Phase 2 Single Arm Study of Efficacy and Safety of P1101 for Polycythemia Vera (PV) Patients for Whom the Current Standard of Treatment is Difficult to Apply
Phase: PHASE2
Conditions: Polycythemia Vera (PV)
Sponsor: PharmaEssentia Japan K.K.

PharmaEssentia Corporation 
Clinical Study Protocol: P1101 in Japanese PV (A19-201) 
Property of PharmaEssentia Corporation 
Confidential 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be used, divulged, published, or otherwise disclosed without the written consent of 
PharmaEssentia Corporation. These restrictions on disclosure will apply equally to all future information 
supplied to you which is indicated as privileged or confidential. 
 
Pegylated Proline-Interferon Alfa-2b (P1101) 
Clinical Study Protocol: P1101 in Japanese PV 
 
Study Title:  Phase 2 single arm study of efficacy and safety of P1101 for polycythemia vera 
(PV) patients for whom the current standard of treatment is difficult to apply. 
 
 
Development phase: 
Phase 2 
Document status: 
FINAL 
Version date: 
September 14th, 2020 
Version: 
4.0 
IND No.: 
NA 
Sponsor: 
 
PharmaEssentia Japan 
 
 
 
 

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Version Control Record 
Version 
Creation / Revision 
1.0 
September 30th, 2019 
2.0 
November 8th, 2019 
3.0 
November 29th, 2019 
4.0 
September 14th, 2020 
 
 
 
 
 

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Table of Contents 
1 
SYNOPSIS ...............................................................................................................8 
2 
SIGNATURE PAGE FOR SPONSOR .................................................................... 15 
3 
SIGNATURE PAGE FOR INVESTIGATORS ....................................................... 16 
4 
ABBREVIATIONS AND TERMS ......................................................................... 17 
5 
INTRODUCTION AND RATIONALE .................................................................. 20 
5.1 
Background ............................................................................................................ 20 
5.2 
Overview of Nonclinical Studies ............................................................................. 21 
5.2.1 
Safety Pharmacology ....................................................................................... 21 
5.2.2 
Nonclinical Pharmacokinetics and Pharmacodynamics .................................... 21 
5.2.3 
Toxicology ...................................................................................................... 21 
5.3 
Overview of Clinical Studies .................................................................................. 22 
5.4 
Study Rationale....................................................................................................... 24 
5.5 
Risks and Benefits .................................................................................................. 25 
5.6 
Justification of Study Drug Route of Administration, Dosage, Dosage Regimen, and 
Treatment Duration ................................................................................................. 25 
5.7 
Justification of Study Target Subject Population ..................................................... 26 
6 
STUDY OBJECTIVES ........................................................................................... 26 
6.1 
Primary Objective ................................................................................................... 26 
6.2 
Secondary Objectives:............................................................................................. 26 
7 
STUDY ENDPOINTS ............................................................................................ 26 
7.1 
Primary Efficacy Endpoint ...................................................................................... 26 
7.2 
Secondary Endpoints .............................................................................................. 27 
7.3 
Exploratory Endpoint .............................................................................................. 27 
7.4 
Safety Endpoints ..................................................................................................... 27 
7.5 
PPK and E-R Endpoints .......................................................................................... 27 
7.6 
Immunogenicity endpoints ...................................................................................... 27 
8 
OVERVIEW OF STUDY DESIGN ........................................................................ 27 
8.1 
Disease Progression/Withdrawal Criteria ................................................................ 28 
9 
STUDY POPULATION ......................................................................................... 28 
9.1 
Inclusion Criteria .................................................................................................... 29 
9.2 
Exclusion Criteria ................................................................................................... 30 
9.3 
Justification of Inclusion/Exclusion Criteria ............................................................ 31 
9.3.1 
Justification of Inclusion Criteria ..................................................................... 31 
9.3.2 
Justification of Exclusion Criteria .................................................................... 31 
10 
RANDOMIZATION AND BLINDING .................................................................. 32 
11 
ASSIGNMENT TO STUDY ................................................................................... 32 

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12 
STUDY DRUG....................................................................................................... 32 
12.1 
Investigational Treatment ........................................................................................ 32 
12.2 
Physical, Chemical, Pharmaceutical Properties, and Formulations .......................... 33 
12.3 
Packaging, Labeling and Storage ............................................................................ 34 
12.4 
Supply of Study Drug at Site ................................................................................... 34 
12.5 
Dosage and Dosing Schedule .................................................................................. 34 
12.5.1 Aspirin ............................................................................................................ 35 
12.5.2 Dose Reduction and Dose Interruption ............................................................ 35 
13 
COMPLIANCE ...................................................................................................... 35 
14 
PRIOR AND CONCOMITANT THERAPY........................................................... 35 
14.1 
Allowed Concomitant Therapy ............................................................................... 36 
14.2 
Prohibited Concomitant Therapy ............................................................................. 36 
14.3 
Contraception Use................................................................................................... 36 
15 
STUDY EVALUATIONS ...................................................................................... 37 
15.1 
Study Procedures by Visit ....................................................................................... 37 
15.1.1 Overview......................................................................................................... 37 
15.1.2 Screening (-28 days/-1 day) ............................................................................. 37 
15.1.3 Treatment Period Week 0 to Week 52 ............................................................. 38 
15.1.4 Safety Follow-up or End of Study Visit ........................................................... 38 
15.2 
Pharmacokinetic and Immunogenicity Evaluations ................................................. 39 
15.3 
Assessment of Efficacy ........................................................................................... 39 
15.3.1 Efficacy Measurements and Time Points ......................................................... 39 
15.3.2 Assessment of Safety ....................................................................................... 41 
15.3.3 Subject Demographics and Medical History .................................................... 41 
15.3.4 Physical Examination ...................................................................................... 41 
15.3.5 Vital Signs ...................................................................................................... 41 
15.3.6 Electrocardiograms .......................................................................................... 41 
15.3.7 Bone Marrow Assessment ............................................................................... 42 
15.3.8 Ocular Examination ......................................................................................... 42 
15.3.9 Lung X-Ray and Heart ECHO ......................................................................... 42 
15.3.10 
ECOG Performance Status ........................................................................... 42 
15.3.11 
Adverse Events ............................................................................................ 42 
15.3.12 
Laboratory Evaluations ................................................................................ 43 
15.4 
Appropriateness of Measurements .......................................................................... 43 
16 
SAFETY REPORTING .......................................................................................... 44 
16.1 
Adverse Events ....................................................................................................... 44 
16.2 
Abnormal Clinical Laboratory Test Results ............................................................. 44 

