Clinical trial NCT04202965
Conditions: Hereditary Hemochromatosis
Sponsor: Protagonist Therapeutics, Inc.
Start date: 2020-03-19; Completion date: 2022-02-15
Enrollment: 16 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will be conducted at multiple sites and every patient will get treated with PTG-300. The objective of the study is to assess the effect of PTG-300 in treating adult hereditary hemochromatosis patients.

Detailed description:
This study is a multicenter, open-label study. The objective of the study is to assess the effect of PTG-300 on transferrin saturation (TSAT) and serum iron in adult hereditary hemochromatosis patients.

Arms: arm 1: PTG-300 Subcutaneous
Interventions: intervention 1: PTG-300
Intervention descriptions: intervention 1: Active treatment with PTG-300 injected subcutaneously.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Number PTG-300-06 
Protagonist Therapeutics, Inc. 
Protocol Amendment 3 – 14 September 2020 
CONFIDENTIAL AND PROPRIETARY 
1 of 67 
Open-label Study of PTG-300 in Subjects with Hereditary Hemochromatosis 
Protocol Number: PTG-300-06
 
NCT04202965 
Development Phase: Phase 2 
Document Version: Protocol Amendment 3, dated 14 September 2020
SPONSOR 
Protagonist Therapeutics, Inc 
7707 Gateway Boulevard, Suite 140 
Newark, CA 94560-1160 
The information in this document is confidential and proprietary to Protagonist Therapeutics, 
Inc. The information may only be used by the entities to which it was disclosed for the purpose it 
was disclosed. To the maximum extent permissible by law, the information must not be disclosed 
to any third parties without the prior written consent of Protagonist Therapeutics, Inc. 


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September 17, 2020


Protocol Number PTG-300-06 
Protagonist Therapeutics, Inc. 
Protocol Amendment 3 – 14 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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INVESTIGATOR’S AGREEMENT 
 
Protocol No.:  
PTG-300-06 
Protocol Title:  
Open-label Study of PTG-300 in Subjects with Hereditary Hemochromatosis 
 
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure(s) (IB), Case Report Forms (CRFs), and other scientific data. 
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB). No changes will be made to the study protocol without the 
prior written approval of the Sponsor and the IRB, except where necessary to avert an immediate 
hazard to the subjects. 
I have read the protocol and agree that the study will be conducted in compliance with the 
protocol and in accordance with the principles of the current version of the Declaration of 
Helsinki (Ethical Principles for Medical Research Involving Human Subjects), and with 21 CFR 
Part 50. The conduct of the study will be in accordance with the Integrated Addendum to ICH 
E6(R1): Guideline for Good Clinical Practice ICH E6(R2) and applicable parts of 21 CFR. 
I acknowledge that I am responsible for the overall study conduct. I agree to personally conduct 
or supervise the described clinical study. I agree to ensure that all associates, colleagues and 
employees assisting in the conduct of the study at my site are informed about their obligations. 
Mechanisms are in place to ensure that site staff receive the appropriate information throughout 
the study. 
 
 
 
 
Investigator Name (Print) 
 
Investigational Site 
 
 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 


Protocol Number PTG-300-06 
Protagonist Therapeutics, Inc. 
Protocol Amendment 3 – 14 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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2. 
SYNOPSIS 
 
Name of Sponsor/Company: Protagonist Therapeutics, Inc. 
Name of Investigational Product: PTG-300 
Protocol Number: PTG-300-06 
Country: Multiple 
Title of Study: Open-label Study of PTG-300 in Subjects with Hereditary Hemochromatosis 
Study center(s): Multicenter 
Phase of development: 2 
Indication:  Hereditary hemochromatosis (HH) 
Objectives: 
1. To assess the safety and tolerability of PTG-300 in HH subjects. 
2. To assess the effect of PTG-300 therapy on transferrin saturation (TSAT) and serum ferritin. 
3. To assess the effect of PTG-300 on iron absorption in a subset of subjects. (For subjects 
participating in the iron absorption substudy). 
4. To assess PTG-300’s efficacy for treating HH subjects as defined by incidence of phlebotomy. 
5. To assess the effect of PTG-300 on quality of life (QoL). 
6. To assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of 
PTG-300. 
Study Design: 
This is a multicenter, single-arm, open-label study in subjects with HH. Subjects will receive 
subcutaneous PTG-300 for up to 24 weeks. Subjects will start at an initial dose of 10 mg per week 
subcutaneously. The dose may be increased to 20 mg per week, and subsequently to 40 mg and to 
80 mg per week if needed, based on tolerability and the pharmacodynamic marker TSAT. In addition, 
subcutaneous dosing schedules of 10 mg, 20 mg, and 40 mg twice weekly (Day 1 and either Day 4 or 
Day 5) may be tested. 
Subjects’ safety and blood iron parameters (serum iron, serum ferritin, transferrin, and TSAT) will be 
collected to monitor the pharmacodynamic effect of PTG-300. Effect on phlebotomy need and QoL 
data (36-Item Short Form Health Survey [SF-36], and Patient’s Global Impression of Change 
[PGI-C]) will also be collected and tabulated. 
A subset of subjects (approximately 6 subjects) will participate in a two-way crossover sequential iron 
(57Fe) absorption substudy. The oral iron absorption substudy will be conducted once during the 
3-week screening period and then following approximately 4 to 6 weeks of PTG-300 treatment. 
Methodology: 
Screening (Study Day -21 to -1) 
After giving written informed consent, subjects will be screened for eligibility according to 
inclusion/exclusion criteria (see Diagnosis and Main Criteria for Inclusion section) within 21 days of 
dosing. Subjects will continue their individual iron restricted diet throughout the study. During this 
period liver iron concentration (LIC) will be assessed by magnetic resonance imaging (MRI). 
Subjects will begin treatment with PTG-300 within approximately 7 days following a regular 


Protocol Number PTG-300-06 
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Protocol Amendment 3 – 14 September 2020 
CONFIDENTIAL AND PROPRIETARY 
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phlebotomy, with iron parameters measured before (Screening labs) and after the phlebotomy (pre-
dose Study Day 1). Each individual subject’s pre-phlebotomy serum ferritin level and TSAT will be 
used as a criterion for phlebotomy during the study, i.e., the threshold at which a phlebotomy should 
be considered during the study. The serum ferritin level and TSAT obtained during Screening will be 
used as baseline to assess the change from these measurements post-dosing with PTG-300. 
After eligibility has been confirmed, subjects will be enrolled in the study. 
Treatment Period (Week 1 to Week 25) 
Study Drug Administration: Dosing with PTG-300 at 10 mg will be initiated in the clinic. On clinic 
visit days, PTG-300 doses will be administered in the clinic. All doses should be administered in the 
clinic until the subject or caregiver demonstrates the ability to perform subcutaneous injections 
properly. 
Subjects will begin treatment with 10 mg PTG-300 administered weekly. Subjects will receive their 
first subcutaneous (SC) injection at the clinic and will be instructed on how to self-administer the 
injection (or have a caregiver administer the injection) and on appropriate safety monitoring before 
being discharged. 
On Study Day 2, subjects will return to the clinic for serum iron parameters and PTG-300 blood 
concentration (PK) measurements. 
Individual Subject Dose and Schedule Escalation: Individual subject dose and schedule will be 
determined based on the pharmacodynamic (PD) marker TSAT measured at two time points: once at 
peak PD effect one day post dose and once at trough PD effect. The intent of dose and schedule 
adjustment is to reduce TSAT and serum iron levels. The dose of PTG-300 may be increased weekly 
in a sequential manner from 10 mg to 20 mg and, if necessary, to 40 mg and 80 mg until the TSAT is 
less than approximately 40% at peak PD effect one day post dose and at the trough PD effect prior to 
the next dose of PTG-300. In addition, the dose may be adjusted to maintain serum ferritin to no more 
than 1.5 times the screening value or 150 ng/mL, whichever is greater. Investigators may consider 
once a week or twice a week dosing of PTG-300 to achieve these objectives. The trough PD effect is 
the TSAT value measured 7 days after the PTG-300 dose (and before the next dose) for once weekly 
dosing or 7 days after the first dose in a week for twice weekly dosing. For the twice weekly regimen, 
the doses should be given at least 3 days apart (e.g., on Day 1 and Day 4 or 5 of each week). The 
twice weekly PTG-300 dose may be escalated to a maximum of 40 mg twice weekly. To facilitate 
dose escalation and the identification of a therapeutic dose, investigators may assess TSAT values on 
days subjects come to the clinic for any dose adjustments. These assessments may occur at times 
other than the regular scheduled visits indicated on the schedule of events. 
Subjects will continue treatment by self-administering PTG-300 at home (or in the clinical center as 
appropriate) for up to 24 weeks based on acceptable safety and tolerability of the drug (see Safety 
Monitoring). Subjects will return for clinic visits to have safety assessments; serum iron parameters 
plus soluble transferrin receptor (sTfR), hepcidin and antidrug antibodies (ADA); and efficacy 
evaluated according to the schedule of assessments. 
Subjects’ iron parameters will be monitored throughout the study. 
Change in Starting Dose: The starting dose may be increased from 10 mg to 20 mg, 40 mg, or 80 mg 
as appropriate if <2 of the first 4 subjects (or ≤25% of a larger number of subjects) treated at a given 
dose have both peak and trough TSAT values approximately <40% and no safety signals have been 
noted. 
Criteria for a Phlebotomy: Subjects should undergo an on-study phlebotomy when the subject’s 
serum ferritin levels and TSAT value are higher than the pre-phlebotomy serum ferritin and TSAT 
values obtained during Screening. In addition, a phlebotomy may be performed when the Investigator 
assesses it is necessary for subject care. 


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Iron Absorption Substudy 
Iron absorption subjects will be treated and monitored in an identical manner as the rest of the study 
population. 
Subjects consenting to participate in the iron absorption substudy will receive the stable iron isotope 
57Fe orally (approximately 4 mg as ferrous sulfate) on two occasions; once prior to starting PTG-300 
(i.e., after the phlebotomy performed during the Screening period; Iron Absorption A), and a second 
dose approximately 4 to 6 weeks after starting PTG-300 (i.e., post-treatment; Iron Absorption B). The 
post-treatment Iron Absorption B administration will occur approximately 24 hours following a 
PTG-300 dose. 
Subjects will receive 57Fe orally after an overnight fast of at least 8 hours. Subjects should fast for 
approximately 4 hours after the 57Fe dose. Blood samples will be collected at 0, 4, 8, 12, and 24 hours 
for measurement of 57Fe levels and for measurement of iron parameters—serum iron, serum ferritin, 
transferrin, and TSAT. Additional blood samples will be obtained at 0, 4, 8, 12, and 24 hours 
following Iron Absorption B for measurement of PTG-300 concentrations. 
Post-Treatment / Early Termination Safety Follow-up (Week 29) 
Subjects who complete the treatment or who discontinue treatment early will undergo Visit 8/end of 
treatment (EOT) assessments as well as follow-up safety evaluations approximately 4 weeks after the 
last dose of study drug (Visit 9/end of study [EOS]). 
Safety Monitoring: 
Safety will be monitored throughout the study. 
Safety measures (including but not limited to physical examinations, clinical laboratory tests, 
complete blood count [CBC], vital signs, electrocardiograms [ECGs], adverse event monitoring 
[AEs], and concomitant medications) will be evaluated and recorded over the course of the study. 
Any adverse event (AE) that emerges from the time the subject signs an informed consent form (ICF) 
until Study Exit will be recorded and reported. Safety will be assessed using the National Institutes of 
Health (NIH) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. 
Safety Criteria for Dose Interval Increase or Dose Reduction 
The presence of at least one of the following criteria will require a dose reduction: 
• 
CTCAE Grade 3 hematological toxicity or worsening of ≥2 grades in hematological 
parameters not clearly resulting from the underlying disease and/or without a clear-cut 
alternative that does not respond adequately to medical therapy. 
• 
CTCAE Grade 3 non-hematological toxicities not clearly resulting from the underlying 
disease and/or without a clear-cut alternative that does not respond adequately to medical 
therapy. 
• 
Treatment-related decrease of hemoglobin (Hgb) from baseline >20% or Grade 2 anemia, 
whichever is lesser, confirmed by a repeat value and not due to phlebotomy. Prior to 
resumption of PTG-300 at a reduced dose a follow-up Hgb should be assessed to confirm that 
Hgb has stabilized or improved to Grade 1. 
• 
Investigator determines that the subject has experienced a clinically significant decrease in 
Hgb due to PTG-300. 
If a treatment-related increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>3 × upper limit of normal (ULN) is seen, dosing with PTG-300 should be held, with resumption at a 
reduced dose if the AST and/or ALT levels return to baseline within 14 days; if the levels do not 
return to baseline within 14 days, a magnetic resonance imaging (MRI) should be conducted to assess 
whether there is an increase in iron accumulation. 


