of ANK-700 on 
D1, and clinic visits on D4, D15, D29, and at 3 and 6 months. 
The maximum duration of study participation for patients in Part B is approximately 393 days, 
which includes a screening period of up to 28 days, followed by 3 doses of ANK-700 or PBO 
on D1, D4, and D7, and clinic visits on D22, D43, and at 3, 6, and 12 months. 
Assessment of Safety 
Safety will be assessed through the monitoring of AEs, clinical laboratory, vital signs, and 
physical examination findings, and disease relapse through EDSS and MRI evaluations.  
Patients will be monitored continuously for AEs from the signing of the ICF until the final 
follow-up visit. AE severity will be assessed using the National Cancer Institute Common 
Terminology Criteria for AEs (NCI-CTCAE) version 5.0 or higher.  
In relation to patient safety during the COVID-19 pandemic, current national laws and local 
recommendations should be strictly adhered to during the study.  
Patient safety will be evaluated during Part A (SAD) and Part B (MAD) to determine dose 
escalation. The dose-escalation safety monitoring period in Part A is from the single 
IV administration of ANK-700 through the D15 clinic visit. The dose-escalation safety 
monitoring period in Part B is from the first IV administration of ANK-700 through the D22 
clinic visit. In both parts, patients will be monitored in the clinic for AEs for 24 hours after 
completion of the first IV infusion. In Part B, patients will be monitored in the clinic for AEs 
for 4 hours after completion of the second and third IV infusion. Any DLT experienced during 


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Anokion US, Inc. 
Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
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the dose-escalation safety monitoring period will result in a pause in the study and review of 
all the available safety data by the SMC before treating additional patients and/or continuing 
dose escalation.  
Primary Endpoint  
• Incidence and severity of treatment-emergent AEs as assessed by the NCI-CTCAE 
v5.0 or higher 
Secondary Endpoint  
• Plasma concentrations and PK parameters of ANK-700 
  
 
   
 
 
Pharmacokinetics 
PK samples will be collected during both Part A and Part B to understand the PK profile of 
escalating doses of ANK-700 in humans. PK parameters and concentration data will be 
summarized for Part A and Part B and will be combined for doses with more than 2 patients in 
each dose group.   
In Part A and Part B, samples for PK assessment will be collected according to the schedules 
outlined in Table 1 and Table 2.  
Statistical Methods 
Statistical methods will be descriptive. No hypothesis will be formally tested. For Part A and 
Part B, summary statistics will be provided by cohort. For Part B only, placebo-treated patient 
data will be pooled. Categorical variables will be summarized using numbers and percentages. 
Continuous variables will be summarized by total number (n), mean, standard deviation, 
median, and range (minimum and maximum). 
For the first dose, Part A and Part B will be pooled and summarized for demographic and PK 
analysis. A formal statistical analysis plan will be developed and finalized before study 
database lock. 
 
 
 














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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
Version 4 (06 June 2022) 
CONFIDENTIAL 
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TABLE OF CONTENTS 
INVESTIGATOR APPROVAL ......................................................................................................2 
SPONSOR APPROVAL .................................................................................................................3 
CONTACT INFORMATION ..........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
BACKGROUND ................................................................................................25 
1.1. 
Multiple Sclerosis ...............................................................................................25 
1.2. 
ANK-700.............................................................................................................25 
1.3. 
Selection of Patient Populations .........................................................................26 
1.4. 
Determination of Doses and Regimen ................................................................27 
2. 
OBJECTIVES .....................................................................................................28 
2.1. 
Primary ................................................................................................................28 
2.2. 
Secondary ............................................................................................................28 
2.3. 
 
3. 
ENDPOINTS ......................................................................................................29 
3.1. 
Primary Endpoint ................................................................................................29 
3.2. 
Secondary Endpoint ............................................................................................29 
3.3. 
 
4. 
STUDY DESIGN................................................................................................30 
4.1. 
PART A – Single Ascending Dose .....................................................................30 
4.2. 
PART B – Multiple Ascending Dose..................................................................31 
4.3. 
Dosing Frequency ...............................................................................................33 
4.4. 
Blinding...............................................................................................................33 
4.5. 
Monitoring of Adverse Events ............................................................................34 
4.6. 
Dose-Limiting Toxicities ....................................................................................34 
4.7. 
Dose Escalation Safety Monitoring Period .........................................................34 
4.8. 
Safety Monitoring Committee ............................................................................35 


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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
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4.9. 
Individual and Cohort Stopping Rules ................................................................35 
4.10. 
Treatment Discontinuation..................................................................................35 
4.11. 
Study Withdrawal ...............................................................................................36 
5. 
STUDY POPULATION .....................................................................................37 
5.1. 
Inclusion Criteria ................................................................................................37 
5.2. 
Exclusion Criteria ...............................................................................................37 
6. 
STUDY PROCEDURES AND ASSESSMENTS ..............................................39 
6.1. 
Screening and Treatment Procedures and Assessments .....................................39 
6.1.1. 
Informed Consent................................................................................................39 
6.1.2. 
Inclusion and Exclusion Criteria .........................................................................39 
6.1.3. 
Medical History, Demographics, and Disease History .......................................39 
6.1.4. 
Concomitant Medications and Procedures..........................................................39 
6.1.5. 
Expanded Disability Status Scale (EDSS) Assessment ......................................39 
6.1.6. 
Physical Examination and Vital Signs ................................................................40 
6.1.7. 
Electrocardiogram ...............................................................................................40 
6.1.8. 
Brain Magnetic Resonance Imaging ...................................................................40 
6.1.9. 
Clinical Laboratory Tests ....................................................................................41 
6.1.10. 
ANK-700 Administration ...................................................................................42 
6.1.11. 
Pharmacokinetic Sampling .................................................................................42 
6.1.12. 
Antidrug Antibody Sampling ..............................................................................42 
6.1.13. 
 
6.1.14. 
 
6.1.15. 
Adverse Events ...................................................................................................43 
6.2. 
Safety Follow-up Visit ........................................................................................43 
7. 
CONCOMITANT MEDICATIONS ..................................................................44 
7.1. 
Prohibited Concomitant Therapies .....................................................................44 
7.2. 
Permitted Concomitant Therapies.......................................................................44 
7.3. 
Treatment for Symptoms of MS .........................................................................45 
8. 
CONTRACEPTION AND PREGNANCY ........................................................46 
9. 
OTHER RESTRICTIONS RELATED TO COVID-19 .....................................47 


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10. 
ANK-700 MATERIALS AND MANAGEMENT .............................................48 
10.1. 
ANK-700 and Placebo ........................................................................................48 
10.2. 
Dosage and Administration.................................................................................48 
10.3. 
Storage ................................................................................................................48 
10.4. 
Post-Infusion Medications ..................................................................................49 
10.5. 
Infusion-Related Reactions .................................................................................50 
10.6. 
Drug Accountability............................................................................................50 
10.7. 
Assignment to Treatment ....................................................................................51 
11. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ............52 
11.1. 
Adverse Events ...................................................................................................52 
11.1.1. 
Definition of an Adverse Event ..........................................................................52 
11.1.2. 
Protocol-Defined MS Relapse ............................................................................52 
11.1.3. 
Definition of a Serious Adverse Event ...............................................................52 
11.2. 
Procedures for Recording and Reporting Adverse Events .................................53 
11.2.1. 
Recording Adverse Events ..................................................................................53 
11.2.2. 
Relationship to ANK-700 ...................................................................................53 
11.2.3. 
Adverse Event Severity.......................................................................................54 
11.2.4. 
Abnormal Laboratory Values .............................................................................54 
11.2.5. 
Medication Errors, Misuse, and Abuse of ANK-700 .........................................55 
11.2.6. 
Reporting of Serious Adverse Events .................................................................55 
11.2.7. 
Reporting of Serious Adverse Events to Regulatory Authorities, Ethics 
Committee, and Institutional Review Board .......................................................56 
11.2.8. 
Pregnancy and In Utero Drug Exposure .............................................................56 
12. 
STATISTICAL METHODS ...............................................................................58 
12.1. 
Sample Size .........................................................................................................58 
12.2. 
Analysis Sets .......................................................................................................58 
12.3. 
Background Characteristics ................................................................................58 
12.3.1. 
Patient Disposition ..............................................................................................58 
12.3.2. 
Demographics and Baseline Characteristics .......................................................59 
12.4. 
ANK-700 Exposure ............................................................................................59 
12.5. 
Safety Analyses ...................................................................................................59 


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12.6. 
Adverse Events ...................................................................................................59 
12.7. 
Clinical Laboratory Assessments ........................................................................60 
12.8. 
Pharmacokinetic Analyses ..................................................................................60 
12.9. 
Analysis of Antidrug Antibodies ........................................................................61 
12.10. 
 
12.11. 
 
13. 
STUDY ADMINISTRATION............................................................................62 
13.1. 
Good Clinical Practice Statement .......................................................................62 
13.2. 
Informed Consent................................................................................................62 
13.3. 
Patient Confidentiality ........................................................................................62 
13.4. 
Institutional Review Board/Ethics Committee Requirements ............................63 
13.5. 
Case Report Forms and Source Documentation .................................................63 
13.6. 
Study Monitoring ................................................................................................63 
13.7. 
Quality Assurance ...............................................................................................64 
13.8. 
Study or Clinical Site Termination .....................................................................64 
13.9. 
Duration of the Study, Expected Duration of Patient Participation, and End of 
Study ...................................................................................................................64 
13.10. 
Records Retention ...............................................................................................65 
13.11. 
Publications .........................................................................................................65 
14. 
REFERENCES ...................................................................................................66 
APPENDIX 1. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V5.0 
(CTCAE) .............................................................................................................67 
APPENDIX 2. EXPANDED DISABILITY STATUS SCALE (EDSS) ....................................68 
 
 
 
 
 
 


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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments Part A (SAD) .....................................................................12 
Table 2: 
Schedule of Assessments Part B (MAD) COHORT 4 ONLY ...................................14 
Table 3: 
Schedule of Assessments Part B (MAD) COHORT 5 ONLY ...................................16 
Table 4: 
List of Abbreviations and Definitions of Terms .........................................................23 
Table 5:  
Pharmacokinetic Parameter Definitions .....................................................................61 
LIST OF FIGURES 
Figure 1: 
Overview of Study ANK-700-01................................................................................33 
 
 
 
 
 


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Study ANK-700-01 in Relapsing-Remitting Multiple Sclerosis 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 4: 
List of Abbreviations and Definitions of Terms 
Acronym / Abbreviation 
Definition 
ADA 
Anti-drug antibodies 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CIS 
Clinically isolated syndrome 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019, caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) 
CS 
Clinically significant 
D 
Study day 
DLT 
Dose-limiting toxicity 
DMT 
Disease modifying therapy 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDSS 
Expanded disability status scale 
 
 
FDA 
Food and Drug Administration 
FIH 
First in human 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
 
 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent ethics committee 
 
 
IRB 
Institutional review board 


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Acronym / Abbreviation 
Definition 
IRR 
Infusion-related reaction 
IRT 
Interactive response technology 
IV 
Intravenous 
LEC 
Local ethics committee 
mAb 
Monoclonal antibody 
MAD 
Multiple ascending dose 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging 
MS 
Multiple sclerosis  
MTD 
Maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute common terminology criteria for adverse 
events 
NOAEL 
No observed adverse effect level 
NTD 
Non-tolerated dose 
 
 
PBO 
Placebo 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
PK 
Pharmacokinetics 
PI 
Principal investigator 
PPMS  
Primary progressive multiple sclerosis 
RRMS 
Relapsing-remitting multiple sclerosis 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SMC 
Study Monitoring Committee 
SPMS 
Secondary progressive multiple sclerosis 
StD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood cell 
WCBP 
Women of childbearing potential 
 


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1. 
BACKGROUND 
1.1. 
MULTIPLE SCLEROSIS 
Multiple sclerosis (MS) is a chronic and often disabling autoimmune disease of the central 
nervous system (CNS) characterized by loss of motor, sensory, cognitive, and autonomic 
function. The prevalence has increased noticeably, with a recent study determining the 
prevalence in the United States to be 309 per 100,000, and more commonly occurring (2.8 times 
higher) in women than men (Wallin 2019). The prevalence of MS varies with geography and 
ethnicity, with northern Europeans having the highest prevalence (Leray 2016). MS is associated 
with the human leukocyte antigen (HLA) DRB1*15:01 allele, and patients with a homozygous 
genotype have an increased risk, both for susceptibility of inheriting the disease and in the 
severity of their disease (Barcellos 2003).  
The course and disease progression vary depending on the type of MS. Relapsing forms of MS, 
including relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), typically 
evolve over time, displaying early signs of inflammation and neurodegeneration, but progress to 
non-relapsing disability. Primary progressive MS (PPMS) lacks the initial relapsing-remitting 
course and typically results in earlier disability compared to relapsing MS. Clinically isolated 
syndrome (CIS) is classified as the first episode exhibiting 1 or more neurological symptoms for 
≥ 24 hours. If the diagnosis of MS is subsequently confirmed, CIS represents the first relapse. 
Diagnosis of MS is typically made after a symptomatic attack using magnetic resonance imaging 
(MRI) and the McDonald criteria (Thompson 2018).  
The characteristic pathology of MS includes perivenular inflammatory lesions, which produce 
demyelination and axonal damage (Frohman 2006). The inflammation is autoimmune, involving 
T cells reactive to myelin self-antigens (Allegretta 1990, Bronge 2019, Zhang 1994). During the 
RRMS phase of the disease, the peripheral immune response against myelin is thought to drive 
the disease process (Hemmer 2015). 
1.2. 
ANK-700 
ANK-700 is a synthetic 
 composed of a CNS-derived synthetic peptide, 
ANK-07, 
 to enable liver-specific distribution 
and immune tolerance induction. The mechanism of action of ANK-700 harnesses natural 
tolerogenic pathways in the liver to re-educate pathogenic immune cells to become tolerant 
towards MS antigens. ANK-700 specifically targets the immune cells that drive MS and leaves 
the otherwise healthy components of the immune system intact to perform their natural, 
protective functions. Surrogates of ANK-700 have demonstrated efficacy in mouse models of 
MS. The mechanism by which ANK-700 induces immunologic tolerance is mediated by 
3 mechanisms: 
• Deletion of antigen-specific T cells 
• Induction of anergy/clonal exhaustion of antigen-specific T cells 
• Induction of regulatory T cells which control the antigen-specific T-cell response 


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Previous clinical research exploring the use of altered peptide ligands, derived from myelin 
peptides, to induce immunological tolerance in MS patients have observed an exacerbation of 
disease and/or an increase in inflammatory lesions (Bielekova 2000). However, subsequent 
studies using different peptide sequences and technologies to induce antigen-specific T-cell 
tolerance to myelin antigens have not shown these effects (Chataway 2018, Zubizarreta 2019). 
Treatment for RRMS depends upon patient characteristics and comorbidities, the severity and 
activity of disease, and the safety profile of available therapies (Montalban 2018). Many current 
therapies suppress or modulate the immune system, but without the ability to target specific 
antigens. Many of the approved therapies for RRMS require vigilant monitoring against 
toxicities, including serious infections. There remains an unmet medical need for effective, 
targeted, well-tolerated therapies to treat RRMS.   
For more information on the nonclinical findings, please see the ANK-700 Investigator’s 
Brochure. 
This first-in-human (FIH) study will be conducted in patients with RRMS with the aim of 
evaluating the tolerability of single and multiple intravenous (IV) administrations of ANK-700. 
1.3. 
SELECTION OF PATIENT POPULATIONS 
An RRMS patient population has been selected for the FIH study of ANK-700. T cells that react 
to myelin antigens have been observed in healthy subjects (Hellings 2001). Considering the 
potential risk that treatment with antigen-specific tolerizing agents in healthy subjects may 
provoke symptoms consistent with MS, an RRMS patient population is considered appropriate 
for this FIH study.  
The study population includes adults with RRMS based on revised McDonald criteria (2017) 
with an Expanded Disability Status Scale (EDSS) score ≤ 6.5. Patients must be neurologically 
stable with no evidence of relapse within the 28 days before signing the informed consent form. 
These criteria have been implemented to evaluate the safety and tolerability of ANK-700 in a 
diverse RRMS population which has an appropriate risk/benefit profile based upon the severity 
of their disease. Efficacy is not being assessed in this study and enrolled patients are not 
expected to receive direct clinical benefit from treatment with ANK-700. The population 
selected for this study (i.e., those with relatively well controlled and neurologically stable 
RRMS) is appropriate for the FIH study, as highly active disease may obscure the assessment of 
safety and tolerability of ANK-700 and may require active management during the study period. 
Patients who experience a relapse during screening may be rescreened after 28 days. Patients 
who have renal or hepatic impairment will be excluded. The age range will be limited to 
patients 18 to 60 years to avoid confounding by the possible neurological conditions prevalent in 
older individuals.  
Patients will be allowed to remain on stable doses of fumarates (dimethyl fumarate or diroximel 
fumarate) during the study because fumarate drugs do not interfere with the mechanism of action 
of ANK-700. Because both dimethyl fumarate and diroximel fumarate are metabolized to the 


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same active metabolite, either drug will be allowed during the study. Patients using any other 
disease modifying therapies (DMT) to treat MS will be excluded.  
1.4. 
DETERMINATION OF DOSES AND REGIMEN 
The planned doses of ANK-700 in this FIH study allow for a robust characterization of the safety 
and pharmacokinetics (PK) profile of ANK-700 encompassing pharmacologically active doses 
identified in nonclinical models of MS. The cumulative toxicology, safety pharmacology, and 
PK data acquired from animal studies support dosing of ANK-700 in humans. A 4-week repeat-
dose Good Laboratory Practice (GLP) toxicity study examining doses up to 87.5 mg/kg in naïve 
Sprague Dawley rats demonstrated no significant findings at any dose of ANK-700 examined. 
The no-observed-adverse-effect-level (NOAEL) was established as 87.5 mg/kg (the highest dose 
tested) from the GLP study, which supports a starting dose of 0.3 mg/kg in the FIH study, a dose 
that is more than 40-fold lower than the NOAEL.  
In nonclinical mouse models of MS, administration of surrogate molecules of ANK-700 were 
effective at ameliorating disease. From these nonclinical models, it was concluded: 
• Doses of surrogate molecules equivalent to 0.3 to 7.2 mg/kg of ANK-700 have 
demonstrated efficacy on disease severity in nonclinical models of MS. 
• Three doses of surrogate molecules administered every 3 days was significantly more 
effective in inducing tolerance and improving disease outcome compared with 3 doses 
administered weekly. 
The starting dose of 0.3 mg/kg was chosen based on the pharmacologically active doses 
observed in nonclinical models of disease and is supported by the NOAEL. For additional 
information on the dose selection and safety margins, please see the Investigator’s Brochure.  
In Part A (single ascending dose [SAD]), 3 escalating dose groups are planned: 0.3 mg/kg 
(Cohort 1), 1.0 mg/kg (Cohort 2), and 3.0 mg/kg (Cohort 3). The dosing schedule requires that 
successively higher doses will only be administered after the safety, tolerability, and available 
PK data of the preceding dose group have been evaluated by the Safety Monitoring Committee 
(SMC) and dose escalation is approved by the Sponsor. If necessary, doses may be adjusted 
based on the PK and safety findings of the preceding dose group(s) with a protocol amendment.  
For Part B (multiple ascending dose [MAD]), Cohort 4 will be initiated only after SMC review 
of the SAD Cohort 2, recommendation by SMC, and approval by the Sponsor. Part B will 
examine multiple doses (3) of ANK-700 and includes 2 escalating dose cohorts: 0.3 mg/kg 
(Cohort 4) and 1.0 mg/kg (Cohort 5). During Part B, ANK-700 will be administered every 3 days 
for a total of 3 doses. Cohort 5 will only commence after review of the safety, tolerability, and 
available PK data of all the SAD cohorts (Cohorts 1 to 3) and Cohort 4, recommendation by the 
SMC, and approval by the Sponsor. 
Based on data obtained during both the SAD and MAD parts of the study, the protocol may be 
amended to explore additional higher dose levels and alternative dosing schedules if supported 
by the data, recommended by the SMC, and approved by the Sponsor. 