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16.3 
Abnormal Physical Examination Findings ............................................................... 44 
16.4 
Pregnancy ............................................................................................................... 45 
16.5 
Adverse Events of Special Interest .......................................................................... 45 
16.6 
Serious Adverse Events .......................................................................................... 45 
16.7 
Instructions for Expedited Notification of Serious Adverse Events .......................... 46 
16.7.1 Reporting Responsibility ................................................................................. 46 
16.7.2 Reporting Procedures ...................................................................................... 46 
17 
STATISTICAL ANALYSIS ................................................................................... 46 
17.1 
General Consideration............................................................................................. 46 
17.2 
Sample Size Estimation .......................................................................................... 46 
17.3 
Populations for Analysis ......................................................................................... 47 
17.3.1 Enrolled Population ......................................................................................... 47 
17.3.2 Intent-to-Treat (ITT) Population ...................................................................... 47 
17.3.3 Per Protocol Population (PPP) ......................................................................... 47 
17.3.4 Protocol Deviations ......................................................................................... 47 
17.3.5 Safety Population ............................................................................................ 47 
17.4 
Efficacy Endpoints Analysis ................................................................................... 47 
17.4.1 Primary Efficacy Endpoint Analysis ................................................................ 48 
17.4.2 Secondary Efficacy Endpoints Analyses .......................................................... 48 
17.5 
Exploratory Analysis .............................................................................................. 48 
17.6 
PPK, E-R, and Immunogenicity Endpoints Analyses............................................... 49 
17.7 
Safety Endpoints Analysis ...................................................................................... 49 
17.8 
Handling of Missing Data ....................................................................................... 49 
18 
ETHICAL AND REGULATORY ASPECTS ......................................................... 49 
18.1 
Ethics and Good Clinical Practice ........................................................................... 49 
18.2 
Institutional Review Board ...................................................................................... 49 
18.3 
Subject Information and Informed Consent ............................................................. 49 
18.4 
Confidentiality ........................................................................................................ 50 
19 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................ 50 
19.1 
Source Data and Records ........................................................................................ 50 
19.2 
Periodic Monitoring ................................................................................................ 50 
19.3 
Confidentiality of Subjects´ Data ............................................................................ 50 
20 
DATA HANDLING AND RECORDKEEPING ..................................................... 51 
20.1 
Responsibilities of Investigators .............................................................................. 51 
20.2 
Case Report Forms.................................................................................................. 51 
20.3 
Changes to Case Report Form Data ......................................................................... 51 
20.4 
Recording, Access, and Retention of Source Data and Study Documents ................ 51 

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21 
CHANGES IN THE CONDUCT OF THE STUDY ................................................ 52 
21.1 
Protocol Amendments ............................................................................................. 52 
21.2 
Premature Study Termination.................................................................................. 52 
21.3 
Publication of Results ............................................................................................. 52 
22 
LIABILITIES AND INSURANCE ......................................................................... 52 
23 
REFERENCES ....................................................................................................... 53 
24 
APPENDICES ........................................................................................................ 55 
24.1 
Appendix 1. Study Flowchart .................................................................................. 56 
24.2 
Appendix 2. Pharmacokinetic Sampling Schedule ................................................... 60 
24.3 
Appendix 3. Immunogenecity Sampling ................................................................. 60 
24.4 
Appendix 4. ECOG Performance Status .................................................................. 60 
24.5 
Appendix 5. Diagnosis of the PV-Related Cardiovascular Complications as Adverse 
Events of Special Interest ........................................................................................ 61 
24.6 
Appendix 6. HU resistance and intolerance criteria according to ELN (Barosi et al. 
2010). ..................................................................................................................... 62 
24.7 
Appendix 7. Transition phase from previous HU treatment to P1101 (for all patients 
on active HU ........................................................................................................... 62 
24.8 
Appendix 8. Hospital Anxiety and Depression Scale ............................................... 63 
 
LIST OF TABLES 
Table 12-1  Packaging and Labeling ..................................................................................... 34 
Table 15-1  Clinical Laboratory Measurements..................................................................... 43 
 
LIST OF FIGURES 
Figure 12-1  P1101 Structural Formula and Amino Acid Sequence ....................................... 33 
 
 

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SPONSOR CONTACT INFORMATION 
• PharmaEssentia Japan 
• FORECAST Shinjuku AVENUE, 5F, CROSSCOOP 
• 2-5-12 Shinjuku, Shinjuku, Tokyo  
• 160-0022, JAPAN 
• Tel. +81-3-6866-9531 
• FAX +81-3-6866-9532 
•  
 
 

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1 SYNOPSIS 
 
Name of Sponsor/Company: 
PharmaEssentia Japan 
Name of Investigational Product: 
P1101 (ropeginterferon alfa-2b) 
Name of Active Ingredient: 
Ropeginterferon (P1101) is a mono-pegylated form of the P1040 drug intermediate 
(Proline-IFNα-2b) that has been reacted with a 40 kDa branched PEG-aldehyde. The pegylation site 
is predominantly at the N-terminal proline of the P1040 drug intermediate; more precisely, the drug 
substance P1101 is an N-terminally mono-pegylated drug intermediate of P1040. 
Title of Study:  
Phase 2 single arm study of efficacy and safety of P1101 for polycythemia vera (PV) patients for 
whom the current standard of treatment is difficult to apply. 
Study Countries and Center(s): Japan 
Coordinating Investigator:  
Prof. Keita KIRITO (Yamanashi University) 
Planned Studied Period: 
September 2019 to August 2021 
Phase of 
development:  
Phase 2 
Objective:  
The primary objective is to demonstrate safety and efficacy of P1101 in terms of complete 
hematologic response (CHR) without phlebotomy with Japanese patients diagnosed with PV for 
whom the current standard of treatment is difficult to apply.  
The primary endpoint “complete phlebotomy-free hematologic response (CHR)” is defined as a 
condition that meets the following hematological criteria, hematocrit (<45%), WBC (≤10 x 109/L), 
platelets (≤400 x 109/L) and require no phlebotomy at month 9 and month 12.  
The secondary objective is to demonstrate safety and efficacy of P1101 in terms of changes in Hct, 
WBC, PLT, spleen size, molecular and cytogenetic response from baseline, time to requiring no 
phlebotomy, numbers of phlebotomy required, time to response, duration of response maintenance, 
ratio of CHR rates of subjects with/without prior treatment with HU and Proportion of subjects 
without thrombotic events. 
Study Design:  
This is a Phase 2 single arm study to investigate efficacy and safety of P1101 for adult Japanese 
patients with PV. Eligible patients will be treated with P1101, starting at 100 μg (or 50 μg in patients 
under another cytoreductive therapy). The dose should be gradually increased by 50 μg every two 
weeks (in parallel, other cytoreductive therapy should be decreased gradually, as appropriate) until 
stabilization of the hematological parameters is achieved (hematocrit <45%, platelets <400 x 109/L 
and leukocytes <10 x 109/L). The maximum recommended single dose is 500 μg injected every two 
weeks. 
At week 36 (month 9) and week 52 (month 12), the primary study endpoint, phlebotomy-free CHR, 
will be analyzed. After completion of the 52-week study duration, provision and administration of 
P1101, collection of the long-term follow up information (blood parameters, molecular and 

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cytogenetic data, safety parameters and as also the optional bone marrow data) will be continued 
until the drug becomes commercially available for all study subjects..  
Number of Patients (planned):  
30 patients (all recruited in Japan) 
 