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Dose reduction has two steps. Initially subjects continue to receive the same dose of PTG-300 but the 
dosing frequency is reduced from twice weekly to weekly, or from weekly to every 2 weeks. If the 
subject continues to meet criteria for dose reduction, the dose is then decreased one dose level. 
PTG-300 Discontinuation or Stopping 
The following are stopping criteria for an individual subject and will result in discontinuation of the 
subject from further treatment with study drug: 
• 
Any CTCAE Grade 4 hematological or non-hematological toxicity not clearly resulting from 
the underlying disease and/or without a clear-cut alternative. 
• 
CTCAE Grade 3 hematological toxicity or worsening of ≥2 grades in hematological 
parameters not clearly resulting from the underlying disease and/or without a clear-cut 
alternative persists over 7 days after adequate PTG-300 dose decrease. 
• 
CTCAE Grade 3 non-hematological toxicities not clearly resulting from the underlying 
disease and/or without a clear-cut alternative explanation that do not improve within 14 days 
with maximal medical therapy and adequate PTG-300 dose decrease. 
• 
When the Investigator in consultation with the medical monitor (MM) considers that it is in 
the subject’s best interest to discontinue treatment with PTG-300 (i.e., persistent, worsening 
or recurrent AEs). 
• 
If a subject requires a dose reduction below 10 mg administered every 2 weeks. 
• 
ALT, AST >5 × ULN and rising. 
• 
ALT, AST remains >5 × ULN with no change in total bilirubin for more than 2 weeks. 
• 
A worsening of clinical symptoms with no other acceptable explanation. 
• 
The product meets Hy’s Law 
— Any test showing an increase of serum ALT >3 × ULN or >2 × ULN total bilirubin 
should be repeated within 48 to 72 hours for ALT, AST, alkaline phosphatase (ALP), 
and total bilirubin. If the repeat value for ALT or total bilirubin is unchanged or indicates 
decreasing activity, monitoring should continue at weekly intervals until the results are 
acceptable or normalized. 
• 
Evidence of increased iron accumulation in liver from baseline. 
Number of subjects (planned): Approximately 28 subjects will be enrolled in the study to ensure a 
total of 20 subjects complete at least 16 weeks of treatment. Approximately 6 subjects will participate 
in the iron absorption substudy. 
Diagnosis and main criteria for inclusion: 
Inclusion Criteria: Subjects must meet ALL of the following inclusion criteria to be enrolled: 
1. Male and female subjects aged 18 years or older. 
2. Have a confirmed diagnosis of HFE-related hereditary hemochromatosis with prior genotype 
testing. 
3. Documented stable phlebotomy for ≥6 months prior to screening; with a phlebotomy 
frequency of at least 0.25 per month (e.g., received at least three phlebotomies over the 
previous 12 months, or at least four phlebotomies over the previous 15 months) and a 
phlebotomy frequency of less than 1 per month. 
4. Screening hemoglobin >11.5 g/dL. 
5. Serum ferritin <300 ng/mL at screening (before screening phlebotomy). 


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6. Women of childbearing potential (WOCBP) and men with partners of childbearing potential 
agree to use a highly effective contraceptive measure (based on the Clinical Trials Facilitation 
Group [CTFG]) during the duration of the study and for 28 days after the last dose of study 
drug in the case of women and 90 days after the last dose of study drug in the case of men. 
7. Subject understands the study procedures, is willing and able to adhere to study requirements 
and agrees to participate in the study by giving written informed consent. 
Exclusion Criteria: Subjects must meet NONE of the following exclusion criteria to be enrolled: 
1. Clinically meaningful laboratory abnormalities at Screening including, but not limited to: 
a. Absolute neutrophil count <1000/µL 
b. Platelet count <100,000/µL 
c. Estimated Glomerular Filtration Rate (eGFR) <40 mL/min/1.73 m2 
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 × upper limit 
of normal (ULN) or direct bilirubin >1.5 × ULN 
e. C-reactive protein (CRP) ≥5.0 mg/L. 
2. Receiving iron chelation therapy. 
3. Receiving erythrocytapheresis. 
4. Pregnant or lactating females. 
5. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic 
infection within 3 months of dosing; any infection requiring antimicrobial therapy within 
4 weeks of dosing. Prophylactic antibiotics are allowed. 
6. Any serious or unstable medical or psychiatric condition that would prevent (as judged by the 
Investigator) the subject from properly providing informed consent or any condition which 
would jeopardize compliance with the study or assessment of the study’s endpoints. 
7. Organ damage from iron overload, that (as judged by the Investigator) may be worsened by 
participation in this trial. 
8. Known primary or secondary immunodeficiency. 
9. Known history of autoimmune/inflammatory diseases. 
10. Positive for active hepatitis B or hepatitis C or known human immunodeficiency virus (HIV) 
infection. Active hepatitis B is defined as a known positive hepatitis B surface antigen 
(HBsAg) result. Active hepatitis C is defined by a positive hep C Ab result and known 
quantitative hepatitis C virus (HCV) ribonucleic acid (RNA) results greater than the lower 
level of detection of the assay. Subjects who have a history of HCV infection but have 
documented sustained virologic response 12 weeks after HCV therapy (SVR12) are eligible. 
11. Any surgical procedure requiring general anesthesia within 1 month prior to screening or 
planned elective surgery during the study (within 3 months for joint replacement surgery). 
12. History of invasive malignancies within the last 2 years, except non-melanoma skin cancer 
and localized cured prostate cancer, cervical cancer, and ductal carcinoma in situ (DCIS). 
13. Current or recent history of alcohol dependence or illicit drug use within 6 months prior to 
screening. 
14. Subject is unable to give informed consent. 
15. Receipt of an investigational agent within 30 days of screening. 


Protocol Number PTG-300-06 
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Protocol Amendment 3 – 14 September 2020 
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Test product(s), dose, and mode of administration: This study is a single-arm, open-label study. 
PTG-300 is formulated in an aqueous buffered solution and pre-filled at 0.5 mL and 1.0 mL into a 
1-mL glass syringe. Study drug will be administered by subcutaneous (SC) injections either weekly or 
twice weekly, using a needle and a pre-filled syringe. 
Subjects will receive doses of 10 mg to 80 mg SC weekly or 10 mg to 40 mg SC twice weekly. 
57Fe (~4 mg) is provided by Protagonist as a ferrous sulfate solution for oral administration. 
Duration of treatment: Individual subjects will participate in this study for up to 31 weeks as 
follows: 
• 
Screening: Up to 3 weeks 
• 
PTG-300 Treatment: Up to 24 weeks 
• 
Safety Follow-Up: 4 weeks 
Study endpoints: 
Baseline Definition: The serum ferritin level and TSAT obtained during Screening will be used as 
baseline. 
Efficacy: 
• Change from baseline in serum ferritin. 
• Duration of time that serum ferritin is below baseline measurement. 
• Change from baseline in TSAT. 
• Duration of time that TSAT is below baseline measurement. 
• Time to first phlebotomy after dosing. 
• Change in frequency of phlebotomies based on historical phlebotomy data (24 weeks). 
• Proportion of subjects who achieve phlebotomy independence. 
• Additional Endpoints: 
− 
SF-36 
− 
PGI-C 
− 
Change in iron absorption following administration of PTG-300. (For subjects 
completing iron absorption substudy.) 
− 
PTG-300 pharmacokinetics: PTG-300 concentration as a function of dose and time 
since last dose. 
− 
PD: Change from baseline in serum iron, transferrin, and sTfR. 
− 
Change from baseline in LIC assessed by MRI. 
− 
Incidence of ADA. 


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Safety: 
• Tabulate frequency of treatment-emergent adverse events (TEAEs) and SAEs; treatment-
related TEAEs and SAEs; TEAEs leading to study discontinuation. 
• Summarize vital signs, safety laboratory assessments, ECGs, and physical examination 
findings. 
Statistical methods: This trial is exploratory and no rigid criteria for sample size are pre-specified. 
The choices are based on risk/benefit assessment of accumulating results. However, there will be at 
least 80% power for a sample size of 20 subjects to detect a 50% reduction in the number of 
phlebotomies from baseline. The power calculation is based on a hypothesized effect size of 
0.5 (mean change = 1, with SD = 2) over 24 weeks using a 1-sided one-sample t-test at alpha = 10% 
level. Twenty-eight (28) subjects will be enrolled in the study, assuming an approximate 25% 
dropout. 
Summary statistics for all efficacy and PK/PD data will be provided. Frequency distribution for 
adverse events and summary statistics for laboratory assessments, ECGs and vital signs will be 
provided. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
5. 
INTRODUCTION ......................................................................................................18 
5.1. 
Background .................................................................................................................18 
5.1.1. 
Rationale for the Development of PTG-300 ...............................................................18 
5.2. 
Summary of Nonclinical and Clinical Studies............................................................19 
5.2.1. 
Nonclinical Studies .....................................................................................................19 
5.2.2. 
Clinical Studies ...........................................................................................................20 
5.3. 
Study Design and Target Population ..........................................................................21 
5.4. 
Selection of Doses ......................................................................................................21 
5.5. 
Summary of Potential Risks and Benefits ..................................................................21 
6. 
OBJECTIVES .............................................................................................................23 
7. 
INVESTIGATIONAL PLAN .....................................................................................24 
7.1. 
Overall Study Design ..................................................................................................24 
7.1.1. 
Screening (Study Day -21 to -1) .................................................................................24 
7.1.2. 
Treatment Period (Week 1 to Week 25) .....................................................................25 
7.1.3. 
Iron Absorption Substudy (See Table 3) ....................................................................26 
7.1.4. 
Post-Treatment / Early Termination Safety Follow-Up (Week 29) ...........................26 
7.2. 
Safety ..........................................................................................................................26 
7.2.1. 
Safety Criteria for Dose Interval Increase or Dose Reduction ...................................27 
7.2.2. 
PTG-300 Discontinuation or Stopping .......................................................................27 
7.3. 
Number of Subjects ....................................................................................................28 
7.4. 
Treatment Assignment ................................................................................................28 
7.5. 
Dose Adjustment Criteria ...........................................................................................28 
7.6. 
Endpoints ....................................................................................................................28 


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7.6.1. 
Efficacy .......................................................................................................................28 
7.6.2. 
Safety ..........................................................................................................................29 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................30 
8.1. 
Subject Inclusion Criteria ...........................................................................................30 
8.2. 
Subject Exclusion Criteria ..........................................................................................30 
8.3. 
Subject Withdrawal Criteria .......................................................................................31 
9. 
STUDY PROCEDURES ............................................................................................31 
10. 
TREATMENT OF SUBJECTS ..................................................................................36 
10.1. 
Description of Study Drug ..........................................................................................36 
10.2. 
Concomitant Medications ...........................................................................................36 
10.2.1. 
Contraceptive Requirements .......................................................................................36 
10.3. 
Treatment Compliance ................................................................................................36 
10.4. 
Randomization and Blinding ......................................................................................37 
11. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................38 
11.1. 
PTG-300 .....................................................................................................................38 
11.1.1. 
Study Drug ..................................................................................................................38 
11.1.2. 
Study Drug Packaging and Labeling ..........................................................................38 
11.1.3. 
Study Drug Storage .....................................................................................................38 
11.1.4. 
Study Drug Administration.........................................................................................38 
11.1.5. 
Study Drug Accountability .........................................................................................38 
11.1.6. 
Study Drug Handling and Disposal ............................................................................39 
11.2. 
57Fe Ferrous Sulfate Solution......................................................................................39 
12. 
ASSESSMENT OF EFFICACY ................................................................................40 
12.1. 
Clinical Endpoints ......................................................................................................40 
12.1.1. 
Phlebotomy and Iron Parameters ................................................................................40 
12.1.2. 
Iron Absorption (Iron Absorption Substudy) .............................................................40 
12.2. 
Quality of Life Instruments ........................................................................................40 
12.2.1. 
Medical Outcome Study Questionnaire Short Form Health Survey (SF-36) .............40 
12.2.2. 
Patient Global Impression of Change (PGI-C) ...........................................................40 
12.3. 
Anti-Drug Antibodies (ADA) .....................................................................................41 
13. 
PHARMACOKINETIC, PHARMACODYNAMIC AND IRON 
ABSORPTION ASSESSMENTS ..............................................................................42 
13.1. 
Blood Sample Collection Schedule in Each Study Period .........................................42 