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3. 
ENDPOINTS 
3.1. 
PRIMARY ENDPOINT  
• Incidence and severity of treatment-emergent adverse events (TEAEs) as assessed by the 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 or higher 
3.2. 
SECONDARY ENDPOINT 
• Plasma concentrations and PK parameters of ANK-700 
3.3. 
  
 
   
 
 
 
 


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Version 4 (06 June 2022) 
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4. 
STUDY DESIGN 
Study ANK-700-01 is a Phase 1, FIH study designed to evaluate the initial safety, tolerability, 
and activity of ANK-700 in patients with RRMS. An overview of the 2 parts and proposed dose 
cohorts is presented in Figure 1.  
4.1. 
PART A – SINGLE ASCENDING DOSE 
The SAD phase will include up to 3 cohorts with 3 patients each. Patients within each dose 
cohort will receive 1 dose of ANK-700 IV and will be monitored for up to 6 months. All patients 
in Part A will be dosed ≥ 14 days apart to monitor for acute and subacute reactions; this length of 
time is supported by nonclinical exposure data that suggest ANK-700 will have cleared > 5 half-
lives and nonclinical animal model data demonstrating that the tolerance induction mechanism 
can develop and immunologically active peptide is cleared within 1 week from dosing (see 
Section 4.7 for more information).  
Patients will arrive at the clinic on the morning of dosing (Day 1 [D1]) and will be monitored in-
clinic for 8 hours after completion of ANK-700 infusion for assessment of acute safety and PK 
blood sample collection. A follow up phone call 24 hours after dosing must be performed to 
ensure the patient did not experience any acute safety events after discharge.  
• If patients are experiencing active AE(s) which require clinical monitoring at the end of 
the clinic/hospital unit monitoring period, they should not be discharged and followed up 
per PI assessment 
• If feasible, patients should be advised to have someone stay with them after discharge 
until 24 hours have elapsed after study drug administration on D1. 
• If patients do not live within 1-hour travel time of an emergency medical facility, they 
should remain in the clinic/hospital unit for the first 24 hours after study drug 
administration. 
• Patients should be instructed not to drive themselves to seek emergency medical 
treatment at any time during the study. 
Doses evaluated in Part A include 0.3 mg/kg (Cohort 1), 1.0 mg/kg (Cohort 2), and 3.0 mg/kg 
(Cohort 3). After all patients within a given dose cohort have been followed for ≥ 14 days post-
dose, a safety review will be performed by the SMC to review all adverse events (AEs) and 
available clinical laboratory and PK data. Initiation of the next dose level will commence upon 
recommendation by the SMC and approval by the Sponsor. 
Part A will employ a 3+3 design to evaluate single ascending doses of ANK-700. At any dose 
level, if none of the first 3 patients dosed experience a dose-limiting toxicity (DLT) within the 
dose-escalation safety monitoring period (D1 to D15), then escalation to the next dose level may 
proceed if recommended by the SMC and approved by the Sponsor. If 1 of the first 3 patients in 
the cohort experiences a DLT within the dose-escalation safety monitoring period (D1 to D15), 
the dose level may expand to a maximum of 6 patients. If no DLT occurs among the 3 additional 


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patients enrolled at that dose level, then escalation to the next dose level may proceed if 
recommended by the SMC and approved by the Sponsor.  
For all patients in Part A, the study will consist of a 28-day screening period, a single dose of 
ANK-700 administered on D1, and an 8-hour monitoring period in the clinic/hospital unit and a 
phone call 24 hours after dosing. Patients will return to the clinic on D4±1, D15, and D29±1. 
Additionally, patients will return to the clinic after 3 and 6 months for follow-up. Blood and 
serum samples will be collected for PK and anti-drug antibody (ADA) assessments during Part 
A. Patients in Part A may be replaced if they do not receive the full dose of study drug or do not 
complete the D15 visit, as long as the discontinuation was not due to a DLT. In the event that 
patients are unable to return to the clinic for protocol-specified visits, alternative methods for 
safety assessments and data collection may be employed to ensure the safety of the patients 
where appropriate. 
Please see Table 1 for the complete schedule of assessments for Part A. 
4.2. 
PART B – MULTIPLE ASCENDING DOSE 
The first MAD cohort (Cohort 4) will be initiated after the safety review of SAD Cohort 2 
(Part A), a recommendation to proceed by the SMC, and approval by the Sponsor. 
Patients in the MAD part will be randomized 2:1 to either ANK-700 or PBO. Patients will be 
stratified based upon their use of fumarate at study entry within the interactive response 
technology (IRT) system. A total of 12 patients will be enrolled per dose cohort (ANK-700, 
n = 8; PBO, n = 4). Patients will arrive at the clinic on the morning of dosing and will be 
monitored in-clinic for 8 hours after completion of their first infusion for assessment of acute 
safety and PK blood sample collection. A follow up phone call 24 hours after dosing will be 
performed to ensure the patient did not experience any acute safety events after discharge.  
• If patients are experiencing active AE(s) which require clinical monitoring at the end of 
the clinic/hospital unit monitoring period they should not be discharged and followed up 
per PI assessment 
• If feasible, patients should be advised to have someone stay with them after discharge 
until 24 hours have elapsed after study drug administration on D1. 
• If patients do not live within 1-hour travel time of an emergency medical facility, they 
should remain in the clinic/hospital unit for the first 24 hours after study drug 
administration. 
• Patients should be instructed not to drive themselves to seek emergency medical 
treatment at any time during the study. 
A total of 3 doses (1 dose every 3 days on D1, D4, and D7) will be administered in Part B, a 
regimen that was effective in animal models of MS. Patients will return to the clinic on D22, 
D43±2, and at 3, 6, and 12 months for follow-up.  


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Doses planned for evaluation in Part B include 0.3 mg/kg (Cohort 4) and 1.0 mg/kg (Cohort 5). 
Both Part B cohorts will employ sentinel dosing to monitor for the acute and subacute safety of 
multiple doses of ANK-700. In this design, the first 2 patients in each cohort (1 ANK-700 and 1 
PBO) will complete all 3 doses and complete an additional 14 days of safety monitoring (through 
D21) before initiating dosing for any subsequent patients. Based upon the expected short half-life 
(< 7 minutes) of ANK-700, no accumulation is anticipated with multiple doses administered 
3 days apart. 
After all patients within the first MAD cohort (Cohort 4) have been followed for 21 days, a 
safety review will be performed by the SMC to review all AEs and available laboratory test and 
PK data from Cohort 4 and all SAD cohorts. Initiation of Cohort 5 will only commence after 
review of the safety, tolerability, and available PK data of all the SAD cohorts (Cohorts 1 to 3) 
and Cohort 4 through D22, recommendation by the SMC, and approval by the Sponsor.   
For all patients in Part B, the study will consist of a screening period of up to 28 days, followed 
by 3 doses of ANK-700, 1 dose administered on D1, D4, and D7. The first dose on D1 will be 
followed by a 8-hour monitoring period in the clinic/hospital unit; each additional dose will be 
followed by a 4-hour monitoring period in the clinic/hospital unit. Blood and serum samples will 
be collected for PK and ADA assessments during Part B of the study. Patients in Part B may be 
replaced if they do not receive the full 3 doses of study drug or do not complete the D22 visit, as 
long as the discontinuation was not due to a DLT.  In the event that patients are unable to return 
to the clinic for protocol-specified visits, alternative methods for safety assessments and data 
collection may be employed to ensure the safety of the patients where appropriate. 
Please see Table 2 for the complete schedule of assessments for Part B. 
 
 


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Figure 1: 
Overview of Study ANK-700-01 
 
Single Ascending Dose (SAD) (Part A): 3 patients will be dosed IV with ANK-700 in each cohort. Initiation of 
the next dose cohort will commence once all patients in a cohort reach D15 and upon acceptable safety review 
and recommendation by SMC and approval by the Sponsor.  
Multiple Ascending Dose (MAD) (Part B): the first MAD cohort (Cohort 4) will be initiated only after acceptable 
safety review of SAD Cohort 2, recommendation by the SMC, and approval by the Sponsor. Patients are 
randomized 2:1 to ANK-700 or PBO. Initiation of Cohort 5 will commence once all patients in Cohort 4 reach 
D22 and upon acceptable safety review of Cohorts 1 to 4, recommendation by the SMC, and approval by the 
Sponsor.  
Abbreviations: D = day; IV = intravenously; MAD = multiple ascending dose; PBO = placebo; SAD = single 
ascending dose; SMC = Safety Monitoring Committee.  
4.3. 
DOSING FREQUENCY  
In Part A, patients will receive a single IV infusion of ANK-700 on D1.  
In Part B, patients will receive a total of 3 IV infusions of either ANK-700 or PBO 
(double-blind). A single IV infusion will be administered on D1, D4, and D7.   
4.4. 
BLINDING 
Part A is open-label. 
Part B is double-blinded, such that study personnel (e.g., investigators, site coordinators) and 
patients are blinded to treatment assignments and will remain blinded throughout the study.   
Unblinded personnel include those involved in drug preparation and allocation (e.g., data 
systems support and pharmacists) and those involved in SMC data preparation, including the 
study pharmacokineticist, to allow for expedited review of PK data before SMC review.  
The data reviewed for dose escalation in Part B will be presented and reviewed by the SMC in a 
blinded fashion.   
 
 


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If a medical emergency occurs, the site may be unblinded if knowledge of the study treatment is 
necessary to provide appropriate urgent medical care. 
4.5. 
MONITORING OF ADVERSE EVENTS 
Patients will be monitored continuously for AEs while on study. AE severity will be assessed 
using the NCI-CTCAE v5.0 or higher (Appendix 1).  
4.6. 
DOSE-LIMITING TOXICITIES 
Dose-limiting toxicities for Study ANK-700-01 include any Grade 2 AE not resolving within 
14 days or any ≥ Grade 3 AE occurring during the dose-escalation safety monitoring period (D1 
to D15 in Part A; D1 to D22 in Part B). DLTs do not include those AEs attributable solely to 
intercurrent illness or other concomitant medications. Any DLT experienced during the dose-
escalation safety monitoring period will result in study pause and review by the SMC.  
Any ≥ Grade 4 AE will result in notification to the Food and Drug Administration (FDA) in 
parallel with the SMC; all study dosing and enrollment will be paused pending review by FDA.    
4.7. 
DOSE ESCALATION SAFETY MONITORING PERIOD  
In Part A, the dose-escalation safety monitoring period is from the beginning of the 
IV administration of ANK-700 through the D15 clinic visit. Any AEs that meet the criteria 
defined in Section 4.6 but occur after the dose-escalation safety monitoring period of Part A, 
may be considered by the SMC in the evaluation for Part B dose selection.  
The dose-escalation safety monitoring period in Part B is from the beginning of the first 
IV administration of ANK-700/PBO through the D22 clinic visit.  
The monitoring period is supported by nonclinical animal data, which demonstrate: 
• ANK-700 is cleared from circulation in < 7 minutes, ensuring that > 5 half-lives have 
elapsed during the safety monitoring period 
• T-cell tolerance induction can be observed as early as 1 week after drug administration in 
nonclinical models, ensuring the mechanism of action will be active and robust during the 
safety monitoring period 
• Immunologically active antigen cannot be detected in animals 7 days after GP-peptide 
administration, ensuring that any processed antigen will be cleared during the safety 
monitoring period 
AEs and any abnormal clinical parameters, including laboratory findings, observed during this 
period will be used by the SMC to determine whether dose escalation should proceed.  
No patient with a DLT will be replaced.  
In both parts, patients will be monitored in the clinic for 8 hours after the completion the first IV 
administration of ANK-700/PBO. In Part B, patients will be monitored in the clinic for 4 hours 
after completion of their second and third dose.  


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4.8. 
SAFETY MONITORING COMMITTEE 
This study will utilize an independent SMC that will meet regularly during dose escalation to 
review all accumulated and available data, including safety and PK. The SMC will be composed 
of 3 independent medical reviewers, including at least 1 medical expert in MS, as voting 
members. Non-voting members will include the study Medical Monitor, a medical representative 
from the Sponsor, and other relevant study and site staff as required to address study conduct. 
The SMC will make recommendations concerning dose escalation and/or any changes to the 
dosing paradigm based on review of the received data. The SMC will also make 
recommendations about the dose(s) selected for Part B. The final decisions related to dose 
escalation or the dosing paradigm will be made by the Sponsor. 
4.9. 
INDIVIDUAL AND COHORT STOPPING RULES 
During the dose-escalation safety monitoring period, any DLT will result in a pause in 
enrollment and a thorough review by the SMC before treating any additional patients. Any 
≥ Grade 4 AE will result in notification of the FDA in parallel with the SMC, and study dosing 
and enrollment will be paused pending review by FDA.    
For Part A, if 1 of the first 3 patients experiences a DLT within the safety monitoring period (D1 
to D15) in a given cohort, 3 additional patients will be enrolled and evaluated in that cohort 
before dose escalation can occur if recommended by the SMC and only after consultation with 
the FDA for any ≥ Grade 4 AE. If 2 or more patients experience a DLT at a given dose level 
during the dose escalation evaluation period of Part A (D1 to D15), then that dose level will be 
considered to have exceeded the non-tolerated dose (NTD), and no further escalation will 
proceed.  
If a patient experiences a DLT during the dose-escalation safety monitoring period of Part B, no 
additional doses will be administered to that patient. If 1 patient experiences a DLT during the 
dose-escalation safety monitoring period of Part B, the study will be paused to determine if any 
dose adjustments are needed and/or if the study should dose any additional patients. For 
any ≥ Grade 4 AE, the study will only continue after consultation with the FDA. If 2 or more 
patients experience a DLT during the dose-escalation safety monitoring period of Part B (D1 to 
D22), then that dose level will be considered to have exceeded the NTD, and no further 
escalation will proceed. 
The maximum tolerated dose (MTD) will be defined as the proximal dose level below the dose 
exceeding the NTD administered during the study. Of note, dose escalation may not identify an 
NTD or MTD. 
4.10. 
TREATMENT DISCONTINUATION  
Patients will be discontinued from treatment for any of the after reasons: 
• An AE that requires permanent discontinuation of study treatment* 
• Noncompliance with the protocol  


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• Investigator decision  
• patient becomes pregnant 
• patient death 
• patient lost to follow-up  
• termination of the study by the Sponsor 
• voluntary withdrawal of consent by patient  
*AEs leading to the discontinuation of ANK-700 will be followed until resolution, resolution to baseline, or until the 
event is considered stable or chronic. 
The reason for treatment discontinuation will be documented. 
All patients will have a final follow-up approximately 6 months (D182 ± 7) after the single dose 
of ANK-700 in Part A and approximately 1 year (D365 ± 14) after the first dose in Part B unless 
the patient withdraws from the study prematurely (Section 4.11). 
4.11. 
STUDY WITHDRAWAL  
Patients may voluntarily withdraw from the study at any time for any reason without prejudice.  
Patients will be withdrawn from the study for any of the following reasons: 
• Investigator’s decision  
• Patient death 
• Patient lost to follow-up  
• Termination of the study by the Sponsor 
• Voluntary withdrawal of consent by patient 


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5. 
STUDY POPULATION 
5.1. 
INCLUSION CRITERIA 
1. Male or female adults aged 18 to 60 years inclusive at screening 
2. Diagnosed with RRMS per revised McDonald criteria (2017) with an EDSS score ≤ 6.5 
at screening  
3. Neurologically stable with no evidence of relapse within the 28 days prior to signing the 
informed consent form (ICF)  
Note: Patients who experienced relapse during the screening period (i.e., after signing the 
ICF but before dosing) may be rescreened after 28 days 
4. Either not currently receiving disease modifying MS therapy or currently using fumarate 
drugs (i.e. dimethyl fumarate, diroximel fumarate)  
Note: Patients on fumarate drugs are only eligible if they have been on a stable dose 
≥ 6 months before administration of study drug 
5. Patients must use a highly effective method of birth control or are sterile or 
postmenopausal as confirmed by study Investigator for the first 3 months (through D90) 
of the study 
6. Patient has signed and understands the ICF 
5.2. 
EXCLUSION CRITERIA 
1. Diagnosis of PPMS or SPMS 
2. Uncontrolled or significant medical conditions (including active infection, chronic 
hepatitis, or Neuromyelitis Optica Spectrum Disorder) which, in the opinion of the 
Investigator, preclude participation 
3. Has any of the following laboratory parameters at screening: 
a. Hemoglobin < 10 g/dL 
b. Platelet count < 100 x 109/L 
c. White blood cell count outside the normal range and assessed as clinically 
significant by the Investigator 
d. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline 
phosphatase (ALP) > 1.5 × the upper limit of normal 
e. Estimated glomerular filtration rate < 60 mL/min/1.73 m2 based on the 
Cockcroft-Gault equation during screening 
4. Positive for HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) 
5. Patients treated with glatiramer acetate, parenteral steroids or adrenocorticotropic 
hormone, β-interferon, or plasma exchange within the 3 months prior to first dose 
6. Patients treated with sphingosine-1-phospate receptor modulators such as fingolimod, 
ozanimod, or siponimod within 6 months prior to first dose 


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7. Patients treated with cytotoxic agents (including but not limited to cladribine, 
mitoxantrone, cyclophosphamide, azathioprine, and methotrexate), laquinimod, 
teriflunomide, or IV gamma globulin within 12 months prior to first dose 
8. Patients treated with monoclonal antibody (mAb) therapy (including natalizumab, 
daclizumab, rituximab, and ocrelizumab) within 24 months prior to first dose except anti-
severe acute respiratory syndrome coronavirus 2 monoclonal antibodies 
9. Patients receiving any vaccination within 28 days prior to first dose 
10. Patients previously treated with alemtuzumab, total lymphoid irradiation, mesenchymal 
stem cell or hematopoietic stem cell transplantation, or tolerance-inducing therapies for 
MS 
11. Patients with clinical signs and symptoms consistent with suspected COVID-19 or 
confirmed COVID-19 infection by appropriate laboratory test within the last 4 weeks 
prior to screening or on admission  
Note: Patients who experienced symptoms consistent with COVID-19 or confirmed 
infection during the screening period (i.e., after signing the ICF but before dosing) may 
be rescreened after 4 weeks  
12. Patients with a prior severe course of COVID-19 requiring extracorporeal membrane 
oxygenation or mechanical ventilation  
13.  Patient does not agree to limit alcohol intake to 2 drink equivalents or less per day during 
the study 
14. Contraindication to or inability to undergo gadolinium-enhanced MRI scan 
15. Use of any investigational drug or experimental procedure within previous 6 months that 
would interfere with the assessment of ANK-700 
16. Patients who are pregnant or breastfeeding   
 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
Time points for assessments collected throughout the study can be found in the Schedule of 
Assessments (Table 1 and Table 2). A brief description of each assessment can be found below. 
6.1. 
SCREENING AND TREATMENT PROCEDURES AND ASSESSMENTS  
6.1.1. 
Informed Consent 
An ICF must be signed by prospective patients before initiating any study-specific procedures. 
Standard of care assessments performed prior to ICF signing may fulfill study eligibility 
requirements if performed within the screening period. Patients will be required to sign ICF for 
rescreening. 
6.1.2. 
Inclusion and Exclusion Criteria 
Inclusion and exclusion criteria (Section 5) will be reviewed for each potential patient. Eligibility 
will be documented in the electronic case report form (eCRF).  
6.1.3. 
Medical History, Demographics, and Disease History 
Complete medical history will be obtained, including demographics, previous therapies, and 
disease history. MS is considered part of medical history and should include: 
• duration since MS symptom onset  
• duration since MS diagnosis  
• number of relapses within the last year and 3 years 
• date of last relapse 
• previous MS treatment(s) 
6.1.4. 
Concomitant Medications and Procedures 
At screening, concomitant medications will be recorded. Assessment of any change in 
concomitant medications, or procedures since the last visit will occur at all further patient visits 
through the final Follow-Up Visit. 
6.1.5. 
Expanded Disability Status Scale (EDSS) Assessment 
Assessment of EDSS score will be captured at the time points specified in the Schedule of 
Assessments (Table 1 and Table 2). The EDSS is based on a standard neurological examination, 
incorporating the pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, and cerebral 
[or mental] functional systems, and ambulation, rated and scored as functional system scores. 
The EDSS is a disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death) 
(Kurtzke 1983). The EDSS must be administered by a certified examiner. All patients with new 