Diagnosis and Main Criteria for Inclusion and Exclusion:  
• Inclusion Criteria 
1. Male or female patients ≥20 years old at the time of informed consent 
2. Patients diagnosed with PV according to the WHO 2008 or WHO 2016 criteria 
3. PV patients for whom the current standard of treatment is difficult to apply. Patients with a 
documented history of refractory to HU are excluded (see Appendix 6; modified ELN criteria 
based on "Barosi et al, 2010 ELN criteria", (Barosi et al. 2010)).  
- 
Younger patients (long-term treatment is anticipated) 
- 
Patients who are categorized as low risk, but cytoreduction is recommended due to 
disease-related signs and symptoms (headache, dizziness, pruritus, night sweats, fatigue, 
erythromelalgia, vision disorders, scintillating scotoma, early satiety, abdominal 
distension). 
- 
Patients with HU intolerance (see Appendix 6; modified ELN criteria based on "Barosi 
et al, 2010 ELN criteria", (Barosi et al. 2010)) 
4. Total HU treatment duration shorter than 3 years (cumulatively) at screening 
5. For cytoreduction naïve patients only: PV in need of cytoreductive treatment, defined by 
fulfilling as one or more of the following criteria at baseline: 
- 
at least one previous well documented major cardiovascular PV-related event in the 
medical history 
- 
poor tolerance of phlebotomy (defined as a phlebotomy/ procedure-related adverse event 
causing significant adverse impact on the patient and limiting ability to apply phlebotomy 
with the intention to keep Hct <45%) 
- 
frequent need of phlebotomy (more than one phlebotomy within last month prior entering 
the study) 
- 
platelet counts greater than 1000 x 109/L (for two measurements within the month prior 
treatment start) 
- 
leukocytosis (WBC>10 x 109/L for two measurements within the month prior treatment 
start) 
- 
manifestation of disease-related signs and symptoms (headache, dizziness, pruritus, night 
sweats, fatigue, erythromelalgia, vision disorders, scintillating scotoma, early satiety, 
abdominal distension) 
6. Adequate hepatic function defined as total bilirubin ≤1.5 x upper limit normal (ULN), 
international normalized ratio (INR) ≤1.5 x ULN, albumin >3.5 g/dL, alanine aminotransferase 
(ALT) ≤2.0 x ULN, aspartate aminotransferase (AST) ≤2.0 x ULN at screening 
7. Hemoglobin (HGB) ≥10 g/dL at screening 
8. Neutrophil count ≥1.5 x 109/L at screening 
9. Serum creatinine ≤1.5 x ULN at screening 
10. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales (Appendix 8). 
 (Patients with a borderline of HADS score (score 7 but <10) or patients with necessity (expected 

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benefits are higher than the risks) based on investigators’ discretion are required to receive 
following assessment by psychiatric specialist to confirm the eligibility for IFNα therapy.). 
11. Males and females of childbearing potential, as well as all women <2 years after the onset of 
menopause, must agree to use an acceptable form of birth control until 28 days following the 
last dose of the study drug  
12. Written informed consent obtained from the patient or the patient’s legal representative, and 
ability for the patient to comply with the requirements of the study 
• Exclusion Criteria 
1. Patients with symptomatic splenomegaly 
2. Previous use of IFNα for any indication 
3. Any contraindications or hypersensitivity to interferon-alfa 
4. Co-morbidity with severe or serious conditions which may impact patient participation in the 
study in investigator’s opinion 
5. History of major organ transplantation 
6. Pregnant or lactating females (Breastfeeding women are not allowed to enter this study by 
discontinuing breastfeeding) 
7. Patients with any other medical conditions, which in the opinion of the Investigator would 
compromise the results of the study or may impair compliance with the requirements of the 
protocol, including but not limited to: 
7.1. History or presence of thyroid dysfunction (clinical symptoms of hyper- or hypo-
thyroidism) of the autoimmune origin, except late stages cases on the oral thyroid 
substitution therapy, where potential exacerbation under interferon therapy will not 
constitute any further harm to the patient 
7.2. Documented autoimmune disease (e.g., hepatitis, idiopathic thrombocytopenic purpura 
[ITP], scleroderma, psoriasis, or any autoimmune arthritis) 
7.3. Clinically relevant pulmonary infiltrates and pneumonitis at screening, patients with a 
history of interstitial pulmonary disease 
7.4. Active infections with systemic manifestations (e.g., bacterial, fungal, hepatitis B [HBV], 
hepatitis C [HCV], or human immunodeficiency virus [HIV]) at screening) 
7.5. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis [CMV], macular 
degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or 
hypertension) based on the ophthalmological assessment by specialists. 
7.6. Uncontrolled depression 
7.7. Previous suicide attempts or at any risk of suicide at screening 
8. Uncontrolled diabetes mellitus (HbA1c level of > 7% at baseline)  
9. History of any malignancy within for the past 5 years (except Stage 0 chronic lymphocytic 
leukemia [CLL], basal cell, squamous cell, and superficial melanoma believed to be cured) 
10. History of alcohol or drug abuse within the last year 
11. History or evidence of post polycythemia vera-myelofibrosis (PPV-MF), essential 
thrombocythemia, or any non-PV MPN;  
12. Presence of circulating blasts in the peripheral blood within the last 3 months 
13. Use of any investigational drug(s), or investigational drug combinations <4 weeks prior to 
the first dose of study drug or not recovered from effects of prior administration of any 
investigational agent 
With regard to acetylsalicylic acid, which will be considered as the background treatment in the 

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study unless contraindicated, the following contraindications are known for low-dose acetylsalicylic 
acid: history of hypersensitivity to Bayaspirin or any salicylic acid preparation, peptic ulceration, 
bleeding tendency, aspirin-induced asthma (asthma attack induced by NSAID etc.) ant its history, 
pregnant women within 12 weeks of estimated date of confinement, baby with a low birth 
weight/newborn infant/ suckling infant. If any of the contraindications are observed, the patient may 
still participate in the study without being administered acetylsalicylic acid. 
Investigational Product and Reference Therapy, Dosage, and Mode of Administration:  
Patients who meet the inclusion criteria and who do not meet the exclusion criteria will start therapy 
with P1101 (ropeginterferon alfa-2b). The investigational product will be administered 
subcutaneously every 2 weeks at the starting dose of 100 μg every two weeks (or 50 micrograms in 
patients under another cytoreductive therapy). The dose should be gradually increased by 50 μg 
every two weeks (in parallel, other cytoreductive therapy should be decreased gradually, as 
appropriate) until stabilization of the hematological parameters is achieved (hematocrit <45%, 
platelets <400 x 109/L and leukocytes <10 x 109/L). The maximum recommended single dose is 500 
μg injected every two weeks. The dose will be maintained at the highest level which can be tolerated 
and delivers best possible disease response. 
Low-dose aspirin (acetylsalicylic acid) (75-150 mg/day per local practice) will be given during the 
12 months of study treatment, unless contraindicated. 
Phlebotomy is performed aiming at a hematocrit < 45%. When the hematocrit value is 45% or 
higher, phlebotomy is performed. The volume of phlebotomy per procedure should be 200 to 400 
mL per one phlebotomy while monitoring the circulatory dynamics such as blood pressure and 
pulse. In the elderly and patients with cardiovascular disorders, a small volume (100 to 200 mL) 
should be considered to avoid rapid changes in hemodynamics. 
Disease Progression 
For this study, disease progression will be defined as: 
• Death due to any cause 
• Development of secondary MF, as evidenced e.g. by bone marrow biopsy 
• Transformation into acute myeloid leukemia or myelodysplastic syndrome, as evidenced by 
bone marrow biopsy 
Withdrawal Criteria 
Discontinuation from the study may occur for the following reasons: 
• Disease progression; 
• Screening failure;  
• Withdrawal of patient consent; 
• Severe Noncompliance; 
• Worsening of the underlying disease in cases when the further participation (with dose 
adjustment) is not expected to provide sufficient medical care to the patient;  
• Study drug-related adverse event (AE) not recovering within the pre-specified period;  
• Medical condition unrelated to the underlying disease or study treatment (study 
drug-unrelated AE);  
• Lost to follow-up.  
Study Procedures:  
For eligibility purposes, local lab data and local evaluations (incl. mutational status, bone marrow) 
will be accepted if properly documented in the source data.  
Patient visits will be scheduled every 2 weeks: at regular visits, safety and AE data collection with 