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13.1.1. 
Sample Collection for All Subjects ............................................................................42 
13.1.2. 
Sample Collection for Iron Absorption Substudy ......................................................42 
13.2. 
Samples Per Subject ...................................................................................................42 
13.3. 
Pharmacokinetic Blood Sample Collection and Processing .......................................42 
14. 
ASSESSMENT OF SAFETY .....................................................................................43 
14.1. 
Safety Parameters .......................................................................................................43 
14.2. 
Adverse Events and Serious Adverse Events .............................................................43 
14.2.1. 
Definition of Adverse Event .......................................................................................43 
14.2.2. 
Definition of Serious Adverse Event ..........................................................................45 
14.2.3. 
Pregnancy ...................................................................................................................45 
14.2.4. 
Other Safety Parameters and Related Information .....................................................46 
14.3. 
Recording Adverse Events .........................................................................................46 
14.4. 
Reporting Adverse Events ..........................................................................................46 
14.5. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................47 
15. 
STATISTICS ..............................................................................................................48 
15.1. 
Study Design and Sample Size Estimation .................................................................48 
15.2. 
Demographics/Baseline Comparability ......................................................................48 
15.3. 
Data Presentation ........................................................................................................48 
15.4. 
Definition of Baseline .................................................................................................48 
15.5. 
Analysis of Efficacy Data ...........................................................................................48 
15.6. 
Analysis Populations ..................................................................................................49 
15.6.1. 
Safety Analysis Set .....................................................................................................49 
15.6.2. 
Intent-to-Treat Analysis Set ........................................................................................49 
15.6.3. 
Iron Absorption Analysis Set......................................................................................49 
15.7. 
Handling of Missing Data ...........................................................................................49 
15.8. 
Analysis of Safety .......................................................................................................49 
15.9. 
Analyses of Pharmacokinetics and Pharmacodynamics .............................................49 
15.10. 
Exploratory Endpoints ................................................................................................50 
16. 
ADMINISTRATIVE PROCEDURES AND ETHICAL 
CONSIDERATIONS ..................................................................................................51 
16.1. 
Study Monitoring ........................................................................................................51 
16.2. 
Audits and Inspections ................................................................................................51 
16.3. 
Institutional Review Board (IRB) Approval ...............................................................51 


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16.4. 
Guidelines for Good Clinical Practice ........................................................................51 
16.5. 
Ethics ..........................................................................................................................51 
16.5.1. 
Ethics Review .............................................................................................................51 
16.5.2. 
Ethical Conduct of the Study ......................................................................................52 
16.5.3. 
Written Informed Consent ..........................................................................................52 
16.6. 
Termination of Study ..................................................................................................52 
16.7. 
Case Report Forms .....................................................................................................52 
16.8. 
Inspection of Records .................................................................................................53 
16.9. 
Retention of Records ..................................................................................................53 
17. 
PUBLICATION POLICY ..........................................................................................54 
18. 
REFERENCES ...........................................................................................................55 
19. 
APPENDICES ............................................................................................................56 
APPENDIX 1. CLINICAL LABORATORY TESTS ................................................................57 
APPENDIX 2. ADDITIONAL LABORATORY TESTS ..........................................................59 
APPENDIX 3. MEDICAL OUTCOME STUDY QUESTIONNAIRE SHORT FORM 
HEALTH SURVEY (SF-36) ......................................................................................60 
APPENDIX 4. PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C)............................67 
 
LIST OF TABLES 
Table 1: 
Abbreviations and Specialist Terms ...........................................................................15 
Table 2: 
Schedule of Assessments for Study PTG-300-06 .......................................................32 
Table 3: 
Schedule of Assessments for Study PTG-300-06 — Iron Absorption 
Substudy (Parts A and B) ...........................................................................................35 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
Cmax 
Maximum concentration 
CRA 
Clinical research associate 
CRF 
Case report form 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTFG 
Clinical Trials Facilitation Group 
DCIS 
Ductal carcinoma in situ 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
FDA 
Food and Drug Administration 
FIH 
First in human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HBsAg 
Hepatitis B surface antigen 
Hct 
Hematocrit 


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Abbreviation or Specialist Term 
Explanation 
HCV 
Hepatitis C virus 
Hgb 
Hemoglobin 
HH 
Hereditary hemochromatosis 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LIC 
Liver iron concentration 
MM 
Medical monitor 
MRI 
Magnetic resonance imaging 
NIH 
National Institutes of Health 
NOAEL 
no-observed-adverse-effect level 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
PI 
Principal Investigator 
PGI-C 
Patient’s Global Impression of Change 
PK 
Pharmacokinetic(s) 
PRO 
Patient reported outcomes 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
QoL 
Quality of life 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SC 
Subcutaneous 
SF-36 
36-Item Short Form Health Survey 
SMC 
Safety Monitoring Committee 


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Abbreviation or Specialist Term 
Explanation 
sTfR 
Soluble transferrin receptor 
SVR12 
Sustained virologic response 12 weeks after therapy 
TEAE 
Treatment-emergent adverse event 
TSAT 
Transferrin saturation 
ULN 
Upper limit of normal 
US 
United States 
WOCBP 
Women of childbearing potential 


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5. 
INTRODUCTION 
5.1. 
Background 
Protagonist Therapeutics, Inc. (Protagonist) is developing PTG-300, an injectable peptide 
mimetic of the endogenous hormone hepcidin, as a potential treatment for hereditary 
hemochromatosis (HH). 
HH is a rare genetic disorder that disrupts the body’s regulation of iron, causing the body to 
absorb too much iron from the diet. In HH types I-III, mutations in genes encoding hepcidin 
regulators, or hepcidin itself lead to diminished production of hepcidin, thus decreasing the 
inhibitory effect of hepcidin on duodenal iron absorption and causing clinical iron overload 
(Brissot 2011). Hepcidin deficiency leads to increased circulating transferrin saturation, and 
ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in 
excess may induce or favor the development of complications such as cirrhosis, liver cancer, 
diabetes, heart failure, hypogonadism, but also, complaints such as asthenia and disabling 
arthritis. If left untreated, HH can lead to morbidity and eventually death (Katsarou 2019). 
Therapeutic phlebotomy to reduce iron loading is standard treatment for HH. The phlebotomy 
frequency required for a patient is based on serial measurements of their serum ferritin levels and 
transferrin saturation (Crownover 2013). Therapeutic phlebotomy is highly efficient in removing 
excess iron and preventing most of the complications associated with excess iron in the body. 
However, this treatment does not target the biological mechanisms involved in the iron 
metabolism disturbance. 
In a hepcidin-deficient mouse model of hemochromatosis, a minihepcidin was effective for 
decreasing iron loading in the liver and heart compared to solvent control in mice that were not 
iron overloaded (Ramos 2012). These observations suggest that a hepcidin mimetic such as 
PTG-300 may be effective for preventing iron overload in patients with hemochromatosis. 
5.1.1. 
Rationale for the Development of PTG-300 
PTG-300 is a peptidic agent structurally related to natural hepcidin that mimics its inhibitory 
activity on ferroportin. Hepcidin is a peptide hormone that is the body’s main regulator of iron 
homeostasis (Liu 2016, Ruchala 2014). Hepcidin binds to ferroportin causing internalization and 
degradation of ferroportin. Hepcidin binding to ferroportin on enterocytes blocks iron absorption 
from the gastrointestinal tract. The inhibitory effect of hepcidin on ferroportin in macrophages 
and hepatocytes leads to a decrease in the efflux of iron from these cellular sites of iron storage 
(Camaschella 2013). Because there are no mechanisms for the efflux of iron from cells other 
than ferroportin, and because iron is both essential and (in excess) toxic, the role of hepcidin is of 
central importance to iron regulation and erythropoiesis. Hepcidin’s critical role in iron 
metabolism suggests that hepcidin mimetics such as PTG-300 may be effective for treating a 
variety of conditions characterized by imbalances in iron metabolism as well as conditions where 
manipulation of iron availability may alter disease pathogenesis. The rationale for testing 
PTG-300 in patients with HH is based on its potential ability to restore normal hepcidin function 
in patients with HH and thereby prevent iron overload. 
The overall goal of the current protocol is to evaluate the safety and efficacy of PTG-300 in 
reducing phlebotomy requirement in patients with HH. The protocol is a Phase 2, single-arm, 
open-label study (with an iron absorption substudy). 


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The study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements. 
5.2. 
Summary of Nonclinical and Clinical Studies 
5.2.1. 
Nonclinical Studies 
PTG-300 is a peptidic agent structurally related to natural hepcidin and PTG-300’s effects in 
toxicology studies mimic the effects of hepcidin. In studies of wild type mice, rats and 
cynomolgus monkeys, single dose subcutaneous or intravenous administration of PTG-300 
caused transient decreases in serum iron. The effect on serum iron is brisk in onset (within a few 
hours of subcutaneous dosing in the thalassemic mouse model) and, depending on the dose, can 
be quite profound and prolonged. For example, in wild type healthy mice, the effect of a 
2.5 mg/kg subcutaneous dose on serum iron persists for at least 30 hours with serum iron 
declining to a nadir (90% reduction) 10 hours after dosing. 
PTG-300 was evaluated in a comprehensive toxicology program including Good Laboratory 
Practice (GLP)-compliant studies. Specific GLP studies included up to 26-week rat and up to 
39-week cynomolgus monkey toxicology studies with 4-week or 5-week reversal periods, as 
well as genetic toxicology studies to assess potential in vitro mutagenesis, in vitro chromosomal 
aberrations, and in vivo chromosomal aberrations. Safety pharmacology studies included hERG 
assay and in vivo studies to assess potential effects on cardiovascular, respiratory, and 
neurobehavioral parameters. 
In toxicology studies, PTG-300 causes exaggerated pharmacological responses in rats and 
cynomolgus monkeys when dosed for up to 26 or 39 weekly doses. The primary effects of 
PTG-300 in rats and cynomolgus monkeys are decreases in red blood cell count, hematocrit, and 
hemoglobin (Hgb) with either compensatory increases of reticulocyte counts at lower doses of 
PTG-300 or decreases of reticulocyte counts at high doses of PTG-300. Rats dosed with 
25 mg/kg PTG-300 for 4 weeks had decreases in red cell mass that were adverse based on 
magnitude of effect, as well as hepatocellular necrosis that could be secondary to excess iron in 
liver. Rats dosed with 10 mg/kg/dose for 13 weeks had non-adverse effects consistent with the 
expected pharmacology of PTG-300. The no-observed-adverse-effect level (NOAEL) was 
determined to be 10 mg/kg/dose based on a 26-week toxicology study in rats receiving weekly 
doses of PTG-300 of up to 10 mg/kg/dose. Cynomolgus monkeys dosed with 10 mg/kg PTG-300 
for 4 weeks had decreases in red cell mass that were adverse based on magnitude of effect. 
Cynomolgus monkeys dosed with 6 mg/kg/dose for 13 weeks had no-adverse effects consistent 
with the expected pharmacology of PTG-300. The NOAEL was determined to be 2 mg/kg/dose 
following 39 weekly doses of PTG-300 at 0.6, 2, and 6 mg/kg/dose in cynomolgus monkeys. 
PTG-300 does not cause adverse injection site reactions in rats dosed up to 26 weeks or 
cynomolgus monkeys dosed up to 39 weeks. In a stand-alone single-dose rat local tolerance 
study with PTG-300 up to 280 mg/kg (280 mg/mL in dose concentration), the incidence and 
severity of injection site reactions were generally proportional to the dose and showed 
incomplete but progressive ongoing reversal by Study Day 14 post-injection. PTG-300 is not 
mutagenic, and had no apparent effect on cardiovascular, respiratory, or neurobehavioral 
parameters. All PTG-300-related effects in the GLP toxicology studies were reversed or 
reversing after a 4- or 5-week treatment-free period. All of the PTG-300-related effects can be 
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PTG-300 was also evaluated for embryo-fetal development toxicity in rats and rabbits and 
fertility and early embryonic development toxicity in both male and female rats. The maternal 
NOAEL was 3 mg/kg/dose and the NOAEL for the embryo-fetal development was 
0.3 mg/kg/dose in the definitive embryo-fetal development toxicity study in rats. The maternal 
NOAEL was 1 mg/kg/dose and the NOAEL for the embryo-fetal development was 
0.3 mg/kg/dose in the definitive embryo-fetal development toxicity study in rabbits. The NOAEL 
for paternal toxicity and the NOEL for effects on male fertility and early embryonic development 
were considered to be 10 mg/kg/dose in fertility and early embryonic development toxicity study 
in male rats. The NOAEL for maternal toxicity and the NOEL for effects on female fertility and 
early embryonic development were 3 mg/kg/dose in fertility and early embryonic development 
toxicity study in female rats. 
Principle findings in nonclinical toxicology studies are alterations in red cell mass. PTG-300 has 
no apparent effect on cardiovascular, respiratory, or neurobehavior in safety pharmacology 
studies. PTG-300 is not genotoxic. 
5.2.2. 
Clinical Studies 
To date, PTG-300 has been studied in one completed Phase 1 study in healthy subjects. A 
Phase 2 study of PTG-300 and the study’s open-label extension for treatment of β-thalassemia 
investigated doses over a range of 3 to 80 mg weekly. 
Sixty-three patients have been treated in these Phase 2 studies in β-thalassemia. Combining data 
for the two studies, subjects have been dosed with PTG-300 for durations ranging from 4 weeks 
to more than 8 months. More than half of the subjects have been dosed for greater than 16 weeks 
and more than 750 doses of PTG-300 have been administered. Safety data indicate that PTG-300 
is well tolerated with no safety concerns. 
The frequency of adverse events did not increase with increasing dose of PTG-300. Most adverse 
events were typical of those expected for subjects with β-thalassemia. The frequency of adverse 
events did not increase with increasing dose of PTG-300. Adverse events reported in >5% of 
subjects were upper respiratory tract infection (11.1%), injection site erythema (9.5%), injection 
site pain (12.7%), urinary tract infections (7.9%), headache (7.9%), fatigue (6.3%), and pyrexia 
(6.3%). One subject experienced an SAE of confusion, which was considered by the investigator 
to be possibly related to PTG-300. The event fully resolved within 2 days. In addition, a Phase 2 
study of PTG-300 in patients with polycythemia vera requiring phlebotomy has been initiated. 
The completed Phase 1 study was a randomized, double blind, placebo controlled, first-in-human 
(FIH), single ascending dose (SAD) and repeat dose study of PTG-300 administered 
subcutaneously (SC) in 62 healthy male subjects to evaluate safety/tolerability, PK and PD 
activity (as assessed by the effect on serum iron parameters). Subjects received single doses of 
1 mg to 80 mg PTG-300 or two 40 mg doses 1 week apart. 
Following single dose administration of PTG-300 there was a dose-related reduction in serum 
iron with a maximal reduction of approximately 65% from baseline. The relationship between 
dose and effect appeared to plateau at 20 mg with higher doses resulting in a longer duration of 
effect. This effect was sustained for at least 72 hours at higher doses. In subjects that received 
two 40-mg doses 1 week apart (QW×2) the effects on iron were comparable for both 40-mg 