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neurological symptoms suggestive of relapse may have an EDSS assessment performed during 
an unscheduled visit, if appropriate (see Section 11.1.2). 
If the screening EDSS has been completed within 3 months of scheduled dosing it would not 
need to be repeated as long as the screen fail is not due to MS relapse.  If the patient needs to re-
screen due to experiencing an MS relapse during the screening period, the patient must wait at 
least 28 days from the relapse resolution and then a new screening EDSS should be obtained.   
6.1.6. 
Physical Examination and Vital Signs 
A full physical examination (PE) and vital signs check will be performed at the time points 
specified in the Schedule of Assessments (Table 1 and Table 2). PEs will also be conducted as 
clinically indicated. 
The PE will include an assessment of general appearance, skin, head, neck, throat, lymph nodes, 
cardiovascular, neurological, thyroid, musculoskeletal/extremities, respiratory, abdomen, height, 
and weight (baseline only). Vital signs will include temperature, pulse rate, and diastolic and 
systolic blood pressure (sitting for 5 minutes). If vital signs need to be repeated during a single 
visit, assessments should be conducted approximately 5 minutes apart.  
Any new clinically significant (CS) abnormality from baseline should be recorded as an AE. 
6.1.7. 
Electrocardiogram  
At screening, a standard 12-lead electrocardiogram (ECG) will be obtained and interpreted by 
the Investigator to confirm eligibility. If the screening ECG has been completed within 3 months 
of scheduled dosing it would not need to be repeated 
At screening, ECGs will be conducted after approximately 10 minutes of rest and obtained as 
outlined in Table 1 and Table 2. 
6.1.8. 
Brain Magnetic Resonance Imaging 
As outlined in Table 1 and Table 2, screening and post-dose brain MRIs will be performed. 
Scans will be performed by trained and certified MRI technicians. The MRI will include the 
acquisition of scans at each time point with and without IV administered gadolinium contrast 
enhancement. 
The following time windows apply: 
• “Screening/baseline” MRI should be performed on or after the Screening Visit, but 
≥ 10 days before the D1 visit. 
• The MRI obtained for the Part A D15 Visit and Part B D22 Visit should be performed up 
to 3 days before or on the scheduled visit day. 
• MRI at Part B visit D90 should be performed within 2 weeks of the scheduled visit. 
MRIs will be performed for assessment of safety only and will be reviewed locally.  


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If a relapse occurs at the time of a scheduled MRI, the MRI should be obtained before initiation 
of corticosteroid therapy or the MRI should be postponed by 1 month.  
If the screening MRI has been completed within 3 months of scheduled dosing it would not need 
to be repeated as long as the screen fail is not due to MS relapse.  If the patient needs to re-screen 
due to experiencing an MS relapse during the screening period, the patient must wait at least 28 
days from the relapse resolution and then a new screening MRI should be obtained (and the re-
screening MRI must be at least 28 days from last MRI assessment).   
All patients with new neurological symptoms suggestive of MS relapse should have an MRI 
performed (which may include the spinal column) during an unscheduled visit, if clinically 
necessary, but before the initiation of steroids (see Section 11.1.2).  
Additional details on MRI acquisition procedures are described the imaging acquisition 
guidelines. 
6.1.9. 
Clinical Laboratory Tests 
The following laboratory parameters will be measured at screening and at the time points 
specified in the Schedule of Assessments (Table 1 and Table 2) and will be analyzed locally by a 
certified laboratory: 
• A serum pregnancy test during screening for all women of childbearing potential 
(WCBP) 
• Serum or urine pregnancy testing for all WCBP before each dose 
• Hematology laboratory parameters include white blood cell (WBC) count, hemoglobin, 
hematocrit, platelet count, and WBC differential  
• Blood chemistry laboratory parameters, including blood urea nitrogen, creatinine, 
glucose, AST, ALT, ALP, bilirubin (total and direct), electrolytes (sodium, chloride, 
bicarbonate, potassium), amylase, lipase, albumin, magnesium, calcium, and phosphorus 
• Coagulation laboratory parameters, including prothrombin time, partial thromboplastin 
time or activated partial thromboplastin time, and international normalized ratio 
• Complete urinalysis with qualitative analysis for protein (dipstick)  
• HIV, HBV (hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface 
antibody), and HCV testing (screening only) 
Unscheduled assessments should be performed as clinically indicated. 
For any out-of-range laboratory findings during screening, repeat laboratory testing may be 
performed at the discretion of the Investigator. Abnormal laboratory findings at screening should 
be recorded as medical history only if considered CS.   
Clinical laboratory assessments should be performed before ANK-700/PBO infusion when 
applicable.  


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Laboratory findings assessed by the Investigator as CS, including but not limited to, those 
findings resulting in a drug interruption/hold/reduction/discontinuation or medical intervention, 
should be repeated to verify the out-of-range findings, followed to a satisfactory clinical 
resolution, and reported as an AE(s) (see Section 11.1.1 for definition of an AE).  
6.1.10. 
ANK-700 Administration 
Detailed instructions on the administration of ANK-700 can be found in Section 10. 
6.1.11. 
Pharmacokinetic Sampling 
PK sample collection time points are shown in Table 1 and Table 2.  
The exact date and time of each sample collection must be recorded for all collected samples. 
Refer to the ANK-700-01 Laboratory Manual for details on processing, storage, and shipment of 
PK samples. 
6.1.12. 
Antidrug Antibody Sampling 
Blood sample collection time points are shown in Table 1 and Table 2.  
The exact date and time of each sample collection must be recorded for all collected samples. 
Refer to the ANK-700-01 Laboratory Manual for details on processing, storage, and shipment of 
ADA samples. 
6.1.13. 
 
 
 
 
6.1.14. 
 
 
  
 
 
 
 
 
 
 
 


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6.1.15. 
Adverse Events 
All AEs should be captured on the source documentation and eCRF from the time of signing of 
ICF through the final Follow-Up Visit/phone call. AEs leading to treatment discontinuation and 
those considered at least possibly related to ANK-700 should be followed until resolution, return 
to baseline, or deemed chronic or stable.   
All serious adverse events (SAEs) will be immediately reported to the Sponsor from the time of 
signing the ICF through the Follow-Up Visit/phone call or until the patient has been deemed to 
be a screen failure. After completion of the AE reporting period (i.e., through the final Follow-
Up Visit/phone call), only SAEs attributed to ANK-700 must be reported to the Sponsor. 
See Section 11.2 for a full description of the collection and reporting of AEs during this study.   
6.2. 
SAFETY FOLLOW-UP VISIT 
All patients in Part A will have a final Follow-Up Visit at D182 (±7 days), 6 months after the 
single administration of ANK-700.  
All patients in Part B will have a final Follow-Up Visit at D365 (±14 days), approximately 1 year 
after the first administration of ANK-700.  
Ongoing AEs considered at least possibly related to ANK-700 treatment should be followed until 
resolution, return to baseline, or are considered stable or chronic. 
 
 


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7. 
CONCOMITANT MEDICATIONS 
7.1. 
PROHIBITED CONCOMITANT THERAPIES  
During the first 3 months of the study period, any DMTs not listed as a permitted concomitant 
therapy to treat RRMS (Section 7.2) or other investigational agents are prohibited, including 
biologic or nonbiologic therapies. All vaccines are prohibited within 4 weeks before dosing and 
for 2 months after dosing. Patients should avoid taking biotin-containing dietary supplements 
throughout the duration of the study. 
Patients previously treated with any of the following DMTs must adhere to the washout periods 
outlined below: 
• 3-month washout  
− glatiramer acetate, parenteral steroids, or adrenocorticotropic hormone, 
β-interferon, plasma exchange  
• 6-month washout 
- fingolimod, ozanimod, or siponimod 
• 12-month washout 
− cytotoxic agents (including but not limited to cladribine, mitoxantrone, 
cyclophosphamide, azathioprine, and methotrexate), laquinimod, teriflunomide, 
or IV gamma globulin 
• 24-month washout 
− mAb therapy (including natalizumab, daclizumab, rituximab, and ocrelizumab) 
After patients have completed the 3-month visit (D90), they may receive alternative DMTs for 
their MS if judged clinically appropriate by their treating physician or the Investigator. 
7.2. 
PERMITTED CONCOMITANT THERAPIES 
Patients currently on a stable dose of fumarate (dimethyl fumarate or diroximel fumarate) for 
≥ 6 months will be allowed to remain on fumarate throughout the study. The dose should remain 
stable during the screening period and for the first 3 months of the study unless medically 
necessary to alter. 
Any medication considered necessary for the patient’s welfare, including non-DMTs used to 
treat symptoms of MS (e.g., antispasmodics or antidepressants), that is not expected to interfere 
with the clinical evaluation of ANK-700 may be given at the discretion of the Investigator. In 
cases involving concomitant therapies whose predicted interference with ANK-700 is unknown 
to the Investigator, the Sponsor should be contacted for discussion.  
Any medication (including over the counter or prescription medications, vitamins, and/or herbal 
supplements) that the patient receives after enrollment through the last study visit must be 
recorded on the eCRF. 


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7.3. 
TREATMENT FOR SYMPTOMS OF MS  
Patients who experience a relapse during the treatment period may receive treatment with IV 
methylprednisolone or oral corticosteroids, if judged to be clinically appropriate by the 
Investigator. If a relapse occurs at the time of a scheduled MRI, the MRI should be obtained 
before initiation of corticosteroid therapy or should be postponed by 1 month. 
See Section 11.1.2 for the protocol-defined criteria for an MS relapse. 
 
 


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8. 
CONTRACEPTION AND PREGNANCY 
The effects of ANK-700 on conception, pregnancy, and lactation are unknown. 
At screening, all patients who are not surgically sterile or postmenopausal must agree to use a 
medically acceptable methods of birth control as confirmed by study Investigator (e.g., use of an 
intrauterine device, a barrier method with spermicide, condoms, any form of hormonal 
contraceptives, or partner sterility) for the first 3 months of the study (through D90). Hormonal 
forms of birth control must have been in continuous use for ≥ 3 months prior to screening to 
ensure their effectiveness. Complete sexual abstinence is only acceptable when it is the 
usual/preferred lifestyle of the patient and has been so for ≥ 3 months before screening. Periodic 
abstinence, calendar timing methods of contraception, or withdrawal are NOT acceptable 
methods of contraception. 
A serum pregnancy test will be administered during screening for all WCBP. A serum or urine 
pregnancy test will be administered to all WCBP before each dose of study drug and must be 
confirmed negative before administration of study drug.  


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9. 
OTHER RESTRICTIONS RELATED TO COVID-19 
Patients will be advised to adhere to local requirements for reduction of the public severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure while ambulatory. All patients 
should be called 1 day prior to every visit for assessing COVID-19 signs and symptoms and 
asked not to attend the site if infection is suspected. In addition, patients will be asked whether 
they have had any contact with a person who has a confirmed infection. If applicable, patients 
will be referred to the local health care system. Physical distancing and person-to-person contact 
restrictions should be applied and explained to patients while staying at the study site, if required 
by local requirements. Where physical distancing is not possible, study participants will be asked 
to use face masks and/or gloves, if deemed appropriate by the Investigator and site staff and 
guided by local requirements. 




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10.4. 
POST-INFUSION MEDICATIONS 
No specific post-infusion medications are required for ANK-700, but appropriate medications 
may be administered at the discretion of the Investigator. 
 


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10.5. 
INFUSION-RELATED REACTIONS 
If an IRR occurs during ANK-700 administration, the following treatment recommendations are 
provided and may be modified per local treatment standards and guidelines as appropriate. 
• Grade 1 (mild): Infusion rate modification not indicated. Administer symptomatic 
treatment (e.g., antihistamines, antipyretics, antiemetics) as needed. Closely monitor 
patient until resolution. Prophylaxis with diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg is recommended ≥ 30 minutes prior to future 
ANK-700 infusions. 
• Grade 2 (moderate): Slow infusion to ≤ 50% of the original infusion rate and treat 
symptoms with appropriate medical therapy, including but not limited to antihistamines, 
antipyretics, and analgesics. Increase monitoring of vital signs as medically indicated 
until patient is deemed stable. Prophylaxis with diphenhydramine 50 mg (or equivalent) 
and/or acetaminophen/paracetamol 325 to 1000 mg is recommended ≥ 30 minutes prior 
to future ANK-700 infusions.  
• Grade 3 (severe): Stop infusion and institute appropriate symptom-directed therapy, 
including but not limited to antihistamines, antipyretics, corticosteroids, bronchodilators, 
and oxygen. Increase monitoring of vital signs as medically indicated until patient is 
deemed stable. If the reaction has not resolved within 6 hours, the remainder of the 
infusion will not be administered, and ANK-700 will be permanently discontinued. After 
the completion or termination of a restarted infusion because of an IRR, all patients must 
be monitored until resolution of symptoms or for 2 hours in the absence of additional 
symptoms. Prophylaxis with diphenhydramine 50 mg (or equivalent) and/or 
acetaminophen/paracetamol 325 to 1000 mg is required ≥ 30 minutes before future 
ANK-700 infusions. The next infusion should initiate at a rate of 2 hours per dose, or 
50% of the rate at which the reaction occurred. If no IRRs are observed within the first 
30 minutes, the infusion rate may increase to the 1-hour-per-dose rate as outlined in 
Section 10.2. Permanently discontinue ANK-700 upon a second occurrence of a Grade 3 
or greater infusion reaction.  
• Grade 4 (life-threatening): Stop infusion and immediately institute appropriate symptom 
directed therapy and supportive measures as necessary, including, but not limited to, 
corticosteroids, bronchodilators, oxygen/respiratory support, and vasopressors. 
Hospitalization and/or intensive care unit admission may be indicated. Permanently 
discontinue treatment. 
10.6. 
DRUG ACCOUNTABILITY 
The Investigator or designee is responsible for taking an inventory of each shipment of ANK-700 
received and comparing it with the accompanying drug order form. All unused ANK-700 will be 
retained at the site. After full drug accountability and reconciliation, the Investigator will either 
dispose of any unused ANK-700 at the clinical study site per site procedures or return unused 
ANK-700 to the Sponsor or its designee. Disposition of all ANK-700 should be documented, 
including any ANK-700 that is lost or damaged.  


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10.7. 
ASSIGNMENT TO TREATMENT 
Once a patient has met all entry criteria, he or she will be assigned a distinct patient identifier. If 
a patient discontinues from the study, the patient identifier will not be reused, and the patient will 
not be allowed to reenter the study.  
In Part A, patients will be assigned to receive open-label ANK-700 at a dose level based on the 
next available spot in the cohort(s) currently being enrolled. Patients in Part A may be replaced if 
they do not receive the full dose of study drug or do not complete the D15 visit, as long as the 
discontinuation was not due to a DLT 
In Part B, patients will be stratified based upon their use of fumarate at study entry within the 
IRT system. For the sentinel group, the first 2 eligible patients within each cohort will be 
randomized through IRT in a 1:1 ratio to receive either ANK-700 or PBO. After completion of 
the sentinel dosing in each cohort, the remaining 10 patients will be randomized to ensure an 
overall 2:1 randomization to ANK-700 and PBO.  Patients in Part B may be replaced if they do 
not receive the full 3 doses of study drug or do not complete the D22 visit, as long as the 
discontinuation was not due to a DLT. 
 