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the basic lab investigations will be performed, while every three months (month 3, 6, 9 and 12) 
extended assessment visits will be scheduled. A safety follow-up visit will take place 28 days after 
the end of the last treatment visit.  
Study procedures are detailed in the study flowchart (Appendix 1). 
Pharmacokinetic (PK) samples will be collected once every 2 weeks at a timing prior to drug 
administration (at steady state), four consecutively at Week 0 (at first dose) and Week 28 (Appendix 
2), at the end of treatment visit, and at the safety follow-up visit. 
Assessment of safety will be determined by vital sign measurements, clinical laboratory tests, 
physical examinations, spleen size measurement by ultrasound, electrocardiogram (ECG) 
evaluation, lung X-ray, Eastern Cooperative Oncology Group (ECOG) performance status, 
ophthalmologic investigations, and the incidence and severity of treatment-emergent AEs (TEAEs).  
At screening, month 9 and 12, central lab will be testing Hct, WBC and platelets for the purposes of 
primary endpoint analysis. 
Also, a central lab will be in charge of the quantitative allelic burden measurement, as also will 
perform all further evaluations.  
Local labs will be used for other measurement in the study. 
Due to the lack of experience of administration of the study drug over 300 μg in Japanese subjects, 
Sponsor introduce careful observation of all the subject after the administrations over 300 μg to 
ensure subjects safety and to respond quickly and appropriately in emergency situations. More 
specifically, all the subjects will be hospitalized for the first 2 days (incl. the date of administration) 
when they receive the study drug over 300 μg (350, 400, 450 and 500 μg). Two days after the 
administration, the subjects can be discharged if there is no evidence of clinically significant adverse 
reactions based on the assessment by the institutional Principal Investigators at each site. All safety 
data up to Day 15 (from previous dose to next dose) will be collected and reviewed by Principal 
Investigators at each site, to determine if any of the criteria for stopping dose escalation has been 
met. Increase to the next higher planned dose level will only occur if the previous dose level was 
deemed to be safe and well-tolerated following review by Principal Investigators at each site. For 
the safety confirmation after administration of 500 μg, the time to dose increase to 500 μg should 
not exceed 32 weeks. In addition, as with the administration of 350 μg, 400 μg, and 450 μg, the 
Principal Investigators and sub-investigators at each medical institution assess that no drug-related 
adverse events requiring dose reduction/interruption/discontinuation occur within 2 weeks after 
dose increase (by Day 15 after the next visit) according to the protocol criteria. If the safety profile 
of the 500 μg dosing level for the 5 subjects in the first 6 evaluable subjects is confirmed by 
Coordinating Principal Investigator, Principal Investigators at each site and Sponsor’s Medical 
Monitor, the observation based on the hospitalization for two days after administration will be 
deactivated and the rest of study subjects will receive the predefined higher dose level of the study 
drug (over 300 μg) without hospitalization. If two or more of the first six evaluable subjects fail to 
meet the criteria for tolerability, the Coordinating Principal Investigator, the Principal Investigators 
at each site and the sponsor's Medical Monitor will perform a comprehensive assessment of 
continuation of the study. 
Study Duration:  
Study duration is approximately 14 months for the core treatment phase with 12 months duration.  
Study Endpoints:  
• Primary efficacy endpoint (month 9 and month 12): 
The primary efficacy endpoint is the phlebotomy-free complete hematologic responder rate (CHR) 
at month 9 and month 12.  
The phlebotomy-free responder rate is defined as the proportion of patients with complete 
hematologic response (CHR) and with no phlebotomies during the previous 3 months. 
A responder in sense of a primary endpoint is a patient who has met all of the following criteria at 

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month 9 and month 12: 
• Hematocrit <45% phlebotomy-free (absence of phlebotomy during the previous 3 months) 
• Platelet count ≤400 x 109/L, 
• WBC count ≤10 x 109/L,  
• Secondary efficacy endpoints: 
• Changes in Hct, WBC, PLT and spleen size from baseline 
• Time to requiring no phlebotomy 
• Time to first response 
• Duration of response maintenance 
• Proportion of subjects without thrombotic or hemorrhagic events 
• Change of JAK2 mutant allelic burden over time vs. baseline 
• PK of P1101 
• Exploratory evaluation: 
• Bone marrow histological remission defined as the disappearance of hypercellularity, 
trilineage growth (panmyelosis) and absence of >grade 1 reticulin fibrosis (optional) 
• Safety evaluation: 
• Incidence, causality, and severity of AEs, according to common terminology criteria for AEs 
(CTCAE 5.0) 
• Incidence, causality, and severity of AEs of special interest (e.g., cardiovascular events 
[Appendix 5]) 
• Events leading to dose reduction or permanent treatment discontinuation 
Statistical Methods: 
Sample size is calculated, based on the following assumptions; 
• The target population of the Japanese local study: Japanese PV patients for whom the current 
standard of treatment is difficult to apply. 
• Study design: P1101 single arm no controlled study (previous proposal was designed as a 
historical control study using PROUD-PV study). 
• Primary study objective: To evaluate the safety and efficacy of P1101 for Japanese PV 
patients for whom the current standard of treatment is difficult to apply. 
• Primary efficacy variable: Complete Hematological Response (CHR) 
• Study period and evaluation visits: 3, 6, 9 and 12 months. The safety follow-up will be 
continued to 12 months and the major efficacy data will be obtained at 12 months. 
• The primary analysis of the primary endpoint: The lower limit of the 95% confidence interval 
of CHR rate is greater than 11%, and also the slope of the linear regression model of the CHR 
rate time course is greater than 0 (positive trend):  
• The rationale: the natural healing rate (placebo response) of CHR rate of PV patients is 0%, 
thus if the lower limit of 95% confidence interval of the CHR rate exceed 11%, the efficacy 
of P1101 can be confirmed. The rationale to set the CHR rate limit as 11% is, (1) 11% is the 
minimum CHR rate value of P1101 obtained in the PROUD-PV study, (2) and the trend of 
the CHR rate is positive, thus 11% can be considered as a limit of the acceptable clinical risks. 
Assuming the above conditions, the power of the study at 9 months will be about 85% with 25 cases 
(CHR rate of the PROUD-PV study at 3, 6, 9 and 12 months are 11%, 27%, 36% and 43%, 
respectively). Considering the uncertainty of maximum 5 patients who are different background 

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from PROUD-PV, a total of 30 cases will be reasonable to evaluate both efficacy and safety. 
 