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doses. Serum iron levels did not return to baseline prior to the second dose. Serum iron levels 
generally returned to baseline approximately 1 to 2 weeks following the second dose of 
PTG-300. Following single dose administration area under the concentration-time curve (AUC) 
and maximum concentration (Cmax) increased with dose; however, the increase was less than 
dose-proportional. 
PTG-300 was well tolerated by subjects in this study, with no SAEs or dose-limiting toxicities 
(DLTs) at single doses as high as 80 mg and a repeat dose of 40 mg weekly for 2 weeks. The 
most frequent adverse events (AEs) were injection site reactions (characterized primarily by a 
transient erythema at the injection site), headaches and upper respiratory tract infections. 
These preclinical and clinical data support clinical development of PTG-300 for the treatment of 
subjects with HH. 
5.3. 
Study Design and Target Population 
This is a multicenter, single-arm, open-label study to assess the safety and efficacy of PTG-300 
treatment in subjects with HH. Subjects will receive subcutaneous PTG-300 for up to 24 weeks. 
PTG-300 doses of 10 mg, 20 mg, 40 mg, and 80 mg subcutaneously per week may be tested. In 
addition, subcutaneous dosing schedules of 10 mg, 20 mg, and 40 mg twice weekly may be 
tested to achieve a sustained pharmacodynamic effect. 
A subset of approximately 6 subjects will participate in a two-way crossover iron absorption 
substudy. 
The study population is subjects with HH who are in maintenance phase and who are on a stable 
phlebotomy regimen. 
5.4. 
Selection of Doses 
Subjects will initially receive a subcutaneous dose of 10 mg per week. The dose was based on 
data in healthy subjects indicating that a dose of 10 mg PTG-300 results in an average reduction 
of approximately 19% in serum iron. Iron levels returned to baseline within 1 week. 
In the current study a subject’s dose may be increased to 20 mg per week and subsequently to 
40 mg and 80 mg per week based on insufficient decrease in TSAT and acceptable safety. The 
PTG-300 doses will be administered as subcutaneous doses once a week or as divided doses 
twice weekly at least 3 days apart (e.g., on Day 1 and Day 4 or 5 of each week). The intent of 
dose and schedule adjustment is to reduce TSAT and serum iron levels. These higher doses are 
based on Phase 1 data that showed greater decreases in serum iron and TSAT and longer 
duration of decrease compared to the 10 mg dose. A Safety Monitoring Committee (SMC) has 
determined that doses as high as 80 mg per week administered for 8 weeks or more are safe for 
treating subjects with β-thalassemia. 
5.5. 
Summary of Potential Risks and Benefits 
Based on the experience of PTG-300 dosing in nonclinical studies and a Phase 1 trial in healthy 
volunteers, the activities of PTG-300 are related to the proposed mechanism of action, allowing 
clinical monitoring. Immunologic responses to PTG-300 have not been observed in nonclinical 
species, however administration of PTG-300 carries theoretical liabilities (immunologically 


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based responses) associated with the systemic administration of a peptide. In the Phase 1 study 
PTG-300 was well tolerated, with the majority of AEs other than injection site reactions 
(primarily transient erythema) considered to be unrelated to PTG-300. In two ongoing Phase 2 
studies in β-thalassemia patients, PTG-300 has been well tolerated with no safety concerns, and 
no deaths have been reported by subjects as of a cutoff date of September 1, 2020. 
The potential risk in this study is causing anemia in subjects, assuming no iron is available for 
erythropoiesis. 
The nonclinical and clinical data to date suggests that PTG-300 has a good safety profile and that 
PTG-300 may be effective for decreasing phlebotomy requirements and decreasing symptoms of 
iron overload. Thus, the potential benefits appear to outweigh the potential risks of PTG-300 and 
clinical testing of PTG-300 for HH is appropriate. 
A subset of approximately 6 subjects will participate in an iron absorption substudy with the 
stable isotope 57Fe. Subjects will receive an oral administration of approximately 4 mg 57Fe as a 
ferrous sulfate solution. Stable isotopes are non-radioactive atoms of the same chemical element, 
which differ only in their number of neutrons (Bodamer 2001). Such studies are common in 
nutrition science and are often conducted to examine the absorption of selected elements (e.g., 
iron) from various foods and the impact of various diseases. These tracers are considered safe 
and may be particularly important for the validation of new treatment modalities, such as novel 
drug treatments (Bodamer 2001). 


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6. 
OBJECTIVES 
The study objectives are as follows: 
1. To assess the safety and tolerability of PTG-300 in HH subjects. 
2. To assess the effect of PTG-300 therapy on transferrin saturation (TSAT) and serum 
ferritin. 
3. To assess the effect of PTG-300 on iron absorption in a subset of subjects. (For subjects 
participating in the iron absorption substudy). 
4. To assess PTG-300’s efficacy for treating HH subjects as defined by incidence of 
phlebotomy. 
5. To assess the effect of PTG-300 on quality of life (QoL). 
6. To assess the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of 
PTG-300. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a multicenter, single-arm, open-label study in subjects with HH. Subjects will receive 
subcutaneous PTG-300 for up to 24 weeks. Subjects will start at an initial dose of 10 mg per 
week subcutaneously. The dose may be increased to 20 mg per week, and subsequently to 40 mg 
and to 80 mg per week if needed, based on tolerability and the pharmacodynamic marker TSAT. 
In addition, subcutaneous dosing schedules of 10 mg, 20 mg, and 40 mg twice weekly (Day 1 
and either Day 4 or Day 5) may be tested. 
Based on a review of the TSAT and safety data from at least the first 4 subjects, the starting dose 
and/or the dosing regimen may be modified for subsequent subjects to reduce exposure to 
ineffective doses. 
Subjects’ safety and blood iron parameters (serum iron, serum ferritin, transferrin, and TSAT) 
will be collected to monitor the pharmacodynamic effect of PTG-300. Effect on phlebotomy 
need and quality of life (QoL) data (36-Item Short Form Health Survey [SF-36], and Patient’s 
Global Impression of Change [PGI-C]) will also be collected and tabulated. 
A subset of subjects (approximately 6 subjects) will participate in a sequential two-way 
crossover iron (57Fe) absorption substudy. The oral iron absorption substudy will be conducted 
once during the 3-week screening period and then following approximately 4 to 6 weeks of 
PTG-300 treatment. 
Subjects will participate in this study for up to 31 weeks as follows: 
• Screening: Up to 3 weeks 
• PTG-300 Treatment: Up to 24 weeks (may include iron absorption substudy for 
selected subjects) 
• Safety follow up: 4 weeks. 
7.1.1. 
Screening (Study Day -21 to -1) 
After giving written informed consent, subjects will be screened for eligibility according to 
inclusion/exclusion criteria (see Section 8) within 21 days of dosing. Subjects will continue their 
individual iron restricted diet throughout the study. During this period liver iron concentration 
(LIC) will be assessed by magnetic resonance imaging (MRI). Subjects will begin treatment with 
PTG-300 within approximately 7 days following a regular phlebotomy, with iron parameters 
measured before (Screening labs) and after the phlebotomy (pre-dose Study Day 1). Each 
individual subject’s pre-phlebotomy serum ferritin level and TSAT will be used as a criterion for 
phlebotomy during the study, i.e., the threshold at which a phlebotomy should be considered 
during the study. The serum ferritin level and TSAT obtained during Screening will be used as 
baseline to assess the change from these measurements post-dosing with PTG-300. All 
concomitant medications received by the subject beginning 30 days prior to Screening should be 
collected. 


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After eligibility has been confirmed, subjects will be enrolled in the study. Those subjects who 
choose to participate and complete informed consent for the iron absorption substudy will 
complete their Iron Absorption A session during Screening (See Section 7.1.3 below). 
7.1.2. 
Treatment Period (Week 1 to Week 25) 
Study Drug Administration: Dosing with PTG-300 at 10 mg will be initiated in the clinic. On 
clinic visit days, PTG-300 doses will be administered in the clinic. All doses should be 
administered in the clinic until the subject or caregiver demonstrates the ability to perform 
subcutaneous injections properly. 
Subjects will begin treatment with 10 mg PTG-300 administered weekly. Subjects will receive 
their first subcutaneous (SC) injection at the clinic and will be instructed on how to self-
administer the injection (or have a caregiver administer the injection) and on appropriate safety 
monitoring before being discharged. 
On Study Day 2, subjects will return to the clinic for serum iron parameters and PTG-300 blood 
concentration (PK) measurements. 
Individual Subject Dose and Schedule Escalation: Individual subject dose and schedule will be 
determined based on the pharmacodynamic (PD) marker TSAT measured at two time points: 
once at peak PD effect one day post dose and once at trough PD effect. The intent of dose and 
schedule adjustment is to reduce TSAT and serum iron levels. The dose of PTG-300 may be 
increased weekly in a sequential manner from 10 mg to 20 mg and, if necessary, to 40 mg and 
80 mg until the TSAT is less than approximately 40% at peak PD effect one day post dose and at 
the trough PD effect prior to the next dose of PTG-300. In addition, the dose may be adjusted to 
maintain serum ferritin to no more than 1.5 times the screening value or 150 ng/mL, whichever is 
greater. Investigators may consider once a week or twice a week dosing of PTG-300 to achieve 
these objectives. The trough PD effect is the TSAT value measured 7 days after the PTG-300 
dose (and before the next dose) for once weekly dosing or 7 days after the first dose in a week 
for twice weekly dosing. For the twice weekly regimen, the doses should be given at least 3 days 
apart (e.g., on Day 1 and Day 4 or 5 of each week). The twice weekly PTG-300 dose may be 
escalated to a maximum of 40 mg twice weekly. To facilitate dose escalation and the 
identification of a therapeutic dose, investigators may assess TSAT values on days subjects come 
to the clinic for any dose adjustments. These assessments may occur at times other than the 
regular scheduled visits indicated on the schedule of events. 
Subjects will continue treatment by self-administering PTG-300 at home (or in the clinical center 
as appropriate) for up to 24 weeks based on acceptable safety and tolerability of the drug 
(Section 7.2). Subjects will return for clinic visits to have safety assessments; serum iron 
parameters plus soluble transferrin receptor (sTfR), hepcidin and antidrug antibodies (ADA); and 
efficacy evaluated according to the schedule of assessments. 
Subjects’ iron parameters will be monitored throughout the study. 
Change in Starting Dose: The starting dose may be increased from 10 mg to 20 mg, 40 mg, or 
80 mg as appropriate if <2 of the first 4 subjects (or ≤25% of a larger number of subjects) treated 
at a given dose have both peak and trough TSAT values approximately <40% and no safety 
signals have been noted. 