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11. 
SAFETY DATA COLLECTION, RECORDING, AND 
REPORTING 
11.1. 
ADVERSE EVENTS  
11.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug, or with 
study participation, whether or not consider related to study treatment.  
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the medicinal product, 
whether or not considered related to the medicinal product.  
AEs include worsening of a pre-existing medical condition, including MS, as well as CS changes 
from baseline laboratory values/conditions. Worsening of the preexisting medical condition (e.g., 
diabetes, hypertension) means that it has increased in severity, frequency, and/or duration, and/or 
has an association with a significantly worse outcome. A pre-existing condition that has not 
worsened during the study is not considered an AE. 
11.1.2. 
Protocol-Defined MS Relapse 
Patients who present with suspected clinical relapse should be assessed by EDSS and/or MRI 
(with and without contrast and may include spinal cord), as appropriate. Protocol-defined MS 
relapse for this study is: 
• Sudden episode of new symptoms or worsening existing MS symptoms that lasts for 
≥ 24 hours and occurs ≥ 30 days after conclusion of previous relapse (patient must be 
stable or improving for the 30 days immediately preceding relapse) and for which there is 
no other cause such as infection or environmental triggers. Episodic spasms, sexual 
dysfunction, fatigue, mood change, or bladder or bowel urgency or incontinence will not 
suffice to establish the diagnosis of a relapse. 
11.1.3. 
Definition of a Serious Adverse Event  
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is immediately life-threatening 
• requires inpatient hospitalization or prolongation of existing hospitalization 
− Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF 
(documented as medical history on the eCRF) is not considered an SAE. 
− Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience, is not considered an SAE. 
• results in persistent or significant disability/incapacity 


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• results in congenital anomaly/birth defect 
• is considered an important medical event 
− If an AE does not meet 1 of the serious criteria, but the Investigator or Sponsor 
considers an event to be clinically important, the event could be classified as an 
SAE under the criterion of an “Important Medical Event.” Examples of such 
medical events may include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, or blood dyscrasias or convulsions that do not 
result in inpatient hospitalization. 
11.2. 
PROCEDURES FOR RECORDING AND REPORTING ADVERSE EVENTS 
11.2.1. 
Recording Adverse Events 
Patients will be instructed to report all AEs and will be asked a general health status question at 
each study visit. All AEs and SAEs occurring in patients will be recorded in the eCRF from the 
time of signing the ICF through the Final Study Visit/phone call. An AE will be followed until it 
is resolved, has returned to baseline, or is determined to be a stable or chronic condition.  
At each protocol-required visit (including safety follow-up phone call) during the study, all AEs 
that have occurred since the previous visit must be reviewed by the Investigator. The Investigator 
must determine if the AE is serious or nonserious.  
The Investigator must assign the following AE attributes: 
• AE diagnosis or syndrome(s) if known 
− If not known at time of the report, record the signs and/or symptoms as AEs and 
provide an updated report with diagnosis when obtained 
• dates of onset and resolution 
• severity as defined per protocol 
• assessment of relatedness to ANK-700/PBO 
• action taken with each ANK-700/PBO dose because of the AE 
In general, an AE that is the primary cause of subsequent events should be identified by the 
primary cause (e.g., for dehydration because of diarrhea, the AE would be diarrhea). However, 
AEs occurring secondary to an initiating event that are separated in time should be recorded as 
independent events (e.g., for sepsis secondary to pneumonia, both events should be recorded). 
Confirmed and suspected SARS-CoV-2 infections and/or COVID-19 cases will be recorded in 
the AE eCRF.   
11.2.2. 
Relationship to ANK-700 
The Investigator must assess whether the AE may be related to ANK-700 (study drug) or any 
protocol mandated procedure, when applicable. The relationship is defined below:   
Relationship assessments that indicate the event is “Not Drug Related”: 


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• None: The event is related to an etiology other than the study product administration (the 
alternative etiology must be documented in the study patient’s medical record). 
• Remote: The event is unlikely to be related to the study product and likely to be related to 
factors other than study product. 
Relationship assessments that indicate the event is “Drug Related”: 
• Possible: There is an association between the event and the administration of ANK-700, 
and there is a plausible mechanism for the event to be related to the study product; but 
there may also be alternative etiology, such as characteristics of the patient’s clinical 
status or underlying disease. 
• Probable: There is an association between the event and the administration of ANK-700, 
there is a plausible mechanism for the event to be related to ANK-700, and the event 
could not be reasonably explained by known characteristics of the patient’s clinical status 
or an alternative etiology is not apparent. 
• Definite: There is an association between the event and the administration of ANK-700, 
there is a plausible mechanism for the event to be related to the ANK-700, and causes 
other than ANK-700 have been ruled out and/or the event re-appeared on re-exposure to 
ANK-700. 
11.2.3. 
Adverse Event Severity 
The Investigator will assess the Grade of the AE per the NCI-CTCAE v5.0 or higher 
(Appendix 1). Toxicities that are not specified in the NCI-CTCAE will be defined as follows:  
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL 
• Grade 4: Life-threatening consequences; urgent intervention indicated 
• Grade 5: Death related to AE 
Note: It is important to distinguish between SAEs and severe AEs. Severity is a measure of 
intensity, whereas seriousness is classified by the criteria based on the regulatory definitions as 
described in Section 11.1.3. 
11.2.4. 
Abnormal Laboratory Values 
The Investigator is responsible for reviewing clinical laboratory tests determining whether an 
abnormal value represents a CS change from the patient’s baseline value. In general, abnormal 
laboratory findings without clinical significance (based on the Investigator’s judgment) should 


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not be recorded as AEs. In general, an abnormal laboratory test result should be reported as an 
AE if the laboratory result:  
• requires an adjustment or discontinuation of ank-700 
• requires treatment with or adjustment to concomitant medications 
• is considered to be an AE by the Investigator 
11.2.5. 
Medication Errors, Misuse, and Abuse of ANK-700 
Overdose, medication error, off-label use, misuse, abuse, and occupational exposure are defined 
as follows: 
• Overdose: refers to the administration of a quantity of ANK-700 given per administration 
or cumulative that is above the maximum dose according to the protocol  
• Medication error: refers to an unintentional error in dispensing or administration of 
ANK-700 not in accordance with the protocol 
• Off-label use: relates to situations where ANK-700 is intentionally used for medical 
purpose not in accordance with the protocol 
• Misuse: refers to situations where ANK-700 is intentionally and inappropriately not used 
in accordance with the protocol 
• Abuse: corresponds to the persistent or sporadic, intentional excessive use of ANK-700, 
which is accompanied by harmful physical or psychological effects 
• Occupational exposure: refers to exposure to ANK-700 because of one’s professional or 
nonprofessional occupation 
Overdoses, medication errors, abuse, or misuse will be collected as part of investigational 
medicinal product dosing information and/or as a protocol violation, as required.  
11.2.6. 
Reporting of Serious Adverse Events 
SAEs will be recorded on the appropriate eCRF and reported to the Sponsor within 24 hours of 
the Investigator’s first knowledge of the event, even if the experience does not appear to be 
related to ANK-700, from the time of signing ICF through the final Follow-Up Visit/phone call.  
The initial SAE eCRF must be as complete as possible and include details of the current illness 
and SAE as well as an assessment of the relationship between the event and ANK-700. 
Additional information relating to a previously reported SAE must also be reported within 
24 hours of the Investigator’s first knowledge of information. The Investigator may also be 
asked, by the Sponsor or designee, to provide clarifications or additional information. 
If the Investigator becomes aware of an SAE considered related to ANK-700 occurring more 
than 30 days after the last dose of ANK-700, the SAE must be reported as described above.  


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11.2.7. 
Reporting of Serious Adverse Events to Regulatory Authorities, 
Ethics Committee, and Institutional Review Board 
The Sponsor or designee will determine expectedness of the Sponsor’s product for each reported 
SAE based on the appropriate reference safety information per local country requirements. The 
Sponsor or designee shall notify regulatory authorities of serious, unexpected, and related AEs or 
other AEs, per local requirements.  
The Sponsor or designee shall notify the Investigator of serious, related, and unexpected AE(s) 
submitted to the regulatory agencies, per local country requirements.  
The Investigator will notify the appropriate Institutional Review Board (IRB)/Local Ethics 
Committees (LECs) of serious, related, and unexpected AE(s), or significant risks to patients, per 
local country requirements. The Investigator must keep copies of all AE information on file, 
including correspondence with the Sponsor or IRBs/LECs. 
11.2.8. 
Pregnancy and In Utero Drug Exposure 
ANK-700 has not been evaluated in pregnant or nursing women. Thus, pregnant women or 
WCBP who are not using effective contraception are excluded from this study (see Section 8 and 
Section 6.1.9 for instructions on birth control and pregnancy testing, respectively). 
Pregnancies occurring in patients or partners of male patients are considered immediately 
reportable events if the pregnancy occurs during the study treatment through the Safety 
Follow-Up Visit (D15 in Part A; D22 in Part B) after the patient’s last dose of ANK-700. If a 
pregnancy occurs in a patient, ANK-700 must be discontinued immediately. The pregnant 
woman should be referred to an obstetrician/gynecologist experienced in reproductive toxicity 
for further evaluation and counseling. 
The pregnancy must be reported to the Sponsor or designee within 24 hours of the Investigator’s 
knowledge of the pregnancy by recording it on the appropriate eCRF. 
The Investigator will follow the pregnancy (the patient or the patient’s partner) until completion 
of the pregnancy and must notify the Sponsor of the pregnancy outcome within 24 hours of the 
Investigator’s knowledge of the outcome. The Investigator will provide this information by 
recording it on the appropriate eCRF. This notification includes pregnancies resulting in live, 
“normal” births. 
If the pregnant patient/patient’s pregnant partner experiences an SAE during pregnancy, or the 
outcome of the pregnancy meets any of the serious criteria (i.e., spontaneous abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs (i.e., 
report the event to the Sponsor or designee within 24 hours of the Investigator’s knowledge of 
the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
causality) should be reported as SAEs to the Sponsor or designee. In addition, any infant death or 


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congenital anomaly occurring after 30 days that the Investigator suspects is related to the in utero 
exposure to ANK-700 should also be reported to the Sponsor or designee.  


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12. 
STATISTICAL METHODS 
Details of the statistical methods for this study will be documented in a Statistical Analysis Plan 
(SAP). When there is a difference between the final approved SAP and the protocol, the methods 
described in the final SAP will prevail. 
Statistical methods will be primarily descriptive in nature. No hypothesis will be formally tested.  
Placebo from each cohort will be pooled for analysis. Part A and Part B will be pooled together 
for the first dose to provide additional tables and listings for all of the patients in the study. 
Summary statistics will be provided for Part A, Part B, and Part A and Part B combined for 
disposition, demographic, and PK analysis. Additional tables will be provided for Part B with 
details included in the SAP. Continuous data will be summarized in terms of the total number of 
subjects, mean, StD, median, minimum, maximum, and number of observations, unless 
otherwise stated. For log transformed data, the geometric mean will be provided along with the 
other summary statistics. Categorical data will be presented by frequency and percent of patients. 
Protocol deviations (missing assessments/visits) related to COVID-19 will be listed separately. 
12.1. 
SAMPLE SIZE  
In Part A, the number of patients enrolled into a treatment group will be based on safety and 
tolerability within a traditional 3+3 design. Under this model, Part A may enroll approximately 
9 patients across 3 treatment groups, depending upon the toxicities observed. No formal 
hypothesis testing is planned for Part A.  
In Part B, the total sample size of 24 patients (n=16 ANK-700; n=8 PBO) across 2 treatment 
groups was chosen to allow for a comparison of safety, PK, and PD between ANK-700 and 
PBO.  
12.2. 
ANALYSIS SETS 
The main analysis sets are defined in this section.  
• The All-Treated Analysis Set is defined as all patients who receive any amount of 
ANK-700. This analysis set will be the primary analysis set for all safety endpoints.  
• The PK Analysis Set will include all enrolled patients who receive ≥ 1 complete dose of 
ANK-700 and have ≥ 1 pre-dose and1 post-dose measurement. This analysis set will be 
used for the analysis of PK parameters as further defined in the protocol.  
Additional analysis sets may be defined in the SAP. 
12.3. 
BACKGROUND CHARACTERISTICS  
12.3.1. 
Patient Disposition 
The number and percentage of patients in each disposition category (e.g., enrolled, included in 
each analysis set, discontinuing treatment, and discontinuing study, with a breakdown of the 
reasons for discontinuation) will be summarized. 


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12.3.2. 
Demographics and Baseline Characteristics 
The following demographics and baseline characteristics will be summarized by treatment group 
(PBO and dose group) for the All-Treated Analysis Set: sex, race, age, concomitant fumarate 
use, and years since MS diagnosis for Part A and Part B. Part A and Part B will be combined. 
Additional parameters may be provided in the SAP.  
12.4. 
ANK-700 EXPOSURE  
Exposure will be calculated for study Part A and Part B by dose level; all exposure data will be 
listed for both parts. The exposure variables include: 
• the cumulative number of days of exposure 
• the number of IV infusions completed  
• the relative dose intensity  
All variables are predefined:  
• The relative dose intensity is defined as the percentage of the planned treatments 
completed. It is the ratio of the cumulative actual dose (mg) and cumulative planned dose 
(mg), multiplied by 100. In this definition, 
− the cumulative actual dose (mg) is the sum of the actual doses (mg) that the 
patient receives during the study  
− the cumulative planned dose (mg) is the cumulative number of days of exposure 
multiplied by the planned dose level (mg)  
12.5. 
SAFETY ANALYSES  
For Part A, all safety data will be listed. For Part B, the number and percentage of AEs and 
TEAEs experienced by patients will be summarized for each dose level and PBO group, 
accompanied by a by-patient listing of potential DLTs for both Part A and Part B.  
The listing will include the description, severity, and relationship of the events to ANK-700 for 
each Medical Dictionary for Regulatory Activities (MedDRA) system organ class and 
preferred term and include details for relation to study drug, discontinuation because of study 
drug, and severity.  
For Part A and Part B, safety data, including vital signs, ECGs, laboratory test results, PEs, 
disease relapses per MRI and EDSS evaluations, and AEs will be listed by dose and assessment 
time points, as appropriate. 
12.6. 
ADVERSE EVENTS 
AEs will be coded using the MedDRA v22.0 (MedDRA March 2019) or higher and will be 
graded according to the NCI-CTCAE v5.0 or higher (Appendix 1).  
A TEAE is an AE that emerges or worsens in the period from the first dose of study treatment to 
the final Follow-Up Visit/phone call after the last dose of ANK-700 or PBO. 


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12.7. 
CLINICAL LABORATORY ASSESSMENTS 
Presentation of laboratory values will be performed using International System units. All 
statistical summaries for laboratory values, including change from baseline, will be by 
dose/treatment group for Part B. Part A will be listed. 
Abnormal laboratory findings will be also listed by number and percentage of patients with 
values ≥ Grade 3 in severity. 
A listing of individual patient hematology (including coagulation) and serum chemistry values 
outside the clinical reference ranges will be provided.  
12.8. 
PHARMACOKINETIC ANALYSES 
Blood samples will be collected for measurement of ANK-700, as specified in Table 1 and 
Table 2. The timing of sampling may be altered based on the emerging PK data. The adjustment 
of the PK sampling schedule is not considered to be a substantial amendment so long as the total 
number of plasma PK samples and the total blood volume to be collected from each participant 
will not change. Any adjusted sampling time points will be documented appropriately. 
PK parameters of ANK-700 will be determined from the serum concentration-time data. 
Parameters will be calculated by noncompartmental modeling methods, using actual sampling 
times where relevant. The parameters that will be calculated are defined in Table 3 and will be 
calculated for single or multiple dosing of ANK-700, as appropriate. Not all listed parameters 
may be calculable, and additional parameters may be calculated, if needed, to fully characterize 
the available data. PK parameters and concentration data will be summarized for Part A and Part 
B and will be combined for doses with more than 2 patients in each dose group.  
 
 
 
 
 
 
 
 
 
 
 
    


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Table 5:  
Pharmacokinetic Parameter Definitions 
Parameter 
Definition 
Cmax  
Maximum observed plasma concentration 
Tmax  
Time to first occurrence of maximum observed plasma concentration 
Ctrough 
Pre-dose plasma concentration 
AUClast 
Area under the plasma concentration-time curve from time 0 to the last measurable time point 
AUCinf  
Area under the plasma concentration-time curve extrapolated to infinity 
AUCtau 
Area under the plasma concentration-time curve over the dosing interval 
t1/2  
Terminal elimination half-life 
CL 
Clearance  
Vz 
Volume of distribution after a single dose  
Racc,AUC 
Accumulation ratio based on AUC  
Racc,Cmax  
Accumulation ratio based on Cmax   
Statistical evaluations of PK data will include dose proportionality assessment using Cmax, 
AUClast, and AUCinf.   
For cohort by cohort PK analysis, not all PK parameters may be calculated, and 
noncompartmental analysis may be done using nominal times. 
Additional details on noncompartmental PK analyses for calculation of PK parameters and 
statistical analyses of PK parameters for dose proportionality will be provided in a PK analysis 
plan.  
12.9. 
ANALYSIS OF ANTIDRUG ANTIBODIES  
Blood samples for assessment of ADAs will be collected at the time points outlined in Table 1 
and Table 2. The raw ADA dataset will be listed by visit and dose. 
12.10. 
   
 
  
 
 
 
 
12.11. 
 
 


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13. 
STUDY ADMINISTRATION 
13.1. 
GOOD CLINICAL PRACTICE STATEMENT 
This study is to be performed in accordance with the protocol, the Declaration of Helsinki, the 
International Conference on Harmonisation (ICH) Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP), and all applicable local regulatory requirements. 
13.2. 
INFORMED CONSENT 
The Sponsor or designee will provide a sample patient ICF for modification, as appropriate, by 
the Investigator. The ICF must include all elements required by ICH and GCP and must adhere 
to the IRB/Independent Ethics Committee (IEC) requirements and the ethical principles that have 
their origin in the Declaration of Helsinki. 
The Investigator or designee will explain the nature of the study, its purpose and associated 
procedures, the expected duration, and the potential risks involved to the patient prior to 
enrollment. The Investigator or designee will obtain written, informed consent. The patient will 
have ample time and opportunity to ask questions and will be informed about the right to 
withdraw from the study at any time without any disadvantage and without having to provide a 
reason for this decision. After the discussion regarding the study, a patient will be asked if he/she 
is willing to sign and personally date a statement of informed consent. Only if the patient 
voluntarily agrees to sign the informed consent statement and has done so, may he/she enter the 
study. A copy of the signed and dated ICF will be provided to the patient. The signed ICF is to 
remain in the Investigator’s file, per local country requirements. 
The ICF and any other written information provided to the patients will be revised whenever 
important new information becomes available that may be relevant to the patient’s consent or if 
there is an amendment to the protocol that necessitates a change to the content of the patient’s 
informed consent. The Investigator will inform the patients of changes in a timely manner and 
will ask the patients to confirm continuation of their participation in the study by their signature 
on the revised ICF (if applicable). Any written ICF and written information must receive the 
approval/favorable opinion of the IRB/IEC in advance of use. Any additional approvals from the 
initial ICF should be forwarded to the Sponsor. 
13.3. 
PATIENT CONFIDENTIALITY 
The written ICF will explain that study data will be stored in a database, maintaining 
confidentiality in accordance with national data legislation. All data processed by the Sponsor or 
its representative(s) will be identified by patient number and study code. 
The written ICF will also explain that for data verification purposes, authorized representatives 
of the Sponsor, a regulatory authority, and an IRB/IEC may require direct access to parts of the 
hospital or clinic records relevant to the study that include patient medical history. 
The Investigator must ensure that patient anonymity is maintained. On the eCRFs or other 
documents submitted to the Sponsor, patients should not be identified by their names, but by 


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their assigned patient number and study code. Documents not for submission to the Sponsor, 
such as signed ICF, should be maintained in strict confidence by the Investigator. 
13.4. 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE REQUIREMENTS  
The final study protocol including the final version of the ICF must be approved or given a 
favorable opinion in writing by an IRB/IEC at each clinical study site. The Principal Investigator 
(PI) must submit written approval from the IRB to the Sponsor before he or she can enroll any 
patient into the study. 
The PI is responsible for informing the IRB/IEC of any amendment to the protocol. In addition, 
the IRB/IEC must approve all advertising used to recruit patients for the study. The protocol 
must be reapproved by the IRB/IEC annually or as required by the IRB, regulations, and 
guidelines. 
Progress reports and notifications of SAEs will be provided to the IRB/IEC according to 
regulations and guidelines. 
13.5. 
CASE REPORT FORMS AND SOURCE DOCUMENTATION  
eCRFs will be provided for the recording of all data. The PI/Sub-Investigator or designee will 
record data from all observations, tests, and assessments specified in the protocol on the eCRFs 
provided by the Sponsor. 
13.6. 
STUDY MONITORING  
Before the first patient signs the ICF to participate in the study, the Sponsor or designee will visit 
or remotely assess the study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) (and other personnel involved with the study) their 
responsibilities related to the protocol and the responsibilities of the Sponsor or designee 
• Confirm that the Investigator(s) (and other personnel involved with the study) have not 
invoked sanctions or demonstrated any scientific misconduct or fraud 
During the conduct of the study, the Sponsor or designee will maintain regular contact, perform 
remote monitoring including data review, and visits to the clinical study site to: 
• Provide information and support the Investigator 
• Confirm that the facilities remain acceptable 
• Confirm that the study team is adhering to the protocol, data are being accurately 
recorded in the eCRFs, and the investigational product is being properly maintained and 
accountability records are current 
• Perform source data verification with access to all original clinical records for each 
patient 


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13.7. 
QUALITY ASSURANCE  
In compliance with GCP and regulatory requirements, the Sponsor, a third party on behalf of the 
Sponsor, and regulatory agencies or IRB/IECs may conduct quality assurance audits at any time 
during or after a study. The Investigator must agree to allow auditors direct access to all study-
related documents, including source documents, and must agree to allocate his/her time and the 
time of the study staff to the auditors to discuss findings and issues. 
Monitoring visits at site will be limited to a minimum required as deemed appropriate during the 
COVID-19 pandemic. 
13.8. 
STUDY OR CLINICAL SITE TERMINATION 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time. Conditions that may warrant termination of the study include, but are not limited to: 
• Discovery of an unexpected, serious, or unacceptable risk to patients enrolled in the study 
• Decision on the part of the Sponsor to suspend or discontinue testing the study treatment 
Conditions that may warrant termination of a study site include, but are not limited to: 
• Failure of the Investigator to comply with GCP 
• Submission of knowingly false information from the clinical study site to the Sponsor or 
regulatory authorities 
• Insufficient adherence to protocol requirements 
If terminating the study, the Sponsor and the Investigator(s) will assure that adequate 
consideration is given to the protection of the patients’ interests. 
13.9. 
DURATION OF THE STUDY, EXPECTED DURATION OF PATIENT 
PARTICIPATION, AND END OF STUDY 
The study is planned to initiate enrollment in September 2020 with the last study visit in 
September 2023. 
In Part A of the study, enrolled patients will receive a single IV infusion of ANK-700 on D1. The 
maximum duration of study participation for patients in Part A is approximately 210 days, which 
includes a screening period of up to 28 days, followed by a single dose of ANK-700 on D1, and 
clinic visits on D4, D15, D29, and at 3 and 6 months. 
In Part B of the study, enrolled patients will receive 3 IV infusions of ANK-700, each on D1, D4, 
and D7. The maximum duration of study participation for patients in Part B is approximately 
393 days, which includes a screening period of up to 28 days, followed by 3 doses of ANK-700 
or PBO on D1, D4, and D7, and clinic visits on D22, D43, and at 3, 6, and 12 months. 