 
 
 

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2 SIGNATURE PAGE FOR SPONSOR 
 
Protocol P1101 in Japanese PV 
Title 
Phase 2 single arm study of efficacy and safety of P1101 for polycythemia vera 
(PV) patients for whom the current standard of treatment is difficult to apply. 
 
 
Approved by the following: 
 
 
September 14th, 2020 
Hiroaki Kawase, 
Head, Clinical Operation 
 
Date 
 
 
 
September 14th, 2020 
Toshiaki Sato, 
Head, Medical Monitor 
 
Date 
 
 
 

PharmaEssentia Japan 
 
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Protocol P1101 in Japanese PV (A19-201) 
 
November 29th, 2019 
3 SIGNATURE PAGE FOR INVESTIGATORS 
 
Protocol P1101 in Japanese PV 
Title 
Phase 2 single arm study of efficacy and safety of P1101 for polycythemia vera 
(PV) patients for whom the current standard of treatment is difficult to apply. 
 
I have read this protocol and agree that it contains all necessary details for carrying out this study. 
I will conduct the study as outlined herein and will complete the study within the time designated, 
in accordance with all stipulations of the protocol and in accordance with Good Clinical Practices, 
local regulatory requirements, and the Declaration of Helsinki. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study drug and the conduct of the study. 
I will use only the informed consent approved by the Institutional Review Board (IRB) and will 
fulfill all responsibilities for submitting pertinent information to the IRB responsible for this study. 
I agree that the Sponsor (PharmaEssentia Japan) or its representatives shall have access to any 
source documents from which case report form information may have been generated. 
I further agree not to originate or use the name of PharmaEssentia Japan or study drug code P1101 
in any publicity, news release, or other public announcement, written or oral, whether to the public, 
press, or otherwise, relating to this protocol, to any amendment to the protocol, or to the 
performance of this protocol, without the prior written consent of PharmaEssentia Japan. 
 
 
 
 
 
 
Investigator Name 
 
Signature 
 
Date 
 
 
 

PharmaEssentia Japan 
 
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Protocol P1101 in Japanese PV (A19-201) 
 
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4 ABBREVIATIONS AND TERMS 
 
Abbreviation 
Term 
ADA 
Anti-Drug Antibody 
AE 
Adverse events 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
AML 
Acute myeloid leukemia 
aPTT 
Activated partial thrombin time 
AST 
Aspartate transaminase 
AUC 
Area under the drug concentration-time curve 
BAT 
Best available therapy 
BNP 
Brain natriuretic peptide 
BUN 
Blood urea nitrogen 
CIOMS 
Council for International Organizations of Medical Sciences 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum plasma concentration 
CMV 
Cytomegalovirus 
CP 
Conditional power 
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for AEs 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
eCRF 
Electronic case report form 
ELN 
European Leukemia Net 
EoS 
End of study 
EoT 
End of treatment 
ET 
Essential thrombocythemia 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEE 
Generalized Estimation Equation 
GGT 
Gamma-glutamyl transferase 
HbsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
hERG 
Human Ether-a-go-go-Related Gene 
HGB 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HU 
Hydroxyurea 
IB 
Investigator’s brochure 
IC50 
Median inhibition concentration 
ICH 
International Conference on Harmonisation 
IFN 
Interferon 
IFN-α 
Interferon-α 

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Protocol P1101 in Japanese PV (A19-201) 
 
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INR 
International normalized ratio 
IRB 
Institutional Review Board  
ITP 
Idiopathic thrombocytopenic purpura 
ITT 
Intent-to-treat 
IV 
Intravenous 
IWG-MRT 
International Working Group-Myeloproliferative Neoplasms 
Research and Treatment 
JAK2 
Janus kinase 2 
LDL 
Low-density lipoprotein 
LDH 
Lactate hydrogenase 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Myelofibrosis 
MI 
Myocardial infarction 
MPL 
Myeloproliferative leukemia 
MPN 
Myeloproliferative neoplasm 
MPN-SAF TSS 
Myeloproliferative Neoplasm Symptom Assessment Form Total 
Symptom Score 
MRI 
Magnetic resonance imaging 
MTD 
Maximum Tolerated Dose 
 
NA 
Not applicable 
NCCN 
National Comprehensive Cancer Network 
NOAEL 
No observed adverse effect level 
NOEL 
No observed effect level 
NR 
Not reported 
NSAID 
Nonsteroidal anti-inflammatory drug  
NT-proBNP 
N-terminal portion of proBNP 
NYHA 
New York Heart Association 
OR 
Odds ratio 
P1101 
Ropeginterferon-interferon-α-2b 
PD 
Pharmacodynamic  
PEG 
Pegylated 
peg-IFNα-2a 
Peginterferon-α-2a  
PET-MF 
Post-ET myelofibrosis 
PK 
Pharmacokinetic 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PPP 
Per Protocol 
PT 
Prothrombin time 
PV 
Polycythemia vera 
QoL 
Quality of life 
QT 
Time corresponding to the beginning of depolarization to 
repolarization of the ventricles 
QTc 
Time corresponding to the beginning of depolarization to 
repolarization of the ventricles, corrected for heart rate 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
sAML 
Secondary acute myeloid fibrosis 
sMF 
Secondary myelofibrosis 
SOHO 
Society of Hematologic Oncology 
SOP 
Standard Operating Procedures 
TSH 
Thyroid stimulating hormone 
TSS 
Total Symptom Score 
ULN 
Upper limit of normal 

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Protocol P1101 in Japanese PV (A19-201) 
 
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US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 