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Criteria for a Phlebotomy: Subjects should undergo an on-study phlebotomy when the subject’s 
serum ferritin levels and TSAT value are higher than the pre-phlebotomy serum ferritin and 
TSAT values obtained during Screening. In addition, a phlebotomy may be performed when the 
Investigator assesses it is necessary for subject care. 
7.1.3. 
Iron Absorption Substudy (See Table 3) 
Iron absorption subjects will be treated and monitored in an identical manner as the rest of the 
study population. 
Subjects consenting to participate in the iron absorption substudy will receive the stable iron 
isotope 57Fe orally (approximately 4 mg as ferrous sulfate) on two occasions; once prior to 
starting PTG-300 (i.e., after the phlebotomy performed during the Screening period, Iron 
Absorption A), and a second dose after 4 to 6 weeks after starting PTG-300 (i.e., post-treatment; 
Iron Absorption B). The post-treatment Iron Absorption B administration will occur 
approximately 24 hours following a PTG-300 dose. 
Subjects will receive 57Fe orally after an overnight fast of at least 8 hours. Subjects should fast 
for approximately 4 hours after the 57Fe dose. Blood samples will be collected at 0, 4, 8, 12, and 
24 hours for measurement of 57Fe levels and for measurement of iron parameters—serum iron, 
serum ferritin, transferrin, and TSAT. Additional blood samples will be obtained at 0, 4, 8, 12, 
and 24 hours following Iron Absorption B for measurement of PTG-300 concentrations. 
Food will be allowed starting 4 hours after the 57Fe administration. Subjects will be monitored in 
the study center for at least 12 hours, after which subjects may stay overnight or be discharged 
home (at the discretion of the subject and investigator) and return the next day (approximately 
24 hours following 57Fe administration). 
7.1.4. 
Post-Treatment / Early Termination Safety Follow-Up (Week 29) 
Subjects who complete the treatment or who discontinue treatment early will undergo Visit 8/end 
of treatment (EOT) assessments as well as follow-up safety evaluations approximately 4 weeks 
after the last dose of study drug (Visit 9/end of study [EOS]). 
7.2. 
Safety 
Safety will be monitored carefully throughout the study. 
Safety measures (including but not limited to physical examinations, clinical laboratory tests, 
complete blood count [CBC], vital signs, electrocardiograms [ECGs], adverse event monitoring 
[AEs], and concomitant medications) will be evaluated and recorded over the course of the study 
according to the schedule of assessments (Table 2). Clinical sites may conduct local laboratory 
tests if required by site procedures. 
Any AE that emerges from the time the subject signs an informed consent form (ICF) until Study 
Exit will be recorded and reported. Safety will be assessed using National Institutes of Health 
(NIH) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. It is 
recommended that prior to reducing the dose the dosing interval is increased to 2 weeks to 
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7.2.1. 
Safety Criteria for Dose Interval Increase or Dose Reduction 
The presence of at least one of the following criteria will require a dose reduction: 
• CTCAE Grade 3 hematological toxicity or worsening of ≥2 grades in hematological 
parameters not clearly resulting from the underlying disease and/or without a clear-
cut alternative that does not respond adequately to medical therapy. 
• CTCAE Grade 3 non-hematological toxicities not clearly resulting from the 
underlying disease and/or without a clear-cut alternative that does not respond 
adequately to medical therapy. 
• Treatment-related decrease of Hgb from baseline >20% or Grade 2 anemia, 
whichever is lesser, confirmed by a repeat value and not due to phlebotomy. Prior to 
resumption of PTG-300 at a reduced dose a follow-up Hgb should be assessed to 
confirm that Hgb has stabilized or improved to Grade 1. 
• Investigator determines that the subject has experienced a clinically significant 
decrease in Hgb due to PTG-300. 
If a treatment-related increase in aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) >3 × upper limit of normal (ULN) is seen, dosing with PTG-300 should be held, with 
resumption at a reduced dose if the AST and/or ALT levels return to baseline within 14 days; if 
the levels do not return to baseline within 14 days, an MRI should be conducted to assess 
whether there is an increase in iron accumulation. 
Dose reduction has two steps. Initially subjects continue to receive the same dose of PTG-300 
but the dosing frequency is reduced from twice weekly to weekly, or from weekly to every 
2 weeks. If the subject continues to meet criteria for dose reduction, the dose is then decreased 
one dose level. 
7.2.2. 
PTG-300 Discontinuation or Stopping 
The following are stopping criteria for an individual subject and will result in discontinuation of 
the subject from further treatment with study drug: 
• Any CTCAE Grade 4 hematological or non-hematological toxicity not clearly 
resulting from the underlying disease and/or without a clear-cut alternative. 
• CTCAE Grade 3 hematological toxicity or worsening of ≥2 grades in hematological 
parameters not clearly resulting from the underlying disease and/or without a clear-
cut alternative persists over 7 days after adequate PTG-300 dose decrease. 
• CTCAE Grade 3 non-hematological toxicities not clearly resulting from the 
underlying disease and/or without a clear-cut alternative explanation that do not 
improve within 14 days with maximal medical therapy and adequate PTG-300 dose 
decrease. 
• When the Investigator in consultation with the medical monitor (MM) considers that 
is in the subject’s best interest to discontinue treatment with PTG-300 (i.e., persistent, 
worsening or recurrent AEs). 
• If a subject requires a dose reduction below 10 mg administered every 2 weeks. 


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• ALT, AST >5 × ULN and rising. 
• ALT, AST remains >5 × ULN with no change in total bilirubin for more than 
2 weeks. 
• A worsening of clinical symptoms with no other acceptable explanation. 
• The product meets Hy’s Law: 
− Any test showing an increase of serum ALT >3 × ULN or >2 × ULN total 
bilirubin should be repeated within 48 to 72 hours for ALT, AST, alkaline 
phosphatase (ALP), and total bilirubin. If the repeat value for ALT or total 
bilirubin is unchanged or indicates decreasing activity, monitoring should 
continue at weekly intervals until the results are acceptable or normalized. 
• Evidence of clinically meaningful increased iron accumulation in liver from baseline. 
7.3. 
Number of Subjects 
Approximately 28 subjects will be enrolled in the study to ensure a total of 20 subjects complete 
at least 16 weeks of treatment. Approximately 6 subjects will participate in the iron absorption 
substudy. 
7.4. 
Treatment Assignment 
This is an open-label study with all subjects receiving PTG-300. 
7.5. 
Dose Adjustment Criteria 
The investigator may increase a subject’s dose up to 80 mg per week based on lack of 
pharmacodynamic (TSAT) response and acceptable safety. The starting dose and/or the dosing 
regimen will be evaluated and modified to enhance clinical benefit (see Section 7.1.2). 
Based on pre-defined safety criteria (see Section 7.2.1), a subject’s dosing frequency and dose 
may be reduced. 
7.6. 
Endpoints 
Baseline Definition: The serum ferritin level and TSAT obtained during Screening will be used 
as baseline. 
7.6.1. 
Efficacy 
• Change from baseline in serum ferritin. 
• Duration of time that serum ferritin is below baseline measurement. 
• Change from baseline in TSAT. 
• Duration of time that TSAT is below baseline measurement. 
• Time to first phlebotomy after dosing. 


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• Change in frequency of phlebotomies based on historical phlebotomy data 
(24 weeks). 
• Proportion of subjects who achieve phlebotomy independence. 
• Additional Endpoints: 
− SF-36 
− PGI-C 
− Change in iron absorption following the administration of PTG-300. (For subjects 
completing iron absorption substudy.) 
− PTG-300 pharmacokinetics: PTG-300 concentration as a function of dose and 
time since last dose. 
− PD: Change from baseline in serum iron, transferrin and sTfR. 
− Change from baseline in LIC assessed by MRI. 
− Incidence of ADA. 
7.6.2. 
Safety 
Safety is assessed using NIH CTCAE v5.0 criteria. 
• Tabulate frequency of treatment-emergent adverse events (TEAEs) and SAEs; 
treatment-related TEAEs and SAEs; TEAEs leading to study discontinuation. 
• Summarize vital signs, safety laboratory assessments, ECGs, and physical 
examination findings. 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria to be enrolled: 
1. Male and female subjects aged 18 years or older. 
2. Have a confirmed diagnosis of HFE-related hereditary hemochromatosis with prior 
genotype testing. 
3. Documented stable phlebotomy for ≥6 months prior to screening; with a phlebotomy 
frequency of at least 0.25 per month (e.g., received at least three phlebotomies over the 
previous 12 months, or at least four phlebotomies over the previous 15 months) and a 
phlebotomy frequency of less than 1 per month. 
4. Screening hemoglobin >11.5 g/dL. 
5. Serum ferritin <300 ng/mL at screening (before screening phlebotomy). 
6. Women of childbearing potential (WOCBP) and men with partners of childbearing 
potential agree to use a highly effective contraceptive measure (based on the Clinical 
Trials Facilitation Group [CTFG]) during the duration of the study and for 28 days after 
the last dose of study drug in the case of women and 90 days after the last dose of study 
drug in the case of men. 
7. Subject understands the study procedures, is willing and able to adhere to study 
requirements and agrees to participate in the study by giving written informed consent. 
8.2. 
Subject Exclusion Criteria 
Subjects must meet NONE of the following exclusion criteria to be enrolled. 
1. Clinically meaningful laboratory abnormalities at Screening including, but not limited to: 
a. Absolute neutrophil count <1000/µL 
b. Platelet count <100,000/µL 
c. Estimated Glomerular Filtration Rate (eGFR) <40 mL/min/1.73 m2 
d. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 × 
upper limit of normal (ULN) or direct bilirubin >1.5 × ULN 
e. C-reactive protein (CRP) ≥5.0 mg/L. 
2. Receiving iron chelation therapy. 
3. Receiving erythrocytapheresis. 
4. Pregnant or lactating females. 
5. Infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic 
infection within 3 months of dosing; any infection requiring antimicrobial therapy within 
4 weeks of dosing. Prophylactic antibiotics are allowed. 
6. Any serious or unstable medical or psychiatric condition that would prevent (as judged 
by the Investigator) the subject from properly providing informed consent or any 


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condition which would jeopardize compliance with the study or assessment of the study’s 
endpoints. 
7. Organ damage from iron overload, that (as judged by the Investigator) may be worsened 
by participation in this trial. 
8. Known primary or secondary immunodeficiency. 
9. Known history of autoimmune/inflammatory diseases. 
10. Positive for active hepatitis B or hepatitis C or known human immunodeficiency virus 
(HIV) infection. Active hepatitis B is defined as a known positive hepatitis B surface 
antigen (HBsAg) result. Active hepatitis C is defined by a positive  hep C Ab result and 
known quantitative hepatitis C virus (HCV) ribonucleic acid (RNA) results greater than 
the lower level of detection of the assay. Subjects who have a history of HCV infection 
but have documented sustained virologic response 12 weeks after HCV therapy (SVR12) 
are eligible. 
11. Any surgical procedure requiring general anesthesia within 1 month prior to screening or 
planned elective surgery during the study (within 3 months for joint replacement 
surgery). 
12. History of invasive malignancies within the last 2 years, except non-melanoma skin 
cancer and localized cured prostate cancer, cervical cancer, and ductal carcinoma in situ 
(DCIS). 
13. Current or recent history of alcohol dependence or illicit drug use within 6 months prior 
to screening. 
14. Subject is unable to give informed consent. 
15. Receipt of an investigational agent within 30 days of Screening. 
8.3. 
Subject Withdrawal Criteria 
Subjects may choose to withdraw at any time. 
Subjects should be withdrawn if the Investigator or Sponsor thinks withdrawal is in the subject’s 
best interest. 
A subject must be withdrawn if the subject becomes pregnant, is non-compliant with study 
procedures so that assessment of safety and efficacy are significantly compromised, starts an 
experimental therapy for HH, or meets dose stopping criteria (Section 7.2.2). 
9. 
STUDY PROCEDURES 
Study procedures should be completed as designated in the Schedules of Assessments (Table 2 
and Table 3). 