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13.10. 
RECORDS RETENTION  
All correspondence related to this clinical study should be kept in appropriate study files. 
Records of patients, source documents, eCRFs, ANK-700 inventory, IRB, and Sponsor or 
designee correspondence pertaining to this study must be kept on file. All study documents must 
be kept secured for a period of 2 years after a marketing application is approved for ANK-700, or 
for 2 years after the last shipment and delivery of ANK-700 for investigational use on study, or 
as long as required by local regulations, whichever is longer. There may be other circumstances 
for which the Sponsor is required to maintain study records and, therefore, the Sponsor should be 
contacted before removing or relocating study records for any reason. 
13.11. 
PUBLICATIONS 
Publication by the clinical study site(s) of any data from this study must be carried out in 
accordance with the Clinical Site Agreement. 




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APPENDIX 1. COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V5.0 (CTCAE) 
CTCAE Terms  
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure that 
may or may not be considered related to the medical treatment or procedure. An AE is a term 
that is a unique representation of a specific event used for medical documentation and scientific 
analyses. Each CTCAE v5.0 term is a MedDRA Lowest Level Term. 
Definitions  
A brief definition is provided to clarify the meaning of each AE term.  
Grades  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through Grade 5 with 
unique clinical descriptions of severity for each AE based on this general guideline:  
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting selfcare 
ADL**  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade.  
A single dash (-) indicates a grade is not available. 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 5 
options for Grade selection. Grade 5 (Death) is not appropriate for some AEs and therefore is not 
an option.  
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Selfcare ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Publish date 27 November 2017 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
 



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DOCUMENT: 
 
Statistical Analysis Plan 
 
PROTOCOL: 
 
ANK-700-01 
 
TITLE: 
 
A Phase 1 Study of the Safety and Tolerability of Single and 
Multiple Doses of ANK-700 in Patients with Relapsing-
Remitting Multiple Sclerosis Version 4 
 
SAP DATE: 
 
V1 / 4NOV2022 
 
SPONSOR: 
 
Anokion US, Inc. 
50 Hampshire St., Suite 402 
Cambridge, MA 02139 
 
PREPARED BY: 
 
Nicole Stouffer 
Medical-Research-Support 
8 Wellesley Way 
Medford, NJ 08055 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SIGNATURE PAGE 
This document has been approved and signed on the final pages by the following: 
 
 
 
APPROVERS: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
                                    
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
 
VERSIONS: 
 
Version No. 
Effective Date 
Summary of Change(s) 
Final 1.0 
[DD MMM 
YY] 
New document 


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Table of Contents 
SIGNATURE PAGE ........................................................................................................... 2 
LIST OF ABBREVIATIONS ............................................................................................. 6 
1. 
INTRODUCTION ....................................................................................................... 9 
1.1 
Background ..................................................................................................................... 9 
2. 
GENERAL STUDY DESIGN AND PLAN ............................................................... 10 
2.1 
Study Objectives ........................................................................................................... 10 
2.1.1 
Primary ...................................................................................................................... 10 
2.1.2 
Secondary .................................................................................................................. 10 
2.1.3 
 
2.2 
Study Population ........................................................................................................... 10 
2.3 
Study Design ................................................................................................................. 10 
2.3.1 
PART A: SAD (Single Ascending Dose) ................................................................... 11 
2.3.2 
PART B: MAD (Multiple Ascending Doses) ............................................................. 12 
2.4 
Study Drug Dosage and Administration......................................................................... 13 
3. 
SAMPLE SIZE, RANDOMIZATION AND BLINDING ........................................ 13 
3.1 
Sample Size .................................................................................................................. 13 
3.2 
Randomization and Blinding ......................................................................................... 14 
3.2.1 
Part A (SAD) – Open Label ....................................................................................... 14 
3.2.2 
Part B (MAD) – Double Blind ................................................................................... 14 
3.3 
Withdrawal Criteria ....................................................................................................... 15 
4. 
CLINICAL PROCEDURES AND ASSESSMENTS ................................................ 16 
5. 
STUDY OBJECTIVES .............................................................................................. 16 
5.1 
Primary ......................................................................................................................... 16 
5.2 
Secondary ..................................................................................................................... 16 
5.3 
 
6. 
ASSESSMENTS ......................................................................................................... 16 
6.1 
Safety Assessments ....................................................................................................... 16 
6.1.1 
Adverse Events (AE) ................................................................................................. 16 


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6.1.2 
Treatment Emergent Adverse Events (TEAE) ............................................................ 17 
6.1.3 
Adverse Event Severity.............................................................................................. 17 
6.1.4 
Serious Adverse Event (SAE) .................................................................................... 17 
6.1.5 
AE Relationship to Study Medication ........................................................................ 18 
6.1.6 
Dose-Limiting Toxicity (DLT) .................................................................................. 18 
6.1.7 
Clinical Laboratory Endpoints ................................................................................... 18 
6.1.8 
Expanded Disability Status Scale (EDSS) .................................................................. 19 
6.1.9 
Brain Magnetic Resonance Imaging ........................................................................... 19 
6.1.10 
Other Safety Assessments (Physical Exam, Vital Signs and ECG) ............................. 20 
6.2 
Pharmacokinetic Assessments ....................................................................................... 20 
6.3 
Antidrug Antibody ........................................................................................................ 22 
6.4 
 
6.4.1 
 
6.5 
Other Assessments ........................................................................................................ 23 
7. 
ANALYSIS SETS ...................................................................................................... 23 
8. 
STATISTICAL METHODS ...................................................................................... 23 
8.1 
Data Quality Assurance ................................................................................................. 24 
8.2 
Subject Disposition and Screen Failures ........................................................................ 24 
8.3 
Prior and Concomitant Medication ................................................................................ 25 
8.4 
Demographics, Baseline Characteristics, Disease History and Medical History ............. 26 
8.5 
Study Drug Administration and Compliance ................................................................. 26 
8.6 
Dosing and Extent of Exposure ..................................................................................... 26 
8.7 
Protocol Deviations ....................................................................................................... 27 
8.8 
SAFETY ANALYSES .................................................................................................. 27 
8.8.1 
Adverse Events .......................................................................................................... 27 
8.8.2 
Physical Examination ................................................................................................ 28 
8.8.3 
Vital Signs ................................................................................................................. 29 
8.8.4 
Clinical Laboratory Evaluation .................................................................................. 29 
8.8.5 
ECGs ......................................................................................................................... 29 
8.8.6 
Medication for Infusion Reaction ............................................................................... 29 
8.8.7 
MRI of Brain ............................................................................................................. 29 
8.9 
Efficacy Analysis .......................................................................................................... 30 
8.10 
Pharmacokinetics .......................................................................................................... 30 
8.10.1 
Pharmacokinetic Concentration Tables, Figures, and Listings .................................... 30 
8.10.2 
Pharmacokinetic Parameters Tables, Figures, and Listings ......................................... 31 
8.11 
 


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8.11.1 
 
8.11.2 
 
8.11.3 
 
8.11.4 
 
8.12 
 
9. 
ADJUSTMENTS FOR COVARIATES .................................................................... 33 
10. 
DATA HANDLING AND MISSING DATA ......................................................... 34 
10.1 
Missing Start and Stop Dates/Time for Adverse Events ................................................. 34 
10.2 
Missing Start and Stop Dates for Prior and concomitant Medication .............................. 35 
10.3 
Concentrations Below the Limit of Quantification (BLQ) .............................................. 36 
10.4 
Labs and Biomarkers (BLQ and ULQ) .......................................................................... 36 
11. 
INTERIM ANALYSES AND DATA MONITORING ......................................... 36 
11.1 
Pooling Centers ............................................................................................................. 36 
12. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN 
THE PROTOCOL ............................................................................................................ 36 
13. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ................................................ 37 
14. 
APPENDIX 2: COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V5.0 (CTCAE) .................................................................................................. 43 
15. 
APPENDIX 3 EXPANDED DISABILITY STATUS SCALE (EDSS) ................. 44 
 


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LIST OF ABBREVIATIONS 
Abbreviation / 
Acronym 
Definition 
ADA 
Anti-drug antibody 
ADL 
Activities of daily living 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATAS 
All Treated Analysis Set 
AUC 
Area under the concentration-time curve 
AUCinf  
AUC from time zero extrapolated to infinity 
AUCt  
AUC from time zero to the last quantifiable concentration 
AUCτ,ss 
AUC over the dosing interval at steady state 
%AUCex 
Percentage of AUC0-inf that is due to extrapolation beyond Tlast 
BLQ 
Below the Limit of Quantification 
Cmax 
Maximum observed concentration 
Cmax,ss 
Maximum observed concentration at steady state 
Clast 
Last quantifiable concentration at tlast 
Ctrough 
Concentration immediately prior to dosing 
CI 
Confidence interval 
CL/F 
Apparent clearance following oral administration 
CRF 
Case Report Form 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
D 
Study Day 
DBL 
Database Lock 


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Abbreviation / 
Acronym 
Definition 
DLT 
Dose-Limiting Toxicity 
DMT 
Disease Modifying Therapy 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDSS 
Expanded Disability Status Scale 
 
 
EOS 
End-of-Study 
FIH 
First-In-Human 
HBV 
Hepatitis B 
HCV 
Hepatitis C 
 
 
ICF 
Informed Consent Form 
ICH 
International Conference for Harmonisation 
 
 
IRB 
Institutional Review Board 
IRR 
Infusion related Reaction 
IV 
Intravenous 
LLQ 
Lower Limit of Quantification 
MAD 
Multiple Ascending Dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Metabolic Ratio 
MRT 
Mean Residence Time 
MRT(0-inf) 
MRT extrapolated to infinity 
MS 
Multiple sclerosis 
NA 
Not Available 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 


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Abbreviation / 
Acronym 
Definition 
NCS 
Not Clinically Significant 
NTD 
Non-tolerated dose 
PBO 
Placebo 
 
 
PD 
Pharmacodynamic 
PDAS 
Pharmacodynamic Analysis Set 
PE 
Physical exam 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set 
PLT 
Platelet 
PT 
Preferred Term 
PTF 
Peak Trough Fluctuation 
Rac 
Accumulation Ratio 
RRMS 
Relapsing-Remitting Multiple Sclerosis 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error of Mean 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
SoA 
Schedule of Assessments 
t½ 
Apparent terminal elimination half-life  
tlast 
Time of last quantifiable concentration 
TEAE 
Treatment-Emergent Adverse Event 
TESAE 
Treatment-Emergent Serious Adverse Event 
TLF 
Tables, Listings and Figures  




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harnesses natural tolerogenic pathways in the liver to re-educate pathogenic immune cells to 
become tolerant towards MS antigens. ANK-700 specifically targets the immune cells that 
drive MS and leaves the otherwise healthy components of the immune system intact to 
perform their natural, protective functions. Surrogates of ANK-700 have demonstrated 
efficacy in mouse models of MS. 
2. GENERAL STUDY DESIGN AND PLAN 
2.1 
Study Objectives 
2.1.1 Primary  
 Assess the safety and tolerability of escalating doses of ANK-700 in patients 
with RRMS (Relapsing Remitting Multiple Sclerosis)  
2.1.2 Secondary 
 Evaluate the Pharmacokinetic (PK) of escalating doses of ANK-700 in 
patients with RRMS 
2.1.3 
 
 
  
 
 
2.2 
Study Population 
The study population includes adults (18 to 60 years inclusive, at screening) with RRMS 
based on revised McDonald criteria (2017) with an Expanded Disability Status Scale (EDSS) 
score ≤ 6.5. Patients must be neurologically stable with no evidence of relapse within the 28 
days before signing the informed consent form. These criteria have been implemented to 
evaluate the safety and tolerability of ANK-700 in a diverse RRMS population which has an 
appropriate risk/benefit profile based upon the severity of their disease. The population 
selected for this study (ie, those with relatively well controlled and neurologically stable 
RRMS) is appropriate for the FIH study, as highly active disease may obscure the assessment 
of safety and tolerability of ANK-700 and may require active management during the study 
period. 
Patients receiving a stable dose of a fumarate drug (ie, dimethyl fumarate, diroximel 
fumarate) for ≥ 6 months will be allowed to remain on stable doses of fumarates (dimethyl 
fumarate or diroximel fumarate) during the study because fumarate drugs do not interfere 
with the mechanism of action of ANK-700. Patients using any other disease modifying 
therapies (DMT) to treat MS will be excluded. 
2.3 
Study Design 
Study ANK-700-01 is a Phase 1, FIH (First in Human) study designed to evaluate the initial 
safety, tolerability, and activity of ANK-700 in patients with RRMS.  


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A graphic overview of the 2 parts (Part A: Single Ascending Dose (SAD) and Part B: 
Multiple Ascending Doses (MAD)) is presented below. 
Figure 1: Overview Study ANK-700-01 
 
 
Single Ascending Dose (SAD) (Part A): 3 patients will be dosed IV with ANK-700 in each cohort. Initiation 
of the next dose cohort will commence once all patients in a cohort reach D15 and upon acceptable safety 
review and recommendation by SMC and approval by the Sponsor.  
Multiple Ascending Dose (MAD) (Part B): the first MAD cohort (Cohort 4) will be initiated only after 
acceptable safety review of SAD Cohort 2, recommendation by the SMC, and approval by the Sponsor. 
Patients are randomized 2:1 to ANK-700 or PBO. Initiation of Cohort 5 will commence once all patients in 
Cohort 4 reach D22 and upon acceptable safety review of Cohorts 1 to 4, recommendation by the SMC, and 
approval by the Sponsor.  
Abbreviations: D = day; IV = intravenously; MAD = multiple ascending dose; PBO = placebo; SAD = single 
ascending dose; SMC = Safety Monitoring Committee.  
2.3.1 PART A: SAD (Single Ascending Dose) 
The SAD phase will include up to 3 cohorts with 3 patients each. Patients within each dose 
cohort will receive 1 dose of ANK-700 IV and will be monitored for up to 6 months. All 
patients in Part A will be dosed ≥ 14 days apart to monitor for acute and subacute reactions; 
this length of time is supported by nonclinical exposure data that suggest ANK-700 will have 
cleared > 5 half-lives and nonclinical animal model data demonstrating that the tolerance 
induction mechanism can develop, and immunologically active peptide is cleared within 1 
week from dosing.  
Doses evaluated in Part A include 0.3 mg/kg (Cohort 1), 1.0 mg/kg (Cohort 2), and 3.0 mg/kg 
(Cohort 3). After all patients within a given dose cohort have been followed for ≥ 14 days 
post dose, a safety review will be performed by the SMC to review all adverse events (AEs) 
and available clinical laboratory and PK data. Initiation of the next dose level will commence 
upon recommendation by the SMC and approval by the Sponsor. 


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Part A will employ a 3+3 design to evaluate single ascending doses of ANK-700. At any dose 
level, if none of the first 3 patients dosed experience a dose-limiting toxicity (DLT) within 
the dose-escalation safety monitoring period (D1 to D15), then escalation to the next dose 
level may proceed if recommended by the SMC and approved by the Sponsor. If 1 of the first 
3 patients in the cohort experiences a DLT within the dose-escalation safety monitoring 
period (D1 to D15), the dose level may expand to a maximum of 6 patients. If no DLT occurs 
among the 3 additional patients enrolled at that dose level, then escalation to the next dose 
level may proceed if recommended by the SMC and approved by the Sponsor.  
For all patients in Part A, the study will consist of a 28-day screening period, a single dose of 
ANK-700 administered on D1. Patients will return to the clinic on D4±1, D15, and D29±1. 
Additionally, patients will return to the clinic after 3 and 6 months for follow-up. Blood and 
plasma samples will be collected for PK and anti-drug antibody (ADA) assessments during 
Part A.  In the event that patients are unable to return to the clinic for protocol-specified 
visits, alternative methods for safety assessments and data collection may be employed to 
ensure the safety of the patients where appropriate. 
 
2.3.2 PART B: MAD (Multiple Ascending Doses) 
The first MAD cohort (Cohort 4) will be initiated after the safety review of SAD Cohort 2 
(Part A), a recommendation to proceed by the SMC, and approval by the Sponsor. 
Patients in the MAD part will be randomized as described in Section 3.2. Patients will arrive 
at the clinic on the morning of dosing and will be monitored in-clinic for 24 hours after 
completion of their first infusion for assessment of acute safety and PK blood sample 
collection.  
A total of 3 doses (1 dose every 3 days on D1, D4, and D7) will be administered in Part B, a 
regimen that was effective in animal models of MS. Patients will return to the clinic on D22, 
D43±2, and at 3, 6, and 12 months for follow-up.  
Doses planned for evaluation in Part B include 0.3 mg/kg (Cohort 4) and 1.0 mg/kg (Cohort 
5). Both Part B cohorts will employ sentinel dosing to monitor for the acute and subacute 
safety of multiple doses of ANK-700. In this design, the first 2 patients in each cohort (1 
ANK-700 and 1 PBO) will complete all 3 doses and complete an additional 14 days of safety 
monitoring (through D21) before initiating dosing for any subsequent patients. Based upon 
the expected short half-life (< 7 minutes) of ANK-700, no accumulation is anticipated with 
multiple doses administered 3 days apart. 
Initiation of Cohort 5 will only commence after review of the safety, tolerability, and 
laboratory test and available PK data of all the SAD cohorts (Cohorts 1 to 3) and Cohort 4 
through D22, recommendation by the SMC, and approval by the Sponsor.   
For all patients in Part B, the study will consist of a screening period of up to 28 days, 
followed by 3 doses of study drug, 1 dose administered on D1, D4, and D7. Blood and 
plasma samples will be collected for PK and ADA assessments during Part B of the study.  In 


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the event that patients are unable to return to the clinic for protocol-specified visits, 
alternative methods for safety assessments and data collection may be employed to ensure the 
safety of the patients where appropriate. 
2.4 
Study Drug Dosage and Administration 
 
 
. Administration of study drug in 100 mL normal saline will be by IV infusion 
over approximately 30 minutes. 
For Part A, patients will receive a single IV infusion of ANK-700 only (i.e. no PBO).  The 
following doses will be given: 
 
Part A (SAD) 
 ANK-700 0.3 mg/kg 
 ANK-700 1 mg/kg 
 ANK -700 3 mg/kg 
For Part B, patients will receive 3 IV infusions; each administered 3 days apart, of a given 
dose of either ANK-700 or PBO. Dosing groups in Part B will be as follows: 
Part B (MAD) 
 PBO  
 ANK -700 0.3 mg/kg 
 ANK -700 1 mg/kg 
3. SAMPLE SIZE, RANDOMIZATION AND BLINDING 
3.1 
Sample Size 
In Part A, the number of patients enrolled into a treatment group will be based on safety and 
tolerability within a traditional 3+3 design. If 1 of the first 3 patients in a given cohort 
experiences a DLT within the dose-escalation safety monitoring period (D1 to D15), the dose 
level may expand to a maximum of 6 patients under this model, Part A may enroll 9 to 18 
patients across 3 treatment groups, depending upon the toxicities observed. No formal 
hypothesis testing is planned for Part A.  
Patients in Part A may be replaced if they do not receive the full dose of study drug or do not 
complete the D15 visit, as long as the discontinuation was not due to a DLT assessed to be 
related to study drug. 
In Part B, the total sample size of 24 patients (n=8 ANK-700 0.3 mg/kg; n=8 ANK-700 1 
mg/kg; n=8 PBO) was chosen to allow for a comparison of safety between ANK-700 and 
PBO, however no sample size calculation was performed. 