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5 INTRODUCTION AND RATIONALE 
5.1 
Background 
Polycythemia Vera (PV) is the most common type of chronic myeloproliferative neoplasms with 
reported annual incidence rates up to 2.6 per 100.000, and a prevalence rate of approx.  2.0 per 
10,000 (Moulard et al. 2014; Titmarsh et al. 2014; Choi et al. 2015; Stein et al. 2015). It is a long-
term debilitating and life-threatening condition as it is associated with the risk of thrombosis, 
hemorrhage, and a long term propensity to develop myelofibrosis (MF) and secondary acute 
myeloid leukemia (sAML) (Stein et al. 2015; Griesshammer, Gisslinger, and Mesa 2015). 
Therapeutic options for PV are limited and no cure is available. Currently, most PV patients are 
treated with phlebotomy and low-dose aspirin as front-line therapy to correct abnormal blood 
viscosity and to control the risk of vascular events, whereas high-risk patients receive 
cytoreductive treatment (Barbui et al. 2011; Vannucchi et al. 2009; Vannucchi 2014; Tefferi and 
Barbui 2015). Until recently, hydroxyurea (HU) was the only first-line therapy licensed in the 
European Union (EU) for patients requiring cytoreductive treatment. The JAK2 inhibitor 
ruxolitinib has been approved in 2014 as a second-line treatment of PV restricted to patients who 
are resistant to or intolerant of HU (EMA 2015; Vannucchi et al. 2015; Tefferi and Pardanani 
2015). 
The PharmaEssentia Corporation (PEC) develop ropeginterferon, PEG-Pro-IFNα-2b (P1101) for 
the treatment of PV and other MPNs.  
Ropeginterferon alfa-2b, a novel, long-acting, mono-pegylated proline interferon, uniquely 
administered once every two weeks and contains an additional N-terminal Proline, which is 
covalently modified by a 40 kDa Polyethylene glycol (PEG) moiety. Because of the site specific 
mono-pegylation Ropeginterferon alpha-2b represents a long-acting interferon with only one 
major isoform as opposed to the 8-14 isoforms of randomly pegylated interferon products approved 
for indications different than PV. Commercially, Ropeginterferon alfa-2b will be provided in pre-
filled syringe. 
The non-clinical pharmacology program of Ropeginterferon alfa-2b includes the in vivo evaluation 
of 2’,5’-oligoadenylate synthase (2’-5’-OAS) activity induced by Ropeginterferon alfa-2b in 
monkeys, as well as safety pharmacology studies of the effects on the cardiovascular system in 
vitro (human Ether-a-go-go-Related-Gene [hERG] assay) and in monkeys, and on the central 
nervous system (CNS) and respiratory systems in rats. 
The pharmacokinetics (PK) and pharmacodynamics (PD) of Ropeginterferon alfa-2b versus 
Pegasys were evaluated in a study in monkeys. Toxicology assessment includes single-dose 
toxicity studies in rats and monkeys, and repeat-dose toxicity studies of up to 7-days, 14-days, and 
4-weeks (with 4-week recovery) in monkeys with toxicokinetic and immunogenicity evaluations. 
Genotoxicity was evaluated using a bacterial reverse mutation assay and a chromosome aberration 
assay in Chinese Hamster Ovary (CHO) cells. No toxicities different from other licensed pegylated 
interferons were found in these studies. 
The clinical development program for Ropeginterferon alfa-2b in PV includes a Phase I/II open-
label dose escalation study to determine the maximum tolerated dose (MTD), safety and efficacy 
of Ropeginterferon alfa-2b in 51 PV patients (PEGINVERA Study) and a pivotal Phase III 
program comprising (1) PROUD-PV Study, a randomized, open-label, controlled parallel-arm 
non-inferiority study of Ropeginterferon alfa-2b versus HU in 254 patients with PV, (2) 
CONTINUATION-PV Study, an open-label, Phase IIIb extension study assessing the long-term 
efficacy and safety of Ropeginterferon alfa-2b in PV patients who completed the Ropeginterferon 
alfa-2b arm of the PROUD-PV Study in comparison to patients who completed the HU arm of 
PROUD-PV Study and are managed according to standard of care/best available treatment (BAT), 
and (3) PEN-PV Study, an open-label, single-arm Phase III study to assess the self-administration 
of Ropeginterferon alfa-2b using the pre-filled pen intended for commercial use in 36 patients with 
PV.  
P1101 has been approved by EMA in February 2019 to treat PV without symptomatic 
splenomegaly (EMA 2019). In addition to being approved in EU, Ropeginterferon alfa-2b has 
Orphan Drug designation in the United States of America to treat PV, but also ET and MF.  

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Protocol P1101 in Japanese PV (A19-201) 
 
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The PharmaEssentia Corporation develops Ropeginterferon alfa-2b (P1101) also for Japanese 
patients. The Phase 1 study in Japanese healthy subjects in compliance with the Japanese 
Pharmaceutical and Medical Devices Agency (PMDA) regulations has been completed recently.  
The planned study by this protocol will collect efficacy and safety data of treating Japanese PV 
patients with P1101.   
5.2 
Overview of Nonclinical Studies 
Detailed summaries on the nonclinical studies conducted with P1101 are included in the 
Investigator’s Brochure (IB). The studies and the key results are briefly summarized in the 
following sections.   
5.2.1 
Safety Pharmacology 
In a study with rats, activity, behavior, and body temperature were observed after administration 
of a single subcutaneous (SC) dose of P1101. Four groups of rats (n=6) received either placebo or 
a dose of 0.2, 2.0, or 20 mg/kg of P1101. Six Irwin observations were performed post dose and no 
behavioral, physiological, or body temperature changes were observed. 
The in vitro effects of P1101 on human ether-a-go-go-related gene (hERG) channel current were 
observed. P1101 significantly inhibited the hERG current by 10.8% and 49.9% at concentrations 
of 0.3 and 2.5 μM, respectively, compared to 0.4% in the control group. The inhibitory 
concentration (IC50) for the inhibitory effect of P1101 on the hERG potassium current was not 
determined since inhibition was <50%. 
Six male cynomolgus monkeys were pre-instrumented for single-lead telemetry recordings 
following intravenous (IV) infusion of P1101. Each animal received vehicle or test item using 
adjusted Latin square design in doses of 0, 60, and 600 μg/kg. The changes measured indicated 
generally dose-related increases in body temperature and heart rate with consequent time 
corresponding to the beginning of depolarization to repolarization of the ventricles (QT) and QT 
corrected for heart rate (QTc) shortening at doses of 60 and 600 μg/kg. It is important to note that 
no significant effects on body temperature, heart rate, electrocardiograms (ECGs), or QT duration 
were observed with multiple dosing in the monkey toxicity studies with P1101. 
Four groups of rats (N=6) were placed in whole body plethysmograph boxes and initial respiratory 
parameters (tidal volume, respiration rate, and minute volume) were recorded. Each group then 
received either no treatment or was inoculated intravenously with 0.1, 1.0, or 10 mg/kg of P1101 
and respiratory parameters were recorded for a 6-hour period. Intravenous administration of P1101 
did not elicit any statistically significant changes in respiratory parameters in the conscious rat 
during a 6-hour period when compared to the vehicle control group. 
5.2.2 
Nonclinical Pharmacokinetics and Pharmacodynamics 
The pharmacokinetic (PK) and pharmacodynamic (PD) profile of P1101 has been investigated in 
a study in cynomolgus monkeys (n=4/group). In the first phase, the PK and PD profiles of P1101 
were compared with Pegasys® when administered subcutaneously (30 µg/kg). P1101 exhibited a 
PK profile similar to Pegasys. In the second phase, the PK and PD profiles of P1101 were evaluated 
following IV (30 µg/kg) and SC (300 µg/kg) administration. 
Intravenous administration of P1101 at the same dose resulted in greater serum concentration of 
P1101 from 2 to 96 hours in comparison to SC administration in Phase 1. Relative bioavailability 
of P1101 was calculated to be 80%.  
5.2.3 
Toxicology 