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Table 2: 
Schedule of Assessments for Study PTG-300-06 
Assessment 
Screeninga 
24 Weeks of PTG-300 Treatment 
Visit 9/EOS 
Safety 
Follow-Up 
Study Weekb 
D -21 to -1 
Visit 1 
(Wk 1) 
Visit 2 
(Wk 3 
[D15]) 
Visit 3 
(Wk 5 
[D29]) 
Visit 4 
(Wk 9 
[D57]) 
Visit 5 
(Wk 13 
[D85]) 
Visit 6 
(Wk 17 
[D113]) 
Visit 7 
(Wk 21 
[D141]) 
Visit 
8/EOT 
(Wk 25 
[D169]) 
~4 Wks 
After Last 
Dosec 
(~Wk 29) 
D1 
D2 
Informed Consent & HIPAA 
Authorizationd 
X 
 
 
 
 
 
 
 
 
 
 
Significant medical history 
X 
 
 
 
 
 
 
 
 
 
 
Phlebotomy history (for up to 
previous 15 months) 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Physical examination (including 
weight) 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
X 
X 
 
 
X 
 
X 
 
X 
X 
MRI (liver iron concentration) 
X 
 
 
 
 
 
 
 
 
X 
 
Hepatitis B & C screen 
X 
 
 
 
 
 
 
 
 
 
 
Phlebotomy 
Xe 
 
 
 
 
 
 
 
 
 
 
Phlebotomy evaluationf 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Concomitant medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse eventsg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testh 
X 
 
 
 
 
 
 
 
 
 
X 
Urine pregnancy testh 
X 
 
 
X 
X 
X 
X 
X 
X 
CRP 
X 
 
 
 
 
X 
 
X 
 
X 
 


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Assessment 
Screeninga 
24 Weeks of PTG-300 Treatment 
Visit 9/EOS 
Safety 
Follow-Up 
Study Weekb 
D -21 to -1 
Visit 1 
(Wk 1) 
Visit 2 
(Wk 3 
[D15]) 
Visit 3 
(Wk 5 
[D29]) 
Visit 4 
(Wk 9 
[D57]) 
Visit 5 
(Wk 13 
[D85]) 
Visit 6 
(Wk 17 
[D113]) 
Visit 7 
(Wk 21 
[D141]) 
Visit 
8/EOT 
(Wk 25 
[D169]) 
~4 Wks 
After Last 
Dosec 
(~Wk 29) 
D1 
D2 
Iron Absorption Substudyi 
X 
 
 
 
Xi 
 
 
 
 
 
 
Study drug administrationj 
 
Weekly 
 
Clinical laboratory testsk 
X 
X 
 
 
Xk 
X 
Xk 
X 
Xk 
X 
X 
CBC 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Iron parameters: Serum iron, 
transferrin saturation (TSAT), 
serum ferritin, transferrinl,m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Soluble transferrin receptor 
(sTfR) 
X 
 
 
 
 
X 
 
 
 
X 
 
Hepcidin 
X 
 
 
 
 
X 
 
 
 
X 
 
PK blood samples for 
measurement of PTG-300 
concentrationm 
 
Xl 
X 
X 
X 
X 
Xl 
X 
X 
X 
X 
ADA 
 
X 
 
 
 
X 
 
X 
 
X 
X 
SF-36 
X 
 
 
 
 
 
 
 
 
X 
 
PGI-C 
 
 
 
 
 
X 
 
X 
 
X 
 
Assess study drug compliance 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADA = anti-drug antibody, CBC = complete blood count, CRP = C-reactive protein, D = day, ECG = electrocardiogram, EOS = end 
of study, EOT = end of treatment, HIPAA = Health Insurance Portability and Accountability Act, MRI = magnetic resonance imaging, PGI-C = 
Patient’s Global Impression of Change, SF-36 = 36-Item Short Form Health Survey, sTfR = soluble transferrin receptor, TSAT = transferrin 
saturation. 
NOTE: Subjects may require additional visits one day post dose to assess PD effect for dose escalation. 
a Subjects may be rescreened if necessary. Rescreening is considered conducting screening tests outside of the 21-day screening window. 
b Clinical visits should be conducted within an approximately 2-day window (±2 days). All study procedures should occur before study drug administration 
except as indicated (i.e., PK/PD). 


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c Follow-Up procedures are to occur approximately 4 weeks after last dose whether the subject completes the study or terminates early. 
d Subjects enrolled at sites in the United States (US) must sign HIPAA authorization prior to the conduct of any study-specific procedures. 
e Must be conducted within approximately 7 days of PTG-300 dosing. Screening serum iron parameters must be collected before phlebotomy. Note: the pre-
phlebotomy serum ferritin level and TSAT will be used as the subject’s individual phlebotomy threshold for the study, i.e., the designated level at which a 
phlebotomy will be considered. 
f If a subject meets pre-specified criteria for phlebotomy during a visit, schedule a phlebotomy as soon thereafter as possible. 
g Additional tests or examinations, including physical exams, may be conducted as necessary. 
h For women of childbearing potential only. 
i Iron Absorption A is conducted prior to starting PTG-300 (i.e., after the phlebotomy performed during the Screening period). Iron Absorption B should be 
conducted after approximately 4 to 6 weeks of PTG-300 treatment (one day after PTG-300 administration between Week 4 and Week 6). See Table 3 for the 
Iron Absorption substudy schedule of events. 
j Study drug administration: PTG-300 is administered weekly or twice weekly. See Section 7.1.2 for details for monitoring TSAT and dose escalation. 
k See Appendix 1 for list of clinical laboratory tests. At Visits 3, 5, and 7, tests will include chemistry and CBC panel only (no urinalysis). 
l These tests should be conducted every 4 weeks at each clinic visit as well as each time point that PTG-300 PK blood samples are collected. In addition, iron 
parameters must also be measured whenever a subject’s dose is escalated (See Section 13.1 and Appendix 2). Additional tests may be obtained as outlined in 
Individual Subject Dose and Schedule Escalation in Section 7.1.2. 
m All sample collection for iron parameters, PK (PTG-300 concentrations) are conducted pre-dose at each clinic visit, with additional 1-day post-dose collections 
at Week 1 and following any dose escalation. 
 
 


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Table 3: 
Schedule of Assessments for Study PTG-300-06 — Iron Absorption Substudy (Parts A and B) 
Assessment 
Hours Post 57Fe Dosing 
0 
4 
8 
12 
24 
57Fe administrationa 
X 
 
 
 
 
Iron parameters: Serum iron, serum ferritin, TSAT, 
transferrin and 57Fe 
Xb 
X 
X 
X 
X 
PTG-300 concentrationc 
Xb 
X 
X 
X 
X 
Vital signs 
X 
 
 
X 
X 
Adverse events 
X 
 
 
X 
X 
Note: Iron Absorption A is conducted prior to starting PTG-300 (i.e., after the phlebotomy performed during the Screening period). Iron Absorption B should 
be conducted after approximately 4 to 6 weeks of PTG-300 treatment (one day after PTG-300 administration between Week 4 and Week 6). 
Abbreviations: TSAT = transferrin saturation. 
a During Iron Absorption B, 57Fe should be administered approximately one day after PTG-300 administration. 
b Pre-57Fe dosing. 
c Only conducted during Iron Absorption B. 
 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Description of Study Drug 
This study is a single-arm, open-label study; there is no placebo or comparator used. 
PTG-300 will be provided by Protagonist. 
PTG-300 is formulated in an aqueous buffered solution and prefilled at 0.5 mL and 1.0 mL into a 
1-mL glass syringe. Study drug will be administered by subcutaneous (SC) injections, using a 
needle and a pre-filled syringe. 
57Fe will be provided by Protagonist as a ferrous sulfate solution for oral administration. 
10.2. 
Concomitant Medications 
Subjects must receive appropriate care for HH including phlebotomy. Subjects should receive 
full supportive care for any other underlying conditions and all medications taken are recorded. 
Investigational agents must have been discontinued at least 30 days prior to screening and are not 
allowed during the study. All concomitant medications received by the subject beginning 30 days 
prior to Screening should be collected. 
10.2.1. 
Contraceptive Requirements 
Women of childbearing potential (WOCBP) and men must use medically acceptable 
contraception (<1% annual failure rate) during the duration of the study and for 28 days after the 
last dose of study drug in the case of women and 90 days after the last dose of study drug in the 
case of men. Medically acceptable methods of contraception that may be used by the subject 
and/or partner include but are not limited to the following: 
• Combined (estrogen and progesterone containing) hormonal contraceptives (for at 
least 3 months before screening) (oral, intravaginal, or transdermal) 
• Progesterone-only hormonal contraception (oral, injectable, or implantable) 
associated with inhibition of ovulation 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Surgically sterile (e.g., vasectomy, hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy at least 3 months before dosing) 
• Sexual abstinence. 
10.3. 
Treatment Compliance 
Study drug accountability and reconciliation will be performed by the study staff and the study 
monitor(s). 


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10.4. 
Randomization and Blinding 
This is a single-arm, open-label study; no randomization or blinding is used. 


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11. 
STUDY DRUG MATERIALS AND MANAGEMENT 
11.1. 
PTG-300 
Specific instructions about the storage, preparation, administration, and accountability of 
PTG-300 are provided in the Pharmacy Manual. 
11.1.1. 
Study Drug 
PTG-300 is provided by Protagonist in prefilled syringes containing PTG-300 in buffered saline 
solution. PTG-300 is formulated as an aqueous buffered solution, sterilized by filtration, and 
dispensed into 1 mL glass syringes at a 0.5 mL or 1.0 mL fill volume to deliver doses of 10 mg, 
20 mg, and 40 mg. For an 80-mg dose, two 40-mg injections will be administered. Each solution 
is buffered with sodium acetate and adjusted to pH 5.4 with dilute acetic acid. The tonicity of 
each solution is adjusted with sodium chloride. 
11.1.2. 
Study Drug Packaging and Labeling 
PTG-300 will be provided in labeled syringes with one syringe per box. 
11.1.3. 
Study Drug Storage 
PTG-300 Injection must be stored at 2°C to 8°C, protected from light, in a locked area with 
limited access. 
Storage instructions are included on the label. The Pharmacy Manual and Program Guide 
provide more detailed instructions on drug management. 
11.1.4. 
Study Drug Administration 
Injection sites are SC tissue in the abdomen (2 inches away from the navel), triceps, or thighs. 
Sites should be rotated between injections. 
Doses that are administered at the study site on clinic visit days will be given by a trained health 
care practitioner.  
All doses should be administered in the clinic until the subject or caregiver demonstrates the 
ability to successfully administer PTG-300. Additionally, study drug should be administered in 
the clinic whenever the subject is scheduled for a dose on a clinic visit day. 
11.1.5. 
Study Drug Accountability 
Compliance will be assessment throughout the study. 
A record will be maintained by the investigational sites that will account for all dispensing and 
return of any used and unused study drug. 
Investigators will be fully responsible for the security, accessibility, and storage of the study drug 
while it is at investigational sites. Investigators are also responsible for the education of study 
staff in the correct administration of the study drug. 


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11.1.6. 
Study Drug Handling and Disposal 
Upon receipt of the study drug at the investigational site, it must be stored at 2ºC to 8ºC in a 
secure location with limited access. 
At the end of the study the study drug will be reconciled, and a copy of the record given to the 
study monitor. Upon completion of the study any surplus study drug will either be returned to the 
Sponsor or be destroyed at the site upon receipt of written approval from Protagonist. Evidence 
of destruction must be supplied to the study monitor. 
Further information of the storage, handling and administration of study drug will be provided in 
the Pharmacy Manual. 
11.2. 
57Fe Ferrous Sulfate Solution 
57Fe (approximately 4 mg) is provided by Protagonist as an oral ferrous sulfate solution. 
Further information of the storage, handling, and administration of 57Fe will be provided in the 
Pharmacy Manual. 


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12. 
ASSESSMENT OF EFFICACY 
12.1. 
Clinical Endpoints 
12.1.1. 
Phlebotomy and Iron Parameters 
Intermittent therapeutic phlebotomy is standard of care for patients with HH. During the study 
the timing of a subject’s phlebotomy will be based on their established TSAT and serum ferritin 
pre-phlebotomy threshold. 
During the screening phase, subjects will have a phlebotomy within approximately 7 days prior 
to PTG-300 dosing. Each individual subject’s pre-phlebotomy serum ferritin level will be used as 
their individual phlebotomy threshold, i.e., the designated level at which a phlebotomy may be 
performed in the study. 
Subjects’ iron parameters will be monitored throughout the study. A subject will receive a 
therapeutic phlebotomy during the study if his/her TSAT and serum ferritin is above their pre-
phlebotomy level at Screening. 
12.1.2. 
Iron Absorption (Iron Absorption Substudy) 
Subjects consenting to participate in the iron absorption substudy will have their iron absorption 
measured at two time points, pre-treatment with PTG-300 (Iron Absorption A) and after 
approximately 4 to 6 weeks of treatment with PTG-300 (Iron Absorption B). The purpose of the 
iron absorption substudy is to quantify the absorption of iron, marked by the 57Fe isotope and the 
effect of PTG-300 on absorption of iron following oral dosing. 
12.2. 
Quality of Life Instruments 
12.2.1. 
Medical Outcome Study Questionnaire Short Form Health Survey (SF-36) 
The Medical Outcome Study Questionnaire Short Form Health Survey (SF-36; Appendix 3) is a 
36-item short-form (SF-36) questionnaire constructed to survey health status in the Medical 
Outcomes Study (MOS) (Ware 1992). The SF-36 includes one multi-item scale that assesses 
eight health concepts: 1) limitations in physical activities because of health problems; 2) 
limitations in social activities because of physical or emotional problems; 3) limitations in usual 
role activities because of physical health problems; 4) bodily pain; 5) general mental health 
(psychological distress and well-being); 6) limitations in usual role activities because of 
emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. 
12.2.2. 
Patient Global Impression of Change (PGI-C) 
Patient Global Impression of Change (PGI-C; Appendix 4) is a self-report measure that reflects a 
patient’s belief about the efficacy of treatment. The patient will compare his/her condition from 
the start of the study on a 7-point scale ranging from “Very much worse” (1) to “Very much 
improved” (7) at the time of the assessment. 