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In Part B, patients may be replaced if they do not complete all 3 doses and the D22 visit as 
long as they did not discontinue the study because of a related AE. No patient with a DLT 
will be replaced. 
3.2 
Randomization and Blinding 
Once a patient has met all entry criteria, he or she will be assigned a distinct subject 
identifier. If a patient discontinues from the study, the subject identifier will not be reused, 
and the patient will not be allowed to reenter the study. Patients not eligible during the 
screening period, may be rescreened after 4 weeks. Patients who experience a relapse during 
screening may be rescreened after 28 days. 
3.2.1 Part A (SAD) – Open Label 
Part A is open-label. Patients will be assigned to receive open-label ANK-700 at a dose level 
based on the next available spot in the cohort(s) currently being enrolled.  
3.2.2 Part B (MAD) – Double Blind 
Part B is double-blinded, such that study personnel (eg, Investigators, site coordinators) and 
patients are blinded to treatment assignments and will remain blinded throughout the study.  
Unblinded personnel include those involved in drug preparation and allocation (eg, data 
systems support and pharmacists) and those involved in SMC data preparation, including the 
study pharmacokinetic scientist, to allow for expedited review of PK data before SMC 
review. 
 
 
The MAD part of the study includes two cohorts, Cohort 4 (ANK-700 0.3 mg/kg) and Cohort 
5 (ANK-700 1 mg/kg). In each cohort, randomization is stratified based upon a patient‟s use 
of fumarate at study entry within the interactive response technology (IRT) system. 
 
After completion of the sentinel dosing in each cohort, the remaining patients will be 
randomized to ensure an overall 2:1 allocation to either ANK-700 or PBO, respectively. A 
total of 12 patients will be enrolled per each dose cohort (ANK-700 n = 8; PBO, n = 4). 
For the sentinel dosing, the following constraints will occur for the first randomization 
block only (the first block contains the first 3 patients in each stratum): 
 
 Within a cohort/fumarate stratum, the first 2 treatments will not be the same 
treatment.  
 
 Within each cohort, Fumarate yes stratum will not be the same order of treatments as 
the fumarate no stratum.  
 
The below two examples for cohort 4 show what is not permitted to occur in the 
randomization of the first blocks of Cohort 4, nor Cohort 5. 
Patient Order Block 
Cohort 
Fumarate 
Treatment  
 
 
NOT PERMITTED: 
The order of 
treatments for the 
fumarate yes group 
is the same as the 
fumarate no group. 


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Or 
 
Patient 
Order 
Block 
Cohort 
Fumarate 
Treatment 
2 
1 
4 
Yes 
ANK1 
3 
1 
4 
Yes 
PBO 
6 
1 
4 
Yes 
ANK1 
 
 
 
 
 
1 
1 
4 
No 
ANK 1 
4 
1 
4 
No 
ANK 1 
5 
1 
4 
No 
PBO 
 
 
After completion of each dose group in Part B, the data will be presented and reviewed by the SMC in 
a blinded fashion. If a medical emergency occurs, the site may be unblinded for that patient, if 
knowledge of the study treatment is necessary to provide appropriate urgent medical care. 
 
 
 
3.3 
Withdrawal Criteria 
Patients may voluntarily withdraw from the study at any time for any reason without 
prejudice.  Patients will be withdrawn from the study for any of the following reasons:  
 Adverse event 
 Noncompliance with the protocol 
 Lost to follow-up 
 Physician decision 
 Study terminated by sponsor 
 Withdrawal by subject 
 Other 
Treatment may be terminated but patient may be still followed in the study for the following 
reasons: 
1 
1 
4 
Yes 
PBO 
 
 
 
3 
1 
4 
Yes 
ANK 0.3 
 
 
 
5 
1 
4 
Yes 
ANK 0.3 
 
 
 
 
 
 
 
 
2 
1 
4 
No 
PBO 
4 
1 
4 
No 
ANK 0.3 
6 
1 
4 
No 
ANK 0.3 
NOT PERMITTED:  
The first two 
treatments are the 
same. 


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 Adverse event 
 Physician decision 
 Pregnancy 
 Death 
 Lost to follow-up 
 Study terminated by sponsor 
 Withdrawal by subject 
 Protocol deviation 
 Other 
4. CLINICAL PROCEDURES AND ASSESSMENTS 
The assessments collected in the study are outlined in Appendix 1 Table 1 (Part A), Table 2 
(Part B, Cohort 4) and Table 3 (Part B, Cohort 5). 
 
5.  STUDY OBJECTIVES 
Below is an outline of the study objectives 
5.1 
Primary  
 Assess safety and tolerability of escalating doses of ANK-700 in patients with 
RRMS 
5.2 
Secondary 
 Evaluate the PK of escalating doses of ANK in patients with RRMS 
5.3 
  
 
  
 
 
6. ASSESSMENTS 
6.1 
Safety Assessments 
The safety and tolerability of ANK-700 will be assessed by AE and other safety assessments 
as detailed in  Appendix 1 Table 1 (Part A), Table 2 (Part B, Cohort 4) and Table 3 (Part B, 
Cohort 5). 
 
6.1.1 Adverse Events (AE) 
An AE is defined as any untoward medical occurrence associated with the use of a drug, or 
with study participation, whether or not consider related to study treatment. An AE can 


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therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of the medicinal product, whether or 
not considered related to the medicinal product.  
 
AEs include worsening of a pre-existing medical condition, including MS, as well as 
Clinically Significant (CS) changes from baseline laboratory values/conditions. Worsening of 
the preexisting medical condition (eg, diabetes, hypertension) means that it has increased in 
severity, frequency, and/or duration, and/or has an association with a significantly worse 
outcome. A pre-existing condition that has not worsened during the study is not considered 
an AE. 
All AEs are collected from the time of signing of Informed Consent Form (ICF) through the 
final Follow-Up Visit/phone. Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) Version 23.1 (MedDRA Sep 2020) or higher. Ongoing AEs 
considered at least possibly related to ANK-700 treatment should be followed until 
resolution, return to baseline, or are considered stable or chronic. 
6.1.2 Treatment Emergent Adverse Events (TEAE) 
TEAEs are defined as AEs that emerge or worsen in the period from the first dose of study 
treatment to the final Follow-Up Visit/phone call after the last dose study drug.  
The incidence and severity of TEAEs as assessed by the CTCAE v5.0 or higher is considered 
the primary endpoint. 
6.1.3 Adverse Event Severity 
The Investigator will assess the Grade of the AE per the NCI-CTCAE v5.0 or higher 
(Appendix 2). Toxicities that are not specified in the NCI-CTCAE will be defined as follows:  
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
 Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL) 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
6.1.4 Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
 results in death 
 is immediately life-threatening 
 requires inpatient hospitalization or prolongation of existing hospitalization 


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 Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since 
signing the ICF (documented as medical history on the eCRF) is not 
considered an SAE. 
 Scheduled therapy for the target disease of the study, including 
admissions for transfusion support or convenience, is not considered an 
SAE. 
 results in persistent or significant disability/incapacity 
 results in congenital anomaly/birth defect 
 is considered an important medical event 
 If an AE does not meet 1 of the serious criteria, but the Investigator or 
Sponsor considers an event to be clinically important, the event could 
be classified as an SAE under the criterion of an “Important Medical 
Event.” Examples of such medical events may include allergic 
bronchospasm requiring intensive treatment in an emergency room or 
at home, or blood dyscrasias or convulsions that do not result in in 
patient hospitalization. 
6.1.5 AE Relationship to Study Medication 
The Investigator must assess whether the AE may be related to ANK-700 (study drug) or any 
protocol mandated procedure, when applicable. The relationship is defined below:   
Relationship assessments that indicate the event is “Not Drug Related”: 
 Not Related 
 Unlikely Related 
 
Relationship assessments that indicate the event is “Drug Related”: 
 Possibly Related 
 Related 
 
6.1.6 Dose-Limiting Toxicity (DLT) 
Dose-limiting toxicities for Study ANK-700-01 include any Grade 2 AE not resolving within 
14 days or any ≥ Grade 3 AE occurring during the dose-escalation safety monitoring period 
(D1 to D15 in Part A; D1 to D22 in Part B). DLTs do not include those AEs attributable 
solely to intercurrent illness or other concomitant medications. Any DLT experienced during 
the dose-escalation safety monitoring period will result in study pause and review by the 
SMC.  
 
Any ≥ Grade 4 AE will result in notification to the Food and Drug Administration (FDA) in 
parallel with the SMC; all study dosing and enrollment will be paused pending review by 
FDA.    
 


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6.1.7 Clinical Laboratory Endpoints  
The following laboratory parameters will be measured at screening and at the time points 
specified in the Schedule of Assessments and will be analyzed locally by a certified 
laboratory: 
 A serum pregnancy test during screening for all women of child-bearing 
potential (WCBP) 
 Serum or Urine testing for all WCBP prior to each dose 
 Hematology laboratory parameters include white blood cell (WBC) count, 
hemoglobin, hematocrit, platelet count, and WBC differential  
 Blood chemistry laboratory parameters, including blood urea nitrogen, 
creatinine, glucose, AST, ALT, ALP, bilirubin (total and direct), electrolytes 
(sodium, chloride, bicarbonate, potassium), amylase, lipase, albumin, 
magnesium, calcium, and phosphorus 
 Coagulation laboratory parameters, including prothrombin time, partial 
thromboplastin time or activated partial thromboplastin time, and international 
normalized ratio 
 Complete urinalysis with qualitative analysis for protein (dipstick)  
 HIV, HBV (hepatitis B surface antigen, hepatitis B core antibody, and 
hepatitis B surface antibody), and HCV (hepatitis C) testing (screening only)  
6.1.8 Expanded Disability Status Scale (EDSS)  
The EDSS is based on a standard neurological examination, incorporating the pyramidal, 
cerebellar, brainstem, sensory, bowel/bladder, visual, and cerebral [or mental] functional 
systems, and ambulation, rated and scored as functional system scores. The EDSS is a 
disability scale that ranges in 0.5-point steps from 0 (normal) to 10 (death).  See Appendix 3 
for score details. 
6.1.9 Brain Magnetic Resonance Imaging 
Screening and post dose brain MRIs will be performed. Scans will be performed by trained 
and certified MRI technicians. The MRI will include the acquisition of scans at each time 
point with and without IV administered gadolinium contrast enhancement. 
The following time windows apply: 
 “Screening/baseline” MRI should be performed on or after the Screening 
Visit, but ≥ 10 days before the D1 visit. 
 The MRI obtained for the Part A D15 Visit and Part B D22 Visit should be 
performed up to 3 days before or on the scheduled visit day. 
 MRI at Part B visit D90 should be performed within 2 weeks of the scheduled 
visit. 


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MRIs will be performed for assessment of safety only and will be reviewed locally. Data 
collected for each MRI will include number of FLAIR lesions, number of enhancing lesions, 
and presence of restricted diffusion. For post-baseline scans there will be an assessment of 
whether there was improvement or worsening from prior scans. 
If a relapse occurs at the time of a scheduled MRI, the MRI should be obtained before 
initiation of corticosteroid therapy or the MRI should be postponed by 1 month.  
All patients with new neurological symptoms suggestive of MS relapse should have an MRI 
performed (which may include the spinal column) during an unscheduled visit, if clinically 
necessary, but before the initiation of steroids.  
6.1.10 Other Safety Assessments (Physical Exam, Vital Signs and ECG) 
The Physical exam will include an assessment of general appearance, skin, head, neck, throat, 
lymph nodes, cardiovascular, neurological, thyroid, musculoskeletal/extremities, respiratory, 
abdomen, height, and weight (baseline only).  
Vital signs will include temperature, pulse rate, and systolic and diastolic blood pressure 
(sitting for 5 minutes). If vital signs need to be repeated during a single visit, assessments 
should be conducted approximately 5 minutes apart.  
At screening, a standard 12-lead electrocardiogram (ECG) will be obtained at baseline and 
interpreted by the Investigator to confirm eligibility.  
Any new clinically significant (CS) abnormality from baseline should be recorded as an AE. 
 
6.2 
Pharmacokinetic Assessments 
Blood samples will be collected for measurement of ANK-700 as specified in   Appendix 1 
Table 1 (Part A), Table 2 (Part B, Cohort 4) and Table 3 (Part B, Cohort 5).  The timing of 
sampling may be altered based on the emerging PK data. The adjustment of the PK sampling 
schedule is not considered to be a substantial amendment so long as the total number of 
plasma PK samples and the total blood volume to be collected from each participant will not 
change. Any adjusted sampling time points will be documented appropriately. 
PK parameters of ANK-700 will be determined from the plasma concentration-time data. 
Parameters will be calculated by non-compartmental modeling methods, using actual elapsed 
time from start of infusion based on the actual mg administered. The parameters that will be 
calculated are defined in the table below and will be calculated for single or multiple dosing 
of ANK-700, as appropriate. Not all listed parameters may be calculable for every patient, 
and additional parameters may be calculated, if needed, to fully characterize the available 
data. PK parameters and concentration data will be summarized by Part, by Dose, and by Day 
(Single dose Day 1, Multiple dose Day 1, Multiple dose Day 4, Multiple dose Day 7, Single 
and Multiple Dose Day 1 for common doses.        


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Table 1 Pharmacokinetic Parameters for Part A and Part B After Each Dose 
Parameter 
Definition 
Method of Determination 
Cmax  
Maximum observed plasma 
concentration 
Obtained directly from the concentration-time data 
Tmax  
Time to first occurrence of 
Cmax 
Obtained directly from the concentration-time data 
λz 
Terminal elimination rate 
constant 
Terminal phase rate constant calculated by linear 
regression of the log-linear concentration-time curve. 
Only those data points judged to describe the 
terminal log-linear decline will be used in the 
regression.  
A minimum number of three data points in the 
terminal phase will be used in calculating λz with the 
line of regression starting at any post-Cmax data point 
(Cmax should not be part of the regression slope) and 
including Clast, tlast. 
The adjusted correlation coefficient (R2 adjusted) in 
general should be greater than 0.90.  Any value less 
than 0.90 may be used at the PK Scientist‟s best 
knowledge and judgment. 
An appropriate number of decimal places should be 
used for λz to enable the reported value of t½ to be 
calculated. 
t1/2  
Terminal elimination half-life 
Loge(2)/ λz 
AUClast 
 
Area under the plasma 
concentration-time curve from 
time 0 to the last measurable 
time point 
The linear-log trapezoidal method will be employed 
to calculate AUCs. The linear method will be used 
for all incremental trapezoids arising from 
increasing concentrations and the logarithmic 
trapezoidal method will be used for those arising 
from decreasing concentrations.  
AUCt=
 t
0
dt
t
C
)
(
. 
AUCinf 
AUC from time zero 
extrapolated to infinity 
AUCinf =
 t
0
dt
t
C
)
(
＋

t
dt
t
C
)
(
= 
AUCt＋Ct/λz., where Ct is last observed quantifiable 
concentration. 
%AUCex 
Percentage of AUC(0-inf) 
obtained by extrapolation 
(1－[AUCt/AUCinf])×100 
CL 
Clearance  
dose/AUCinf 
Vz 
Volume of distribution during 
terminal phase 
CL/F/λz 
Racc,AUC  
Accumulation ratio based on 
AUC 
 
Racc,Cmax  
Accumulation ratio based on 
Cmax  
 
Ctrough  
Predose plasma concentration 
 


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For cohort by cohort PK analysis, not all PK parameters may be calculated, and non-
compartmental analysis may be done using nominal times from start of infusion. 
6.3 
Antidrug Antibody  
Anti-drug antibody (ADA) sampling will be performed at the time points shown in  Appendix 
1 Table 1 (Part A), Table 2 (Part B, Cohort 4) and Table 3 (Part B, Cohort 5). ADA-positive 
or ADA-negative will be determined for each time point. If the first test comes back positive 
then the reactivity to the pgal and peptide will be assessed separately. Titers will be 
determined for ADA positive sample if the quantity is sufficient for the determination.  
6.4 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 


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6.4.1 
  
 
 
 
 
6.5 
Other Assessments  
Additional assessments will be collected for demographics, medical history, concomitant 
medication, informed consent inclusion/exclusion, study drug administration will be 
explained in more detail in Section 8. 
7. ANALYSIS SETS 
Enrolled Analysis Set is defined as all patients in Part A and Part B who were enrolled in the 
study and signed informed consent form.  
All-Treated Analysis Set (ATAS) is defined as all patients who receive any amount of study 
drug. This analysis set will be the primary analysis set for all safety and exploratory 
endpoints.  
PK Analysis Set (PKAS) will include all enrolled patients who receive ≥ 1 complete dose of 
study drug and have ≥ 1 pre-dose and 1 post-dose measurement. This analysis set will be 
used for the analysis of PK parameters as further defined in the protocol. 
Patients who receive at least one full dose out of the three doses will be included in this 
population; if a patient misses a dose or does not complete a dose then the PK concentration 
data, for that observation, will be considered missing. 
8. STATISTICAL METHODS 
All outputs will be produced using SAS® version 9.4 or a later version.   
No hypothesis will be tested. 
Summary statistics will be presented for all variables of interest for the ATAS population 
unless otherwise specified. Categorical variables will be summarized using numbers and 
percentages and be presented by dose level received. Continuous variables will be 
summarized by total number (n), mean, standard deviation (SD), median, and range 
(minimum and maximum). For log transformed data, the geometric mean will be provided 
along with the other summary statistics. Categorical data will be presented by frequency and 
percent of patients in the treatment group.  
Listings will be sorted by Study Part, subject ID, Treatment, study visit, date and time, where 
applicable, unless otherwise specified.  
Summary statistics for Part A and B will be presented in the following manner: 


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 For Part A, summary statistics will be provided for subject disposition with the 
following tables summarized: 
o Disposition 
o Analysis populations 
o Demographics 
o Protocol Deviations 
o PK analysis 
o Summary of TEAE 
o Summary of TEAE by System Organ Class and Preferred Term 
 
  For Part B alone, summary statistics will be provided by treatment group, pooling the 
placebo group from each cohort for all tables.  
 For Part A and B pooled, summary statistics will be provided by pooling the treatment 
groups with only the following tables summarized: 
o Disposition 
o Analysis Populations 
o Demographics 
o PK analysis 
8.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked 
for consistency, integrity and in accordance with standard Parexel procedures. 
 