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In an active-controlled single- and repeated-dose toxicity study in rats, P1101 was evaluated in 48 
rats assigned to 8 groups (n=6 / group). Group 1 received a placebo control and Groups 2, 3, and 
4 were inoculated with a single dose of P1101 at 200, 2000, and 20000 μg/kg, respectively. Group 
5 received 3 separate doses of a placebo control article and Groups 6, 7, and 8 received doses of 
P1101 at 200, 2000, and 20000 μg/kg, respectively, on Days 1, 4, 8, and 11. No treatment-related 
clinical signs, unscheduled deaths, changes in mean body weight or treatment-related clinical 
pathology or macroscopic findings were observed after single or multiple doses. Based on these 
findings, the no observed effect level (NOEL) was ≥20000 μg/kg. 
The toxicity of P1101 was evaluated after administration of escalating doses via SC injection to 
cynomolgus monkeys. Phase 1 consisted of 2 monkeys receiving an escalating dose (0.675, 2.0, 
and 6.75 mg/kg) of P1101 on Days 1, 5, and 9, respectively. Phase 2 involved 3 groups (n=2) 
receiving a repeat dose of either 0.0, 2.0, or 6.75 mg/kg of P1101 on Days 1, 4, 8, and 11. During 
Phase 1, all animals survived until the scheduled termination, and there were no treatment-related 
effects on clinical observations, food consumption, or body weights. In Phase 2, all animals 
survived, but decreased body weight and food consumption were observed in the 2 mg/kg and 6.75 
mg/kg groups. No macroscopic changes were observed during either phase of the study. Based on 
these findings, the no observed adverse effect level (NOAEL) was determined to be <2 mg/kg. A 
maximum tolerated dose (MTD) was not achieved in this study. 
In a placebo-controlled study, 32 cynomolgus monkeys were assigned to 4 groups to evaluate the 
toxicity of P1101. Group 1 (n=10) received a control article. Groups 2 (n=6), 3 (n=6), and 4 (n=10) 
received 0.675, 2.0, and 6.75 mg/kg of P1101, respectively, on Days 1, 4, 8, 11, 15, 18, 22, and 24. 
No deaths were observed, and treatment-related changes observed were generally minor and 
reversed during the recovery period. Most of these treatment-related changes were observed in 
males and females treated with the highest dose of 6.75 mg/kg and were resolved by the end of the 
29-day recovery period. The maximum plasma concentration (Cmax) and area under the 
concentration curve (AUC) values increased in a linear manner in proportion to dose in the P1101 
treatment groups. Pharmacokinetic parameters decreased after the 8th dose (Day 24), which 
indicated the development of neutralizing antibodies. P1101 sera concentrations decreased after 
the 5th dose, indicating that neutralizing antibodies were developed by Day 17. Because the 
treatment-related effects were not considered to be adverse, the NOAEL was determined to be 6.75 
mg/kg. 
5.3 
Overview of Clinical Studies 
P1101 (also known as ropeginterferon alfa-2b) is being developed in the field of MPNs for the 
indication polycythemia vera (PV). The clinical development program for ropeginterferon alfa-2b 
in PV includes a Phase 1/2 study to determine the MTD, safety, and efficacy of ropeginterferon 
alfa-2b. Two-hundred and fifty-four (254) PV patients have been studied over 3 years under 3 
protocols; the first year under the PROUD-PV protocol, and the second and third year under the 
CONTINUATION-PV protocol to assess the long-term efficacy and safety of ropeginterferon alfa-
2b.  
PEGINVERA is an open-label, prospective, multicenter, Phase 1/2 dose escalation study, 
conducted in Austria with the primary objective to identify the MTD of P1101 in subjects 
diagnosed with PV. Safety and tolerability are assessed and an exploratory analysis of efficacy and 
biomarker modulation is performed in this study. Fifty-one subjects were enrolled into the study 
and received study medication (recruitment between Sep 2010 and Dec 2012, and study is now 
completed). No dose-limiting toxicities (DLTs) were observed at the dose levels up to 540 µg 
infused every two weeks, and efficacy and safety were assessed during the whole study period for 
each subject. Results of the study revealed that efficacy of P1101 in PV: more than 90% of the 
subjects were either complete or partial responders (20-50% of subjects, depending on time period 
for assessment were complete responders). Study drug-related AEs that occurred in >10% of the 
subjects (listed from most to less frequent): included pyrexia, arthralgia, influenza like illness, 
infection site reaction, fatigue, leukopenia, myalgia, pain in extremity, chills, thrombocytopenia, 
nausea, pruritus, alopecia, headache, and neutropenia.  

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PROUD-PV is a randomized, open-label, multicenter, controlled, parallel-arm Phase 3 study 
assessing the efficacy and safety of P1101 versus HU in subjects with PV. The primary objective 
of the study is to compare the efficacy of P1101 versus HU in terms of disease response rate in 
both HU naïve and currently treated subjects, diagnosed with PV. Secondary objectives include 
assessments of efficacy, safety, quality of life (QoL) and change of Janus kinase2 (JAK2) allelic 
burden in the two treatment arms. A total of 254 subjects were randomized and received study 
medication, and 217 completed the study. Overall, 36 serious adverse events (SAEs) occurred in 
this study, 4 of them rated as related to study drug: one case of atrial fibrillation and one case of 
rheumatoid arthritis (study treatment P1101), and two cases of basal cell carcinoma (both occurred 
in subjects receiving HU).  
PROUD-CONTINUATION-PV is an open-label, multicenter study assessing the long-term 
efficacy and safety of P1101 and standard first-line best available treatment (BAT) in subjects with 
PV who previously participated in the PROUD-PV study. The primary objective is to assess the 
long-term efficacy of P1101 or BAT. Secondary objectives further assess the long-term efficacy, 
safety, QoL, and change of JAK2 allelic burden. A total of 171 subjects were enrolled (95 in the 
P1101 treatment arm, 76 in the BAT arm [HU arm in previous PROUD-PV study]). Two cases of 
acute leukemia were assessed as related to BAT (subject received HU). No treatment-emergent 
SAEs were observed in the study. 
PEN-PV is an open-label, single arm study to assess the self-administration of P1101 using a pre-
filled auto-injection pen, developed for the treatment of PV subjects. Primary objective was to 
assess the ease of P1101 self-administration using dedicated questionnaires. Secondary objectives 
include the assessment of safety and tolerability, the assessment of maintenance of the blood 
efficacy parameters (hematological response) as well as the feasibility of P1101 self-administration 
(defined as the ability of the subjects to use the auto-injection pen as a self-administration tool). 
The study was conducted in 8 countries and 36 subjects were enrolled from subjects who 
completed the P1101 arm of the PROUD-PV study (N=5), or participated in the 
CONTINUATION-PV study (N=31). Overall, 1 SAE (atrial fibrillation) occurred in this study and 
was assessed as unrelated to P1101. No treatment-emergent SAEs were observed in the study. 
Single doses of P1101 were investigated in a dose escalation clinical study at doses of 24 (n=5), 
48 (n=6), 90 (n=6), 180 (n=6), 225 (n=6), and 270 (n=5) µg (IB) in healthy adult male subjects. 
The exposure to P1101 was dose-related, and the mean half-life ranged from 68 hours to 117 hours 
(approximately 3 to 5 days).  P1101 reached maximal plasma concentrations (1.8 to 21.3 ng/mL) 
after 75 to 90 hours (Tmax) when 24 to 225 µg single doses were administered subcutaneously 
(n = 4 to 5). The Tmax values observed did not show any dose dependency. However, after SC 
administration of 270 µg dose, maximal levels (24.8 ng/mL) were seen after 116 hours (n=5). With 
SC doses of 24 to 225 µg, the elimination half-life was determined as 61 to 92 hours with no 
obvious dose dependency (n=4 to 5). However, after a SC dose of 270 µg the elimination half-life 
was 118 hours (n=5). 