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12.3. 
Anti-Drug Antibodies (ADA) 
As PTG-300 is a protein drug, subjects may mount an immune response to PTG-300 producing 
ADA. Development of ADA will be monitored throughout the study. Samples will be obtained 
pre-dose at the time points specified in Table 2. 
Should any subject develop ADA, an assessment will be made whether these are neutralizing and 
the impact of ADA on PTG-300’s safety and efficacy in that subject will be evaluated. 


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13. 
PHARMACOKINETIC, PHARMACODYNAMIC AND IRON 
ABSORPTION ASSESSMENTS 
Trough concentrations of PTG-300 by dose will be assessed. In addition, any additional 
pharmacokinetic parameters that can be estimated will be reported. 
13.1. 
Blood Sample Collection Schedule in Each Study Period 
13.1.1. 
Sample Collection for All Subjects 
Blood draws to assess concentration of PTG-300 will be collected during each clinic visit prior 
to a dose of PTG-300 being administered and one day after PTG-300 dose escalation. 
Blood draws to assess iron parameters will be collected during each clinic visit pre-dose 
PTG-300, and one day after each PTG-300 dose escalation. 
See Schedule of Assessments, Table 2. 
13.1.2. 
Sample Collection for Iron Absorption Substudy 
Blood samples (5 mL) for measurement of 57Fe, will be collected at the following time points: 
0 (pre-dose 57Fe) and at 4, 8, 12, and 24 hours post-dose 57Fe (within 10% nominal time). 
Blood samples (5 mL) for measurement of iron parameters will be collected pre-dose 57Fe and at 
4, 8, 12, and 24 hours post-dose 57Fe (within10% nominal time). 
Blood samples (5 mL) for measurement of concentrations of PTG-300 will be obtained at the 
following time points during Iron Absorption B: at pre-dose 57Fe, and at 4, 8, 12, and 24 hours 
post-dose 57Fe (within 10% nominal time). 
See Schedule of Assessments for Iron Absorption substudy, Table 3. 
13.2. 
Samples Per Subject 
Approximately 11 blood samples for PK and iron parameters (approximately 5 mL each) will be 
collected if a subject completes the entire study. In addition, blood samples will be taken for 
assessment of hematology and clinical chemistry. A total of approximately 160 mL of blood will 
be drawn over the 31-week study period for subjects who complete the study. Subjects that 
require dose escalation to 80 mg may have up to approximately 200 mL of blood collected over 
the 31-week study period. An additional 70 mL blood will be collected from subjects who 
complete the iron absorption substudy. 
13.3. 
Pharmacokinetic Blood Sample Collection and Processing 
See the Laboratory Manual for blood sample labeling, processing, storage, and shipment 
instructions. 


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14. 
ASSESSMENT OF SAFETY 
14.1. 
Safety Parameters 
Safety will be assessed by the following parameters: 
• ECGs, clinical laboratory tests including CBC (Appendix 1), and physical 
examinations findings (including vital signs). 
• Adverse events and concomitant medications will be evaluated throughout the course 
of the study. 
• Adverse events of interest will be assessed and reported separately and include the 
following: hematological toxicity > Grade 3 (CTCAE criteria, Version 5.0). 
Vital signs will include blood pressure (systolic and diastolic), heart rate, respiratory rate, and 
temperature. 
Electrocardiograms will include ventricular rate, PR, QRS, QT, RR and QTcF. 
The specific timing of safety assessments is presented in Table 2. 
14.2. 
Adverse Events and Serious Adverse Events 
In this study, AEs and SAEs will be reported in all subjects from the time the subject signs the 
ICF until the completion of the safety follow-up/end of study visit. Treatment-emergent AEs and 
SAEs will be evaluated from study drug dosing until the end of study visit. 
14.2.1. 
Definition of Adverse Event 
An AE is any event, side effect, or other untoward medical occurrence that occurs in conjunction 
with the use of a medicinal product in humans, whether or not considered to have a causal 
relationship to this treatment. An AE can, therefore, be any unfavorable and unintended sign 
(that could include a clinically significant abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. An AE may include an increase in severity of a pre-existing condition 
included in a subject’s medical history, and symptoms or clinical sequelae of a suspected 
overdose. “Lack of efficacy” per se will not be reported as an AE or SAE. However, the signs 
and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they 
fulfil the definition of an AE or SAE. 
The Investigator should attempt to establish a diagnosis of the event based on the signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE (and SAE if serious) and not the individual signs/symptoms. 
14.2.1.1. Severity of an Adverse Event 
Severity of adverse events will be assessed and reported following CTCAE Version 5.0 criteria 
(National Cancer Institute 2010). Severity of adverse events that do not match CTCAE criteria 
will be assessed as follows: 
• Mild (Grade 1): awareness of sign or symptom but easily tolerated  


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• Moderate (Grade 2): discomfort enough to cause interference with usual activity 
• Severe (Grade 3): incapacitating with inability to work or do usual activity 
• Life-threatening (Grade 4): could reasonably lead to death without medical 
intervention 
• Fatal (Grade 5) 
14.2.1.2. Relationship of an Adverse Event to Study Drug 
The Investigator will assess the relationship between study drug and the occurrence of each AE. 
The investigator’s assessment of the relationship of each AE to study drug will be recorded in the 
source documents and the CRF. Alternative causes, such as medical history, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study drug should be 
considered and investigated, if appropriate. The following definitions are general guidelines to 
help assign grade of attribution:  
• Not related: The event is clearly related to other factors such as the subject’s clinical 
state, therapeutic interventions or concomitant drugs administered to the subject. This 
is especially so when an event occurs prior to the commencement of treatment with 
the study drug. 
• Unlikely: The event was most likely produced by other factors such as the subject’s 
clinical state, therapeutic interventions, or a concomitant drug administered to the 
subject and does not follow a known response to the study drug. 
• Possibly: The event follows a reasonable temporal sequence from the time of study 
drug administration or follows a known response to the study drug but could have 
been produced by other factors such as the subject's clinical state, other therapeutic 
interventions, or concomitant drugs administered to the subject. 
• Related: The temporal relationship is compelling between the administration of the 
study drug and the AE cannot be explained by the subject’s medical condition or 
other therapies. 
14.2.1.3. Action Taken with Study Medications 
Action taken with study medications will be recorded on the AE CRF page, as follows, 
regardless if a particular category is possible or not in this study: 
• Dose Increased 
• Dose Not Changed 
• Dose Reduced 
• Dose Interrupted 
• Dose Withdrawn 
• Not Applicable 
• Unknown 


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14.2.1.4. Outcome of an Adverse Event 
Outcome of an AE will be recorded on the AE CRF as follows: 
• Recovered/Resolved 
• Recovering/Resolving 
• Recovered/Resolved with Sequelae 
• Not Recovered/Not Resolving 
• Fatal 
• Unknown 
14.2.2. 
Definition of Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:  
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect. 
Important medical events that are not one of the above may be considered to be SAEs by the 
investigator when, based upon appropriate medical judgement, they are considered to be 
clinically significant and may jeopardize the subject, or when medical or surgical intervention 
may be required to prevent one of the outcomes listed above. 
An AE is considered “life-threatening” if, in the opinion of either the Investigator or the Sponsor, 
its occurrence places the subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death. 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity, 
whereas seriousness is defined by the criteria under Section 14.2.2. An AE of severe intensity 
may not be considered serious. 
14.2.3. 
Pregnancy 
The Investigator must report to the Sponsor any pregnancy occurring in a study subject (or 
subject’s partner) during the subject’s participation. The report should be submitted within the 
same timelines as an SAE, although a pregnancy per se is not considered an SAE unless the birth 
results in a congenital anomaly/birth defect or there is suspicion that the study medication may 
have interfered with the effectiveness of a contraceptive medication or method. Spontaneous 
miscarriages should also be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. 
A pregnancy should be followed-up until reporting of the pregnancy’s outcome and the birth 
date. 


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As information is available, a pregnancy diagnosed during the study will be reported 
immediately to the Investigator and Sponsor (or designee), including pregnancy in female 
partners of male subjects. The pregnancy will be followed to term or outcome and this outcome 
will be reported to the Sponsor. 
14.2.4. 
Other Safety Parameters and Related Information 
Additional safety parameters (laboratory tests including CBC, 12-lead ECGs, physical 
examinations, and vital signs) and concomitant medications are collected as shown in the 
Schedules of Assessments in Table 2. Clinical laboratory assessments are listed in Appendix 1. 
Abnormal findings, other than pharmacodynamic markers, that are deemed clinically significant 
or are associated with signs and/or symptoms must be recorded as AEs (or recorded as an SAE if 
they meet the criteria of being serious) as described previously. 
The Investigator should exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Usually, the 
abnormality should be associated with a clinically evident sign or symptom. 
A clinically significant laboratory abnormality in the absence of clinical signs and symptoms 
may jeopardize the subject and may require intervention to prevent immediate consequences. For 
example, a markedly low serum glucose concentration may not be accompanied by coma or 
convulsions, yet be of a magnitude to require glucose administration to prevent such sequelae. 
14.3. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation will be documented in the medical record in 
accordance with the Investigator’s normal clinical practice and on the AE page of the case report 
form (CRF). SAEs that occur during the study must be documented in the subject’s medical 
record, in the AE CRF, and on the SAE form. 
If there is evidence of an AE or SAE through report or observation, the Investigator or designee 
will evaluate further and record the following information: 
• Time of onset and resolution 
• Severity 
• Causality/relation to study treatment 
• Action taken regarding study drug 
• Outcome 
14.4. 
Reporting Adverse Events 
Adverse Events: All AEs, regardless of their relationship to PTG-300, will be reported on the 
AE Case Report Form. In order to ensure timely safety oversight of the trial, AEs should be 
reported routinely. All reports should include time of onset and resolution, severity (see 
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SAEs: In order to meet the requirements for expedited reporting of SAEs to applicable 
regulatory authorities and IRBs, all SAEs, must be reported to the Sponsor within 24 hours from 
the time the site investigational team first becomes aware of the event. This report may be 
initially achieved by telephone, or by completing a SAE report form and sending it to the 
Sponsor via the contact information printed on the form. 
The SAE report form should be completed as thoroughly as possible and signed by the 
Investigator before transmittal to the study Sponsor. It is very important that the Investigator 
provide an assessment of the causal relationship between the event and study drug at the time of 
the initial report, as this will be useful for submissions to regulatory authorities. 
Initial notification of an SAE by telephone must be confirmed in writing 24 hours from the time 
the site investigational team first become aware of the event using the SAE report form as 
described above. 
As further information regarding the SAE becomes available, such follow-up information should 
be documented on a new serious adverse event report form and marked as a follow-up report. 
Protagonist is responsible for notifying the relevant regulatory authorities of certain events. It is 
the Principal Investigator’s responsibility to notify the IRB or IEC of all SAEs that occur at his 
or her site. Investigators will also be notified of all unexpected, serious, drug-related events (7/15 
Day Safety Reports) that occur during the clinical trial. Each site is responsible for notifying its 
IRB or IEC of these additional SAEs. 
14.5. 
Follow-Up of Adverse Events and Serious Adverse Events 
All AEs and SAEs that are deemed possibly related or probably related to PTG-300 must be 
followed until resolution, until the condition stabilizes, until the event is otherwise explained, or 
until the subject dies or is lost to follow-up. The Investigator is responsible to ensure that follow-
up includes any supplemental investigations as may be indicated to elucidate as completely as 
practical the nature and/or causality of the AE/SAE. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals. 
If a subject dies during participation in the study or during a recognized follow-up period, the 
Sponsor should be provided with a copy of any post-mortem findings, including histopathology. 