8.2 
Subject Disposition and Screen Failures 
The number and percentage of patients in each disposition category (eg, enrolled, analysis 
sets, discontinuing treatment, and discontinuing study, with a breakdown of the reasons for 
discontinuation) will be summarized by treatment group for all patients.  
 
A clear accounting of the disposition of all patients who enter the study will be provided, 
from screening to end of study participation. Number and percentage of patients screened, 
enrolled/randomized, patients completed treatment, patients discontinued from the study and 
discontinuation reasons (including reasons for early withdrawal). 
 
The summary tables will be provided by treatment group for subject disposition on enrolled 
patients. Listing will consist of ICF date, enrollment details (last contact date, reason of 


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screened failure), randomization codes, visit dates, and withdrawal details (including reason 
for discontinuation and duration of treatment prior to discontinuation). 
A by-subject listing will be provided by study part and treatment group for study treatment/ 
randomization codes, study drug completion status, study completion status and subject 
disposition on enrolled patients. Screen failures, and patients who did not meet study 
eligibility criteria listings will be on listing of screened patients. 
8.3 
 Prior and Concomitant Medication 
Medication start and stop dates will be compared to the date of first dose of ANK-700 to 
allow medications to be classified as either Prior only, both Prior and Concomitant, or 
Concomitant only.  Medications starting after the completion/withdrawal date will be listed 
but will not be classified or summarized. 
Medications will be assigned to a time period (prior and /or concomitant) as follows: 

If medications that start and stop prior to the date of first dose of ANK-700, 
the medications will be classified as Prior only.

If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be counted as prior.

If a medication starts before the date of first dose of ANK-700 and stops on or after the 
date of first dose of ANK-700, then the medication will be classified as both Prior 
and Concomitant.

If the start date is missing and the stop date is after the first dose of study drug or the 
medication is continuing, the medication will be counted as concomitant only.

If they have a start date on or after the date of first dose of ANK-700, medications 
will be classified as Concomitant only.

If medication start and/or stop dates are missing or partial, the dates will be compared 
as far as possible with the date of first dose of ANK-700.
All concomitant medication and concurrent therapies as documented by the investigator, will 
be coded using the most current version of the WHO drug dictionary (WHO DD) available at 
the time of database lock. 
If a patient has taken concomitant medications more than once, the patient will be counted 
only once in the total. The number and percentage of patients taking prior and concomitant 
medications will be summarized by WHO Drug Name. 
For Part A and B, summary tables (as described in Section 7) will be provided by treatment 
group for prior and concomitant medications by ATC Levels and PT. 
By-subject listings of concomitant medication and concurrent therapies including dose, route, 
unit frequency of administration, and indication for administration and dates of medication 
will be provided on enrolled patients and sorted by part, subject ID and date of medication 
start. 


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After patients have completed the 3-month visit (D90), they may receive alternative DMTs 
(Disease modifying Therapy) for their MS if judged clinically appropriate by their treating 
physician or the Investigator. Summary statistics for observations after 90 days may be 
presented in a sample size report, stratified by medication, if sample size permits. 
8.4 
Demographics, Baseline Characteristics, Disease History and Medical History 
Patient listings will be presented for all enrolled patients for Part A and Part B, by treatment 
group, center, and subject ID for enrolled patients unless otherwise specified. Listings will be 
sorted by part and subject id unless otherwise specified. 
Demographics and baseline characteristics will be summarized by treatment (PBO and dose 
group) for the All-Treated Analysis Set: sex, race, age, ethnicity, height, weight, BMI . 
All medical history will be coded using Version 23.1 or higher of the Medical Dictionary for 
Regulatory Activities (MedDRA). A count and percentage will be presented for all medical 
history, including disease history and previous therapies. MS history is considered part of 
medical history and the following will be summarized (as stated in Section 7): concomitant 
fumarate use, duration since MS symptom onset, duration since MS diagnosis, number of 
relapses within the last year, number of relapses within the past 3 years, duration since last 
relapse, and use of previous MS treatments.  
8.5 
Study Drug Administration and Compliance 
A by-subject listing for study drug administration and compliance will be provided by study 
part and treatment group on enrolled patients 
 
The treatment compliance (%) at a study part and treatment group will be calculated as total 
received dose (mg) *100/sum of total intended dose (mg) during the treatment. 
 
8.6 
Dosing and Extent of Exposure 
Exposure will be calculated for study Part A and Part B by dose level; all exposure data will 
be listed (for details see Section 7 ) for both parts. The exposure variables include: 
 
the cumulative number of days of exposure- count of days of treatment 
 
the number of IV infusions completed  
 
the relative dose intensity  
 
All variables are predefined:  
 The relative dose intensity is defined as the percentage of the planned treatments 
completed. It is the ratio of the cumulative actual dose (mg) and cumulative planned 
dose (mg) times 100. In this definition, 


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o the cumulative actual dose (mg) is the sum of the actual doses (mg) that the 
patient receives during the study  
o the cumulative planned dose (mg) is the cumulative number of days of 
exposure times the planned dose level (mg) 
8.7 
Protocol Deviations 
Protocol deviations will be reviewed and assessed before database lock. The major protocol 
deviations are defined as those deviations from the protocol that are likely to have an impact 
on the subject‟s rights, safety, well-being, and/or on the validity of the data for analysis. 
 
A summary of the number and percentage of patients with a major/minor protocol deviation 
as well as by type of deviation will be provided. Also, a by-subject listing of major/minor 
protocol deviations will be provided by treatment part, subject ID, and visit. 
8.8 
SAFETY ANALYSES 
Safety analysis will be performed among patients who received at least a partial dose of study 
drug. If a patient experiences the same adverse event more than once, then the patient will be 
counted only once for that adverse event for frequency counts. Similarly, if a patient has 
more than one adverse event in a single SOC, then the patient will be counted only once for 
that SOC. 
 
If a patient has taken the same concomitant medication (as coded to World Health 
Organization (WHO) PT) more than once, then the patient will be counted only once for that 
concomitant medication. 
 
8.8.1 Adverse Events 
The AE terms will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA™) Dictionary (Version 17.1 or 
later). AEs will also be presented by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 (National Cancer Institute) NCI (Version 5.0) from Grade 1-Grade 5 of 
mild, moderate, severe, Life-threatening and death and by relationship to study drug. AEs 
will be presented by severity only when the CTC grade is not collected. 
 
The Following Tables will be Provided for Part A .  
 Overall summary of TEAE will include the number of patients with any TEAEs, 
drug-related TEAEs, ≥ Grade 3 TEAEs, treatment-emergent serious AEs (TESAEs),  
TEAEs leading to discontinuation (treatment and study); 
 A summary of the number and percentage of patients reporting a TEAE by system 
organ class (SOC) and PT;  
 
For Part B (MAD) only, the following AE summaries (as described in Section 7) will be 
provided:  


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 Overall summary of TEAE will include the number of patients with any TEAEs, 
drug-related TEAEs, ≥ Grade 3 TEAEs, treatment-emergent serious AEs (TESAEs),  
TEAEs leading to discontinuation (treatment and study); 
 A summary of the number and percentage of patients reporting a TEAE by system 
organ class (SOC) and PT;  
 A summary of the number and percentage of patients reporting a TEAE by severity, 
SOC and PT. 
 A summary of the number and percentage of patients reporting a TEAE by causality, 
SOC and PT; 
 A summary of the number and percentage of Maximum CTCAE recorded  
 A summary of the number and percentage of patients reporting a Serious TEAE by 
system organ class (SOC) and PT;  
 
 
AE summaries will be ordered in terms of decreasing frequency for SOC, and PT within 
SOC, in the Total group, and then alphabetically for SOC, and PT within SOC.   
 
For each subject and each AE, the worst severity recorded will be attributed and used in the 
by-severity summaries. Similarly, the worst causality (most related to treatment) will be 
attributed and used in the by-causality summaries. 
 
For Part A and Part B, by-subject listings of AEs will be presented by study part and 
treatment group for the following listings: 
 All DLT events 
 All TEAEs 
 All SAEs 
 All TESAEs 
 TEAEs Leading to Study Discontinuation  
 TEAEs Leading to Permanent Discontinuation of Study Drug  
 TEAEs Leading to Death 
 Non-TEAEs 
 
The following information will be included in the listings: verbatim (reported term), PT, 
SOC, AE onset date (and time), AE end date (and time), AE duration, relationship to study 
drug, AE outcome, severity, and SAE indicator flag.  Confirmed and suspected SARS-CoV-2 
infections and/or COVID-19 cases will be recorded in the AE eCRF. 
 
Pandemic related Impact of COVID-19 will be presented in listing, detailing the category of 
impact (example: Missed Visit, Missed Assessment, Early termination, Screen Failure, 
Adverse Event, Withdrawal of consent, Death, Replacement subject). 
 


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8.8.2 Physical Examination  
Physical exam results will be listed for Part A and B, sorted by study Part, subject ID, body 
system and date of exam.  
8.8.3 Vital Signs  
Vital signs (temperature, pulse rate, and diastolic and systolic blood pressure will be 
summarized (as described in Section 7) for observed values and change from baseline, at 
each visit measured.  
8.8.4 Clinical Laboratory Evaluation 
For Part B only, clinical laboratory summary statistics (as described in Section 7) will be 
provided for serum chemistry, hematology, coagulation and urinalysis (specific gravity and 
pH only) for observed values and change from baseline by study visit. 
 
A shift table will be provided to evaluate the change from baseline to each post-baseline visit 
in the lab value status (abnormal high, normal, abnormal low) for serum chemistry, 
hematology, and coagulation. 
The following by-subject laboratory listings (values and change from baseline if applicable) 
will be provided by study part and treatment group using the enrolled patients and sorted by 
subject ID, laboratory evaluation and date measured:  
 Serum Chemistry 
 Hematology 
 Coagulation 
 Urinalysis 
 Virus Serology (screening only) 
 Serum and Urine Pregnancy test 
 Lab abnormality ≥ Grade 3 in Severity. 
 
Toxicity, in reflection of safety laboratory results will be graded locally according to NCI-
CTCAE v5.0 or higher and included in separate listings. 
8.8.5 ECGs 
Screening data collected on ECG (normal/abnormal) will be listed by patient number.  
 
8.8.6   Medication for Infusion Reaction 
A by-subject listing will be provided by study part and treatment group for any medications 
to treat infusion reactions by ATC levels and PT on enrolled patients.  
8.8.7 MRI of Brain 
 Summaries of MRI scans will include: 


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 Number and percentage of patients with Screening scans classified as normal or 
abnormal 
 For post-baseline scans: number and percentage of patients with scans classified as 
improved, worsened, or unchanged since previous scan, by visit 
 Number and percentage of patients with any FLAIR lesions found, by visit 
 Number and percentage of patients with any enhancing lesions found, by visit 
 Number and percentage of patients with evidence of restricted diffusion present, by 
visit 
By-subject listings of MRI findings also will be provided. 
8.9 
Efficacy Analysis 
There is no efficacy analysis. 
8.10 
Pharmacokinetics 
Non-compartmental PK parameters will be determined using Phoenix® WinNonLin (WNL) 
version [8.3] or a later version in a secure and validated environment. All pharmacokinetic 
data analysis will be performed on the PKAS set. 
8.10.1 Pharmacokinetic Concentration Tables, Figures, and Listings 
For Part A (SAD) and Part B (MAD), separately, plasma concentrations for ANK-700 will be 
summarized by treatment group, day of dose, and nominal protocol time point for PKAS. 
Additionally, Part A and B will be pooled for a combined summary concentration table by 
dose on the first (Day 1) dose only for PKAS.  
 
A by-subject listing for plasma concentration data for ANK-700, will be listed by study part, 
treatment group, patient, and day/time of dose for PKAS. Listings will include nominal and 
protocol time, actual sampling time relative to start of infusion, actual infusion duration, 
scheduled infusion duration (30 minutes), and difference between scheduled and actual 
infusion duration. 
 
All individual as well as summary concentration data (mean, SD, minimum, median, 
maximum, and geometric mean) will be reported in Table, Figures, and Listings to the same 
precision as the data provided by the Bioanalytical Lab, e.g, if concentrations are provided as 
3 significant digits, TFLs will also report individual and summary concentration data as 3 
significant digits. N will represent number of subjects in the treatment group, n will represent 
number of concentrations available at a nominal time, n(blq) will represent number of 
concentrations available at a nominal time that are blq, and n (ND) will represent number of 
concentrations available at a nominal time that were not drawn, not analyzed, or analyzed but 
not reportable. N and n‟s will be reported as whole number. Pharmacokinetic Parameters 
Tables, Figures, and Listings 
 
Following figures will be presented for Part A and B, separately, and for Day 1 combined 
parts A and B (except for individual separate plots for each patient): 


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 Linear mean (+/- SD) plasma concentration-time profiles for ANK-700 (all doses on one 
plot)  
 Semilogarithmic mean (+/- SD) plasma concentration-time profiles for ANK-700   (all 
doses on one plot) 
 Linear individual concentration-time profiles for ANK-700 (all patients on same dose on 
one plot) 
 Semilogarithmic individual concentration-time profiles for ANK-700 (all patients on 
same dose on one plot) 
 Linear individual concentration-time profiles for ANK-700 (separate plot for each 
patient) 
 Semilogarithmic individual concentration-time profiles for ANK-700 (separate plot for 
each patient) 
 
8.10.2 Pharmacokinetic Parameters Tables, Figures, and Listings 
For Part A and Part B separately, and Part A and Part B, Day 1 (combined), summary tables 
of ANK-700 calculable pharmacokinetic parameters will be provided that were calculated 
using concentrations available in PKAS.  
 
A by-subject listing for PK parameters for ANK-700 will be listed by study part, by treatment 
group, by patient and day of dose using the PKAS.  
 
Following rules will be followed for reporting PK parameters: 
 
For tmax, only median, minimum and maximum values will be presented. 
 
For all other parameters N, n, mean, SD, CV%, median, minimum, maximum, geometric 
mean, and geometric CV% will be presented. N will represent the number of subjects in the 
treatment group and n will represent calculable PK parameter in the treatment group. 
 
Lambda z dependent PK parameters, i.e. λz, AUCinf, CL, Vz will not be summarized if 
r2adjusted is <0.90, and/or span of the terminal phase is <1.3 times the half-life and/or the 
%extrapolation to calculate AUCinf is >30%, unless otherwise determined by the PK scientist. 
Such parameters will be flagged in parameters listing, and if flagged parameters are not used 
for calculation of descriptive summaries, it will be footnoted in the PK parameters listing. 
For summarizing or calculating the summary PK parameters, the individual parameter values 
as provided by the Phoenix® software will be used without any truncation.  
 
In tables, figures, and listings, individual and summary Cmax will be reported to the same 
precision as that provided by the Bioanalytical Lab, Tmax will be reported in 3 decimal places 
in hours and all other PK parameters will be reported as 3 significant figures. N and n will be 
reported as whole number and CV% will be reported in 2 decimal places. 
 
Box plots for Cmax, AUClast, and AUCinf and corresponding dose normalized parameters will 
be created to visually assess dose proportionality. 


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8.10.2.1 
Assessment of Dose Proportionality 
No formal dose proportionality assessment will be performed. Informal assessment of dose 
proportionality will be done using Box plots, displaying minimum, Q25, median (Q50), Q75 
and maximum will be provided for NK-700 Cmax and AUCs by visit/day and dose level.  
 
8.10.2.2 
Antidrug Antibodies 
For Part B (MAD) only, immunogenicity summaries will be provided by treatment group on 
ATAS. Patients with any ADA positive samples, screening (ADA status) and confirmatory 
assay (titer, specificity, and ADA status) results will be included. The results for 3-Tiers will 
be displayed. If the sample is ADA-positive then the reactivity to the pgal and peptide will be 
included.  
 
A by-subject listing of immunogenicity will be provided by study part and treatment group on 
enrolled patients. 


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8.12 
 
 
 
9. ADJUSTMENTS FOR COVARIATES 
There will be no adjustment for covariates in this study. 
10. DATA HANDLING AND MISSING DATA 
All missing or partial data will be presented in the patient data listing, as they are recorded on 
the eCRF. Patients lost to follow-up or withdrawn will be included in statistical analyses up 
to the point of their last evaluation.  
10.1 
Missing Start and Stop Dates/Time for Adverse Events 
Due diligence will be done to obtain accurate AE information. If all planned methods to 
obtain accurate time AE information have failed, missing and partial AE onset and end dates 
will be imputed. Imputed dates will be flagged in the individual supportive patient listings. 
Unless otherwise specified, the following conventions will be used: 
Missing and Partial AE onset dates: 
 If onset date is completely missing, then onset date is set to date of first dose. 
 If onset year is present and  
- month and day are missing: 
 If onset year = year of first dose, then set onset date to date of first dose. 
 If onset year < year of first dose, then set onset month and day to December 
31st. 
 If onset year > year of first dose, then set onset month and day to January 1st. 
- month is missing: 
 If onset year = year of first dose, then set onset date to date of first dose. 
 If onset year < year of first dose, then set onset month to December. 
 If onset year > year of first dose, then set onset month to January. 
 If onset month and year are present and day is missing: 
- If onset year = year of first dose and 
 onset month = month of first dose then set onset date to date of first dose. 
 onset month < month of first dose then set onset date to last day of month. 
 onset month > month of first dose then set onset date to 1st day of month. 
- If onset year < year of first dose, then set onset date to last day of month. 
- If onset year > year of first dose, then set onset date to 1st day of month. 
 For all other cases, set onset date to date of first dose. 


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Missing and Partial AE end dates: 
 If end date is completely missing, end date is not imputed and the AE is flagged as 
“ongoing”. 
 If year is present and  
- month and day are missing: 
 If year = year of last dose, then set end date to the date of last dose. 
 If year < year of last dose, then set end month and day to December 31st. 
 If year > year of last dose, then set end month and day to January 1st. 
- month is missing: 
 If year = year of last dose, then set end date to date of last dose. 
 If year < year of last dose, then set end month to December. 
 If year > year of last dose, then set end month to January. 
 If month and year are present and day is missing: 
- If year = year of last dose and 
 month = month of last dose then set day to day of last dose. 
 month < month of last dose then set day to last day of month. 
 month > month of last dose then set day to 1st day of month. 
- If year < year of last dose, then set end date to last day of the month. 
- If year > year of last dose, then set end date to 1st day of month. 
 For all other cases, set end date to date of last dose. 
 Screen failures are collected in EDC and will be a part of SDTM. Screen failure data 
are not analyzed and will not be included in the ADaM except for demographics 
(ADSL) and inclusion/exclusion criteria (ADIE).  
Any AEs with incomplete start and end dates/times will be treated as follows: 
 Adverse events with unknown start and/or end times (but where the date is known) 
will be imputed with a time of 00:00 h for the tabulations but will be shown as NK: 
NK in the listings (where NK = Not Known). 
10.2 
Missing Start and Stop Dates for Prior and concomitant Medication 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication starts and stop dates will be imputed as follows: 
 If year and month are present and day is missing, then set day to first day of month for 
start date and set day to last day of month for end date.  
 If year and day are present and month is missing, then set month to January for start 
date, and set month to December for end date.  


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 If year is present and month and day are missing, then set month and day to January 1 
for start date and set month and day to December 31 for end date.  
 Completely missing date will not be imputed. 
The partial dates will be provided as such in the patient data listings (with the imputed dates). 
When imputing a start date, the programmer will ensure that the new imputed date is sensible 
i.e. it is before the end date of prior and concomitant medications. 
10.3 
Concentrations Below the Limit of Quantification (BLQ) 
For PK data, all concentrations BLQ will be labeled as “BLQ” in the concentration data 
listings. Values that are BLQ will be substituted by for the calculation of descriptive statistics 
of concentration tables and for the individual and mean concentration-time plots.  
 
For non-compartmental PK analysis, all below the limit of quantification (BLQ) values pre-
dose to the first dose, and prior to the first quantifiable concentration will be substituted by 
zeros. BLQ values between non-BLQ concentrations will be considered missing before the 
calculation of the PK variables. Terminal BLQ values will be considered missing. 
 
10.4 
Labs 
 (BLQ and ULQ) 
For relevant labs 
, BLQ will be labeled as “BLQ” in the data listings. 
Values will be replaced with ½ LLQ (Lower Limit of Quantification) when summarized in 
tables. Values will also be labeled when they are above the ULQ (upper limit of 
quantification) and will be replaced with the ULQ when summarized in tables. 
 
11. INTERIM ANALYSES AND DATA MONITORING 
No Interim analysis will be performed.  
This study will utilize an independent SMC that will meet regularly during dose escalation to 
review all accumulated and available data, including safety and PK. 
11.1 
Pooling Centers  
Patients will be pooled together for analysis from all study sites. No site adjustment will be 
made. The placebo patients will be pooled from each cohort.  
 
12. CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED IN 
THE PROTOCOL 
 Changes in statistical methods as compared to those stated in the protocol will be 
documented in the CSR. 
 
 


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13. APPENDIX 1: SCHEDULE OF ASSESSMENTS 
Table 1: Schedule of Assessments Part A (SAD)  
Assessment   
Screening  
Study Period  
Early 
Term.  
Study Day  -28 to 0  
1  
4±1  15  29±1  90±7  182±7  
  
Screening Assessments  
 
 
 
 
Informed consent  
X  
  
  
  
  
  
  
  
Medical 
history/demographics  
X  
  
  
  
  
  
  
  
Disease history  
X  
  
  
  
  
  
  
  
Inclusion/exclusion   
X  
  
  
  
  
  
  
  
ECG  
X  
  
  
  
  
  
  
  
HIV, HBV, HCV testing  
X  
  
  
  
  
  
  
  
Clinical Procedures  
 
 
 
 
Physical examination  
X  
  
  
  
  
  
  
X  
Pregnancy test  
X  
Xf,  
  
  
  
  
  
  
Vital signs  
X  
Xg  
  
X  
  
  
  
X  
Concomitant medications and 
procedures  
X  
X  
X  
X  
X  
X  
X  
X  
EDSS  
X  
Xg  
  
X  
  
X  
X  
  
Safety Assessments  
 
 
 
 
Adverse events  
X  
X  
X  
X  
X  
X  
X  
X  
Laboratory tests (safety)  
X  
Xg  
X  
X  
  
  
  
X  
MRIi  
X  
  
  
X  
  
  
  
  
Study Drug Administration   
 
 
 
ANK-700 administration  
  
Xm  
  
  
  
  
  
  
Additional Blood Samples  
 
 
 
 
PK blood sample  
  
Xl  
X  
  
  
  
  
  
ADA samples  
  
Xg  
  
  
X  
  
  
X  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
a All patients should be contacted by site staff 1 day prior to each study visit for assessment of COVID-19 signs 
and symptoms.   
b Early termination visit only if patient discontinues within 28 days of dosing.  
c On D1 patients will be observed in the clinic/hospital unit for 8h after completion of IV infusion and followed 
up with by phone following discharge 24 hours after dosing.  


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d Additional PEs will also be conducted as clinically indicated.  
e Includes weight at screening only.  
f Pregnancy test at screening must be serum; serum or urine tests are acceptable on Day 1 (D1) prior to dosing. 
Screening and D1 pregnancy test must be negative before ANK-700 is administered. Additional pregnancy 
monitoring per local guidelines may be implemented.  
g Samples/measurements to be taken pre-dose.  
h Vital signs include pulse rate, temperature, and diastolic and systolic blood pressure.  
i In the event of a suspected disease relapse, an unscheduled MRI and EDSS assessment may be performed if 
deemed clinically necessary.  
j The screening MRI must be performed ≥ 10 days prior to dosing on D1.  For re-screening, the MRI only needs 
to be repeated if the previous assessment has been completed >3 months of scheduled dosing or if a relapse 
has occurred since last assessment.    
k The MRI at D15 may be performed up to 3 days before the D15 Visit.   
l One PK sample will be taken pre-dose (≥at least 5 min prior to infusion), with all subsequent PK samples 
taken after the end-of-infusion (EOI) at the following time points: EOI 0 (+2) min, EOI 7 (±2) min, EOI 15 
(±2) min, EOI 30 (±5) min, EOI 1 h (±5 min), EOI 2 h (±5 min), EOI 3 h (±5 min), EOI 4 h (±5 min), EOI 6 h 
(±5 min), and EOI 8 h (±5 min). PK samples to be taken from the arm that did not receive the infusion. The 
exact date and time of each sample collection must be recorded for all collected samples.  
m The prepared saline bag and infusion line should be weighed before and after administration. These weights 
should be recorded using any available scale with a precision to at least one tenth of a gram (0.1 grams). Both 
weight measurements should be conducted using the same scale to reduce variability.  
  
Abbreviations: ADA = anti-drug antibodies; D=day; Early Term = early termination; ECG = 
electrocardiogram; EDSS = Expanded Disability Status Scale; 
 
h= hours; EOI = end of infusion; HBV = hepatitis B virus; HCV = hepatitis C virus; 
 
 min = minute; MRI = magnetic resonance imaging; 
; PE 
= physical examination; PK = pharmacokinetics; SAD = single ascending dose. 
 
 


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 Table 2: Schedule of Assessments Part B (MAD) COHORT 4 ONLY  
Assessments  
Screening 
Treatment 
Period  
Study Period  
Early 
Term.  
Study Day  -28 to 0  
1  
4  
7  22  43±2  90±7  182±7 365±14  
  
Screening Assessments  
Informed consent  
X  
  
  
  
  
  
  
  
  
  
Medical 
history/demographics  
X  
  
  
  
  
  
  
  
  
  
Disease history  
X  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion   
X  
  
  
  
  
  
  
  
  
  
ECG  
X  
  
  
  
  
  
  
  
  
  
HIV, HBV, HCV 
testing  
X  
  
  
  
  
  
  
  
  
  
Clinical Procedures   
Physical examination  
X  
  
  
  
  
  
  
  
  
X  
Pregnancy test  
X  
Xf,   Xf ,g  Xf, g    
  
  
  
  
  
Vital signs  
X  
Xg  
  
  
X  
  
  
  
  
  
Concomitant 
medications and 
procedures  
X  
X  X  X  X  
X  
X  
X  
X  
X  
EDSS  
X  
Xg  
  
  
X  
  
X  
X  
X  
  
Safety Assessments  
Adverse events  
  
X  X  X  X  
X  
X  
X  
X  
X  
Laboratory tests 
(safety)  
X  
Xg  Xg  Xg  X  
  
  
  
  
X  
MRIi  
X  
  
  
  
X  
  
X  
  
  
  
Study Drug Administration  
Randomization  
  
X  
  
  
  
  
  
  
  
  
ANK-700 or PBO 
administration  
  
X,q  X,q  Xo,q    
  
  
  
  
  
Additional Blood Samples   
PK blood sample  
  
X  Xg  X  X  
  
  
  
  
  
ADA samples  
  
Xg  
  
  
X  
  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
a All patients should be contacted by site staff 1 day before each study visit for assessment of COVID-19 signs 
and symptoms.  
b Early termination visit only if patient discontinues within 28 days of dosing.  
c On D1 patients will be observed in the clinic/hospital unit for 8h after completion of IV infusion and followed 
up with by phone following discharge 24 hours after dosing.  
d Pes will also be conducted on study as clinically indicated.  
e Includes weight at screening only.  
f Pregnancy test at screening must be serum; serum or urine tests are acceptable on D1, D4, and D7 prior to 
dosing.  Screening and dosing day pregnancy tests must be negative before study drug is administered. 
Additional pregnancy monitoring per local guidelines may be implemented.  


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g Samples/measurements taken pre-dose.  
h Vital signs include pulse rate, temperature, and diastolic and systolic blood pressure.  
i In the event of a suspected disease relapse, an unscheduled MRI and EDSS assessment may be performed if 
deemed clinically necessary.  
j The screening MRI must be performed ≥ 10 days prior to dosing on D1. For re-screening, the MRI only needs 
to be repeated if the previous assessment has been completed >3 months of scheduled dosing or if a relapse 
has occurred since last assessment   
k The MRI at D22 may be performed up to 3 days before the D22 visit.  
l The MRI at D90 may be performed within 2 weeks of the scheduled D90 visit.  
m On D1, patients will be observed in the clinic for 8 h after completion of IV infusion.  
n On D4 and D7, patients will be observed for 4 h after completion of IV infusion.  
o On D1, 1 PK sample will be taken pre-dose (≥ 5 min prior to infusion), with all subsequent PK samples taken 
after the end of infusion (EOI) at the following time points: EOI 0 (+2) min, EOI 7 (±2) min, EOI 15 (±2) 
min, EOI 30 (±5) min, EOI 1 h (±5 min), EOI 2 h (±5 min), EOI 3 h (±5 min), EOI 4 h (±5 min),  EOI 6 h (±5 
min) and EOI 8 h (±5 min). PK samples to be taken from the arm that did not receive the infusion. The exact 
date and time of each sample collection must be recorded for all collected samples.  
p On D7, PK samples to be taken at pre-dose (≥ 5 min prior to infusion), and the following time points after the 
end of infusion (EOI): EOI 0 (+ 2) min, EOI 7 (± 2) min, EOI 15 (± 2) min, EOI 30 (± 5) min, EOI 1 h (± 5 
min), EOI 2 h (± 5 min), EOI 3 h (± 5 min), and EOI 4 h (± 5 min). PK samples to be taken from the arm that 
did not receive the infusion. The exact date and time of each sample collection must be recorded for all 
collected samples.  
q The prepared saline bag and infusion line should be weighed before and after administration. These weights 
should be recorded using any available scale with a precision to at least one tenth of a gram (0.1 grams). Both 
weight measurements should be conducted using the same scale to reduce variability.  
  
Abbreviations: ADA = anti-drug antibodies; D = day; Early Term = early termination; ECG = 
electrocardiogram; EDSS = Expanded Disability Status Scale; 
; 
EOI = end of infusion; h = hours; HBV = hepatitis B virus; HCV = hepatitis C virus; 
 
; IV = intravenous; MAD = multiple ascending dose; min = minutes; MRI = magnetic resonance 
imaging; PBO = placebo; 
; PK = pharmacokinetics; 
 
.  
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3: Schedule of Assessments Part B (MAD) COHORT 5 ONLY  
Assessments  
Screening 
Treatment 
Period  
Study Period  
Early 
Term.  
Study Day  -28 to 0  
1  
4  
7  22  43±2  90±7  182±7 365±14  
  
Screening Assessments  
Informed consent  
X  
  
  
  
  
  
  
  
  
  
Medical 
history/demographics  
X  
  
  
  
  
  
  
  
  
  
Disease history  
X  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion   
X  
  
  
  
  
  
  
  
  
  
ECG  
X  
  
  
  
  
  
  
  
  
  
HIV, HBV, HCV 
testing  
X  
  
  
  
  
  
  
  
  
  
Clinical Procedures   
Physical examination  
X  
  
  
  
  
  
  
  
  
X  
Pregnancy test  
X  
Xf,   Xf, g  Xf, g    
  
  
  
  
  
Vital signs  
X  
Xg  
  
  
X  
  
  
  
  
  
Concomitant 
medications and 
procedures  
X  
X  X  X  X  
X  
X  
X  
X  
X  
EDSS  
X  
Xg  
  
  
X  
  
X  
X  
X  
  
Safety Assessments  
Adverse events  
  
X  X  X  X  
X  
X  
X  
X  
X  
Laboratory tests 
(safety)  
X  
Xg  Xg  Xg  X  
  
  
  
  
X  
MRIi  
X  
  
  
  
X  
  
X  
  
  
  
Study Drug Administration  
Randomization  
  
X  
  
  
  
  
  
  
  
  
ANK-700 or PBO 
administration  
  
X,r  X,r  Xo,r    
  
  
  
  
  
Additional Blood Samples   
PK blood sample  
  
X  Xg  X  X  
  
  
  
  
  
ADA samples  
  
Xg  
  
  
X  
  
X  
X  
X  
X  
  
  
  
  
  
  
  
  
  
  
  
 
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
a All patients should be contacted by site staff 1 day before each study visit for assessment of COVID-19 signs 
and symptoms.  
b Early termination visit only if patient discontinues within 28 days of dosing.  
c On D1 patients will be observed in the clinic/hospital unit for 8h after completion of IV infusion and followed 
up with by phone following discharge 24 hours after dosing.  


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d PEs will also be conducted on study as clinically indicated.  
e Includes weight at screening only.  
f Pregnancy test at screening must be serum; serum or urine tests are acceptable on D1, D4, and D7 prior to 
dosing.  Screening and dosing day pregnancy tests must be negative before study drug is administered. 
Additional pregnancy monitoring per local guidelines may be implemented.  
g Samples/measurements taken pre-dose.  
h Vital signs include pulse rate, temperature, and diastolic and systolic blood pressure.  
i In the event of a suspected disease relapse, an unscheduled MRI and EDSS assessment may be performed if 
deemed clinically necessary.  
j The screening MRI must be performed ≥ 10 days prior to dosing on D1. For re-screening, the MRI only needs 
to be repeated if the previous assessment has been completed >3 months of scheduled dosing or if a relapse 
has occurred since last assessment   
k The MRI at D22 may be performed up to 3 days before the D22 visit.  
l The MRI at D90 may be performed within 2 weeks of the scheduled D90 visit.  
m On D1, patients will be observed in the clinic for 8 h after completion of IV infusion.  
n On D4 and D7, patients will be observed for 4 h after completion of IV infusion.  
o On D1, 1 PK sample will be taken pre-dose (≥ 5 min prior to infusion), with all subsequent PK samples taken 
after the end of infusion (EOI) at the following time points: EOI 0 (+2) min, EOI 7 (±2) min, EOI 15 (±2) 
min, EOI 30 (±5) min, EOI 1 h (±5 min), EOI 2 h (±5 min), EOI 3 h (±5 min), EOI 4 h (±5 min),  EOI 6 h (±5 
min) and EOI 8 h (±5 min). PK samples to be taken from the arm that did not receive the infusion. The exact 
date and time of each sample collection must be recorded for all collected samples.  
p On D7, PK samples to be taken at pre-dose (≥ 5 min prior to infusion), and the following time points after the 
end of infusion (EOI): EOI 0 (+ 2) min, EOI 7 (± 2) min, EOI 15 (± 2) min, EOI 30 (± 5) min, EOI 1 h (± 5 
min), EOI 2 h (± 5 min), EOI 3 h (± 5 min), and EOI 4 h (± 5 min). PK samples to be taken from the arm that 
did not receive the infusion. The exact date and time of each sample collection must be recorded for all 
collected samples.  
q 
  
r The prepared saline bag and infusion line should be weighed before and after administration. These weights 
should be recorded using any available scale with a precision to at least one tenth of a gram (0.1 grams). Both 
weight measurements should be conducted using the same scale to reduce variability.  
  
Abbreviations: ADA = anti-drug antibodies; D = day; Early Term = early termination; ECG = 
electrocardiogram; EDSS = Expanded Disability Status Scale; E
; 
EOI = end of infusion; h = hours; HBV = hepatitis B virus; HCV = hepatitis C virus; 
 
 IV = intravenous; MAD = multiple ascending dose; min = minutes; MRI = magnetic resonance 
imaging; PBO = placebo; 
; PK = pharmacokinetics; 
 
  
  
 
 
 


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14. APPENDIX 2: COMMON TERMINOLOGY CRITERIA FOR ADVERSE 
EVENTS V5.0 (CTCAE) 
CTCAE Terms  
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical treatment or procedure. An AE is a 
term that is a unique representation of a specific event used for medical documentation and 
scientific analyses. Each CTCAE v5.0 term is a MedDRA Lowest Level Term. 
Definitions  
A brief definition is provided to clarify the meaning of each AE term.  
Grades  
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through Grade 5 with 
unique clinical descriptions of severity for each AE based on this general guideline:  
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*  
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
selfcare ADL**  
 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to AE 
A Semi-colon indicates „or‟ within the description of the grade.  
A single dash (-) indicates a grade is not available. 
Not all Grades are appropriate for all AEs. Therefore, some AEs are listed with fewer than 5 
options for Grade selection. Grade 5 (Death) is not appropriate for some AEs and therefore is 
not an option.  
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Selfcare ADL refer to bathing, dressing, and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 


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Publish date 27 November 2017 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50 
15. APPENDIX 3 EXPANDED DISABILITY STATUS SCALE (EDSS) 
Score 
Description 
1.0 
No disability, minimal signs in 1 functional system (FS) 
1.5 
No disability, minimal signs in more than 1 FS 
2.0 
Minimal disability in 1 FS 
2.5 
Mild disability in 1 FS or minimal disability in 2 FS 
3.0 
Moderate disability in 1 FS, or mild disability in 3 or 4 FS. No impairment to 
walking 
3.5 
Moderate disability in 1 FS and more than minimal disability in several others. No 
impairment to walking 
4.0 
Significant disability but self-sufficient and up and about some 12 hours a day. 
Able to walk without aid or rest for 500m 
4.5 
Significant disability but up and about much of the day, able to work a full day, 
may otherwise have some limitation of full activity or require minimal assistance. 
Able to walk without aid or rest for 300m 
5.0 
Disability severe enough to impair full daily activities and ability to work a full 
day without special provisions. Able to walk without aid or rest for 200m 
5.5 
Disability severe enough to preclude full daily activities. Able to walk without aid 
or rest for 100m 
6.0 
Requires a walking aid – cane, crutch, etc. – to walk about 100m with or without 
resting 
6.5 
Requires 2 walking aids – pair of canes, crutches, etc. – to walk about 20m without 
resting 
7.0 
Unable to walk beyond approximately 5m even with aid. Essentially restricted to 
wheelchair, though wheels self in standard wheelchair and transfers alone. Up and 
about in wheelchair some 12 hours a day 
7.5 
Unable to take more than a few steps. Restricted to wheelchair and may need aid 
in transferring. Can wheel self but cannot carry on in standard wheelchair for a full 
day and may require a motorized wheelchair 
8.0 
Essentially restricted to bed or chair or pushed in wheelchair. May be out of bed 
itself much of the day. Retains many self-care functions. Generally has effective 
use of arms 
8.5 
Essentially restricted to bed much of day. Has some effective use of arms retains 
some self-care functions 
9.0 
Confined to bed. Can still communicate and eat 


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Score 
Description 
9.5 
Confined to bed and totally dependent. Unable to communicate effectively or 
eat/swallow 
10.0 
Death due to MS