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15. 
STATISTICS 
Summary statistics for all efficacy, safety, and PK/PD data, along with the estimation of 
PTG-300's treatment effect, will be provided. A detailed statistical analysis plan (SAP) will be 
prepared prior to performing any analysis. In case of differences between the protocol and the 
SAP, the SAP will take precedence. 
15.1. 
Study Design and Sample Size Estimation 
This is a multicenter, single-arm, open-label study. 
This trial is exploratory and no rigid criteria for sample size are pre-specified. The choices are 
based on risk/benefit assessment of accumulating results. However, there will be at least 80% 
power for a sample size of 20 subjects to detect a 50% reduction in the number of phlebotomies 
from baseline. The power calculation is based on a hypothesized effect size of 0.5 (mean change 
= 1, with SD = 2) over 24 weeks using a 1-sided one-sample t-test at alpha=10% level. Twenty-
eight (28) subjects will be enrolled in the study, assuming an approximate 25% dropout. 
15.2. 
Demographics/Baseline Comparability 
The demographics and baseline characteristics will be summarized by groups, with and without 
the iron absorption substudy, respectively, and overall using descriptive statistics. Demographics 
information includes age, sex, race, and ethnicity. Baseline disease characteristics will be 
included if necessary. 
15.3. 
Data Presentation 
Serum chemistries and measurements related to iron studies will be obtained at the clinical site 
and/or at a central laboratory. The central laboratory value will be used for data presentation and 
study endpoints. The clinical laboratory value may be used for clinical decision making. 
15.4. 
Definition of Baseline 
For the phlebotomy frequency, the subjects’ pre-study phlebotomy history will serve as the 
baseline. For serum ferritin and TSAT, measurements obtained during the screening period will 
serve as the baseline. 
15.5. 
Analysis of Efficacy Data 
Efficacy data will be analyzed for all the subjects included in the Intent-to-Treat Analysis Set 
defined below. 
In general, continuous endpoints will be summarized by standard descriptive statistics (mean, 
standard deviation, median, minimum, and maximum). Categorical endpoints will be 
summarized by frequencies and percentages. 
Hypothesis testing will be performed by the t-test for each of the change from baseline endpoints 
listed below to evaluate if the change is significantly different from zero. P-value will not be 
adjusted for multiple comparisons since this is an early phase safety and proof of concept study. 
In addition, the point estimate (i.e., mean and/or median) and the confidence interval associated 


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with the estimate will be provided. Kaplan-Meier estimate will be applied for the time to first 
phlebotomy data. 
Data collected for subjects electing to participate in the iron absorption substudy will be analyzed 
separately in addition to the analyses for all the Intent-to-Treat subjects. Serum iron, 57Fe, TSAT, 
serum ferritin, sTfR, and transferrin pertaining to the iron absorption substudy will be analyzed 
for the subgroup as defined as Iron Absorption analysis set below.  
15.6. 
Analysis Populations 
15.6.1. 
Safety Analysis Set 
The Safety Analysis set will include all subjects who receive any amount of study drug. 
15.6.2. 
Intent-to-Treat Analysis Set 
The Intent-to-Treat (ITT) Analysis Set for efficacy analyses includes all subjects who received 
any study drug and have a baseline and at least one post-baseline efficacy assessment. 
15.6.3. 
Iron Absorption Analysis Set 
The Iron Absorption (IA) Analysis Set will include all ITT subjects who complete Iron 
Absorption B. 
15.7. 
Handling of Missing Data 
Missing data will not be imputed for calculation of mean changes and other quantitative analyses 
since the aim for those analyses is to estimate mean changes and other quantitative outcomes in 
subjects who remain on treatment. Missing data are assumed missing at random for subjects 
remaining on treatment at each respective time point. 
15.8. 
Analysis of Safety 
The safety analysis will include all subjects who receive any amount of study medication. 
Reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
All AEs will be summarized by system organ class and preferred terms within system organ 
class for overall AEs, for AEs any time during the study. The severity, seriousness, and 
relationship to study medication will also be summarized in a similar manner. Each AE (based 
on preferred term) is counted once for a given subject. If the same AE occurred on multiple 
occasions, the highest severity and least complimentary relationship will be assumed. 
The incidence of TEAEs and SAEs will be summarized overall and by the subgroup alone, 
respectively. 
Additionally, laboratory test data, physical examinations, vital signs, and ECGs will be 
summarized overall and by the subgroup alone, respectively. 
15.9. 
Analyses of Pharmacokinetics and Pharmacodynamics 
PK: Concentrations of PTG-300 by dose regimen will be estimated. In addition, concentrations 
will be reported by time point. 


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PD: 57Fe absorption will be estimated using the AUC in the subgroup of subjects who complete 
both iron absorption treatments. Change from baseline in serum iron parameters (serum iron, 
transferrin, serum ferritin, TSAT) and sTfR will be estimated. 
In general, descriptive statistics, including the numbers subjects [n], means, standard deviations 
[SD], medians, minimums, maximums will be provided for PK parameters as well as for the PD 
parameters. 
15.10. 
Exploratory Endpoints 
• Effects of ADA on safety and efficacy. 
• The relationship between PTG-300 pharmacokinetics and pharmacodynamics and 
efficacy will be explored. 


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16. 
ADMINISTRATIVE PROCEDURES AND ETHICAL 
CONSIDERATIONS 
16.1. 
Study Monitoring 
At intervals during the study, as well as after the completion of subject enrollment, the study 
center will be monitored by a clinical research associate (CRA) for compliance, which will 
include ensuring that study procedures are being followed, ensuring that accurate and complete 
data are recorded on CRFs, and reviewing source documentation and drug accountability 
records. The study will be conducted according to the principles of GCP. 
16.2. 
Audits and Inspections 
Authorized representatives of Protagonist, a regulatory authority, an Independent Ethics 
Committee or an Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Protagonist audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization (ICH E6 (R2)), and any other applicable regulatory 
requirements in the country where the trial takes place. The investigator should contact 
Protagonist immediately if contacted by a regulatory agency about an inspection. 
16.3. 
Institutional Review Board (IRB) Approval 
Prior to commencement of the study, written approval is required by the relevant IRB 
responsible for the investigational site. 
16.4. 
Guidelines for Good Clinical Practice 
This study will be conducted in accordance with principles of Good Clinical Practice (GCP) as 
promulgated by the ICH, and applicable regulatory requirements in the country where the trial 
takes place. Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting trials that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, and 
well-being of human subjects are protected under current ethical principles, and that the clinical 
trial data are credible. Current GCP standards may be found in ICH Guidance E6 (R2). This 
guidance describes the principles of GCP and the obligations of the institutional review board 
(IRB), the Investigator and the Sponsor in conducting this study in accordance with those 
principles. 
16.5. 
Ethics 
16.5.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate. Prior to the 


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commencement of the study, written approval will be required by the relevant IRB/IEC 
responsible for the investigational site. 
In addition, the IRB or IEC must approve all advertising used to recruit subjects for the study. 
The investigator must submit written approval to Protagonist before he or she can enroll any 
patient/subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements. The protocol must be re-approved by the IRB or 
IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product. Protagonist will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.5.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. 
16.5.3. 
Written Informed Consent 
A properly executed, written Informed Consent Form, in compliance with the Declaration of 
Helsinki, ICH GCP, and United States (US) Code of Federal Regulations for Protection of 
Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 46, Subpart A), will be 
explained to and signed by each subject prior to entering the trial. The Investigator will provide a 
copy of the signed Informed Consent Form to each subject and will maintain a copy in the 
subject’s record file. 
16.6. 
Termination of Study 
The Sponsor has the right to terminate this study and remove all study material from the site at 
any time for medical or administrative reasons. In this event, the Sponsor will endeavor to give 
adequate notice to allow safe withdrawal of subjects from the study. 
16.7. 
Case Report Forms 
Site personnel should collect and record data for the study as source documents and transfer the 
data into the CRF. 
The Investigator must ensure that complete data for the clinical study are collected and 
accurately documented in the appropriate sections of the CRF and adequately supported by the 
appropriate source documentation. In addition, it is the Investigator’s responsibility to provide 
signatures where requested indicating concurrence with data in the CRF. 


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16.8. 
Inspection of Records 
Protagonist will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
16.9. 
Retention of Records 
International Conference on Harmonization, GCP, and US Food and Drug Administration (FDA) 
guidelines require that essential documents be retained until at least 2 years after the last 
approval of a marketing application and until there are no pending or contemplated marketing 
applications, or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. 
However, the essential documents should be retained for a longer period if required by the 
applicable regulatory requirements or by an agreement with the Sponsor. Records should never 
be destroyed without written approval from the Sponsor. 
If an Investigator leaves the institution, he/she must transfer responsibilities for record retention 
to another individual willing to accept them. The Investigator must notify the Sponsor in writing 
of the transfer of study documents before the transfer of the study. 


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17. 
PUBLICATION POLICY 
The data generated in this clinical study are the exclusive property of Protagonist Therapeutics 
Inc. and are confidential. Any publication of the results of this study must be authorized by the 
Protagonist and Protagonist will have the opportunity to review any publications that arise from 
the investigators before submission for publication. 
Publication and reporting of results and outcomes of this trial will be accurate and honest, 
undertaken with integrity and transparency and in accordance with Protagonist’s Publication 
Policy. Subject confidentiality will be maintained by referring to individual subjects by their 
identifying code used in the trial. Publication of results will be subjected to fair peer-review. 
Authorship on any publication of the results from this study will be based on contributions to 
study design, enrolment, data analysis, and interpretation of results according to International 
Committee of Medical Journal Editors guidelines (http://www.icmje.org). All conflicts arising 
through disputes about authorship will be reviewed by Protagonist. 
Acknowledgment will be given to collaborating institutions and hospitals and other individuals 
and organizations providing finance or facilities. 
In the case of no publication, information will only be released to the public and media in 
accordance with Protagonist’s Policy. 


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18. 
REFERENCES 
Bodamer OA, Halliday D. Uses of stable isotopes in clinical diagnosis and research in the 
paediatric population. Arch Dis Child. 2001 May;84(5):444-8. 
Brissot P, Bardou-Jacquet E, Jouanolle AM, Loreal O. Iron disorders of genetic origin: a 
changing world. Trends Mol Med. 2011;17(12): 707-713. 
Camaschella C. Iron and hepcidin: a story of recycling and balance. Hematology Am Soc 
Hematol Edu Program. 2013; 2013:1-8. 
Crownover BK, Covey CJ. Hereditary hemochromatosis. Am Fam Physician. 2013;87(3):183-
90. 
Katsarou MS, Papasavva M, Latsi R, Drakoulis N. Hemochromatosis: Hereditary 
hemochromatosis and HFE gene. Vitam Horm. 2019;110:201-222. 
Liu J, Sun B, Yin H, Liu S. Hepcidin: A Promising Therapeutic Target for Iron Disorders: A 
Systematic Review. Medicine (Baltimore). 2016 Apr;95(14):e3150. 
National Cancer Institute, National Institutes of Health (NIH) Publication No. 09-540. Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Bethesda, MD: National Cancer 
Institute, Published November 27, 2017. Available at 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf. Accessed October 31, 2018. 
Ramos E, Ruchala P, Goodnough JB, Kautz L, Preza GC, Nemeth E, Ganz T. Minihepcidins 
prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis. Blood. 
2012 Nov 1;120(18):3829-36. 
Ruchala P, Nemeth E. The pathophysiology and pharmacology of hepcidin. Trends Pharmacol 
Sci. 2014 Mar;35(3):155-61. 
Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36).I. Conceptual 
framework and item selection. Med Care. 1992 Jun;30(6):473-83. 
 


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19. 
APPENDICES 
 
 


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APPENDIX 1. CLINICAL LABORATORY TESTS 
 
HEMATOLOGY/CBC 
hemoglobin 
hematocrit 
red blood cell count 
white blood cell count 
% neutrophils 
% lymphocytes 
% monocytes 
% basophils 
% eosinophils 
absolute neutrophils 
absolute lymphocytes 
absolute monocytes 
absolute basophils 
absolute eosinophils 
platelet count 
CHEMISTRY 
sodium 
potassium 
chloride 
carbon dioxide 
blood urea nitrogen (BUN) 
creatinine 
glucose 
calcium 
phosphorous 
albumin 
total protein 
uric acid 
total bilirubin 
direct bilirubin 
indirect bilirubin 
alkaline phosphatase 
alanine aminotransferase 
(ALT, SGPT) 
aspartate aminotransferase 
(AST, SGOT) 
lactate dehydrogenase 
(LDH)
URINALYSIS 
pH 
specific gravity 
blood 
glucose 
ketones 
microscopic exam (RBC 
and WBC, only when 
indicated) 
leukocyte esterase 
protein


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PREGNANCY TEST 
Serum pregnancy test (to be completed on site) for female subjects of childbearing potential at 
Screening and at Safety Follow-Up (Week 29) 
Urine pregnancy test (to be completed on site) for female subjects of childbearing potential. 


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APPENDIX 2. ADDITIONAL LABORATORY TESTS 
 
The following samples to be collected as per Schedule of Assessments (Table 2). 
 
IRON PARAMETERS (PHARMACODYNAMIC PARAMETERS) 
serum iron 
serum ferritin 
transferrin 
TSAT 
 
ADDITIONAL ASSESSMENTS 
sTfR 
hepcidin 
ADA 


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APPENDIX 3. MEDICAL OUTCOME STUDY QUESTIONNAIRE 
SHORT FORM HEALTH SURVEY (SF-36) 
 
 
 


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APPENDIX 4. PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) 
 
The subject will independently rate the following question of Patient Global Impression of 
Change (PGI-C) based on his/her overall impression at Week 9 and Week 25. 
 
Patient Global Impression of Change: 
Compared to your condition prior to your starting on this study, how much has your condition 
changed with your current treatment? 
 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
Very 
Much 
Worse 
Much 
Worse 
Minimally 
Worse 
No 
Change 
Minimally 
Improved 
Much 
Improved 
Very 
Much 
Improved