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Protocol P1101 in Japanese PV (A19-201) 
 
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Another single doses of P1101 were investigated in a dose escalation clinical study at doses of 100 
(n=12), 200 (n=12), and 300 (n=12) µg in healthy adult male subjects (Six Caucasian subjects and 
6 Japanese subjects at each dose level). The first dose of 100 μg (cohort 1) was administered on 
May 30, 2018. To date, one serious adverse event has been observed in 1 subject at the dose of 
100 μg (cohort 1). A 22-year-old Caucasian healthy subject developed neutropenia (ANC 0.8 x 
109) on day 2 (June 1, 2018) after a single dose. Subjects remained healthy without fever, and 
neutropenia resolved spontaneously after 1 week without therapeutic intervention. Because 
neutropenia was considered a significant safety issue per protocol, this event was reported to the 
Australian Government, Department of Health, The Therapeutic Goods Administration (TGA) on 
July 18, 2018. The adverse event corresponded to the original study stopping criteria, so the study 
was temporarily on hold. However, as a result of discussion at the SRC held on June 15, 2018, the 
study stopping criteria were modified, and at the beginning of the new cohort, the study site's 
Medical Monitor judged whether to administer the drug to the remaining subjects after confirming 
safety and tolerability during the first week after administration in sentinel subjects (sentinel 
subject: precautionary subjects for careful and early detection of potentially safety-related events). 
Administration of the remaining subjects with 100 μg dose (cohort 1) were resumed on October 3, 
2018 and ended on November 22, 2018 (Day 35 after administration for the last subject in cohort 
1). Evaluation of PK, PD, and safety data up to the Day 15 after administration of the 100 μg dose 
(cohort 1) was discussed at the SRC on November 13, 2018, and it was agreed to proceed to the 
next dosing level of 200 μg (cohort 2) administration to sentinel subjects. In the 100 μg dose 
(cohort 1), 3 other subjects reported 6 AEs. All the AEs were mild and resolved spontaneously. 
Reported AEs were injection site tenderness, phlebitis, inattention, neutropenia, headache, and 
urinary tract infection. Administration of 200 μg dose (Cohort 2) to sentinel subjects started on 
November 15, 2018 and ended on February 11, 2019 (Day 35 of administration for the last subject 
in Cohort 2). Evaluation of PK, PD, and safety data up to the Day 15 of administration at the 200 
μg dose (Cohort 2) was discussed at the SRC on February 12, 2019, and it was agreed to proceed 
to the next dosing level of 300 μg (Cohort 3) administration to sentinel subjects. No serious adverse 
events were reported in this cohort. No safety issue was identified in vital signs and ECG data from 
any of the subjects. Compared to cohort 1, there was no remarkable trend in cases of neutropenia. 
Forty-nine adverse events were reported in 12 patients, but all adverse events were mild to 
moderate in intensity and resolved. Notable adverse events were: Mild injection site 
reactions/erythema, neutropenia, lymphopenia, headache, influenza-like illness, arthralgia, 
elevated amylase, mild ALT and AST elevations, myalgia, urticaria, hyperesthesia, fatigue, fever, 
chest tightness were noted. Subjects receiving 300 μg (Cohort 3) started receiving treatment as of 
February 14, 2019, and ended treatment as of April 29, 2019 (on Day 35 of treatment in last subject 
in Cohort 2).  No SAE was reported in this cohort.  Among 12 subjects, 37 AEs occurred in 11 
subjects; all of which were mild to moderate, and resolved in the end.  AEs of special interest 
included mild injection site reaction/erythema (4 subjects), mild arthralgia/muscle pain (3 subjects), 
neutrophil count decreased of D3 to D4 (3 subjects), mild pruritus and eruption (2 subjects), and 
mild to moderate fever of D1 (38.1°C, 38.5°C, and 39.5°C) and cold chill (4 subjects).  Neutropenia 
occurred in 3 subjects, all of which were reported to be mild to moderate, and resolved by Day 12 
of treatment.  Other AEs included headache (6 subjects), diarrhoea, nausea, convulsion, pharyngeal 
pain, and urine odour fouls.  On Day 15 and thereafter, 1 subject had AST increase of ≤2 fold of 
the reference value, and ALT increase of ≥2 fold of the reference value, which peaked on Day 17 
(April 11, 2019).  The events were resolved and became normal by July 5, 2019. This event was 
considered to be clinically not important.  Also, there was no clinically-relevant ECG finding. 
This Study was initially designed to allow for dose up to 450 μg; however, a dose greater than that 
was considered to be inappropriate for healthy adults, and thus, 450 μg dose cohort was omitted, 
and the study was terminated. 
Additional safety details on these clinical studies are included in the IB. 
5.4 
Study Rationale 

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Protocol P1101 in Japanese PV (A19-201) 
 
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P1101 has been approved in Europe to treat PV, and regulatory discussions in the USA are on the 
way. To make P1101 accessible also to the Japanese patients and hematologists, PEJ plans to 
conduct the necessary studies of P1101 in Japanese (healthy volunteers, PV patients). Healthy 
volunteers study has been recently completed, while this study will provide efficacy and safety 
data of P1101 in Japanese PV patients. This single arm design is sufficient is complementary to 
the completed development program of P1101 vs HU in PV in Europe. 
5.5 
Risks and Benefits 
Pegylation confers upon P1101 special PK and PD properties that optimize its therapeutic utility. 
Specifically, P1101 is expected to an improved safety and tolerability profile compared to other 
existing PV therapies, which may lead to better adherence to treatment and ultimately, better drug 
efficacy. In addition, a reduction in the frequency of phlebotomies should be achieved. It is 
expected that the reduced intake frequency of P1101 will contribute to higher compliance rates 
than existing IFN therapy.  
The safety profile of IFN-α is well-characterized after nearly 30 years of clinical experience. The 
effects of IFNα-2b (the active moiety of P1101) are also well-characterized in humans based on 
the clinical data supporting the marketing authorization applications for the approved PEG IFN 
products: Pegasys, PegIntronTM, and Intron®A. Because P1101 belongs to the same therapeutic 
class as Pegasys, PegIntron, and IntronA, similar warnings and precautions as for the authorized 
drugs are expected to be applied to P1101, as reflected in the IB and in the EU label of P1101 
(trade name Besremi®) (EMA 2019). 
To minimize safety risks, subject data will be carefully monitored throughout the study, and 
subjects will be discontinued from study treatment if necessitated for safety reasons. Safety 
assessments (e.g., autoantibody measurements, ophthalmologic investigations, ECGs) will be 
implemented to detect any clinical meaningful changes in subject health conditions at the earliest 
possible time point. Subjects with any significant medical conditions at screening, which in the 
opinion of the Investigator may compromise their safety, will not be allowed to enter the study. 
5.6 
Justification of Study Drug Route of Administration, Dosage, Dosage Regimen, and 
Treatment Duration 
The aim of this study is to provide long-term safety and efficacy of P1101 in Japanese PV subjects 
in a single arm setting. The study will be used to complement the regulatory dossier in Japan to 
apply for marketing authorization of P1101 in subjects with PV in Japan. 
In a Phase 1 study with P1101, single SC doses of P1101 from 24 μg to 270 μg were safe and well-
tolerated (Study A09-102). In a Phase 1/2 study (PEGINVERA), the MTD for subjects diagnosed 
with PV was defined at the level of 540 µg every 2 weeks.  
Assessment of the available data (animal studies with the highest tested strength of 3.375 mg/mL 
administered, and also review of the relevant literature; refer to the IB for more details) concluded 
that no differences in absorption, systemic tolerability, or differences in local tolerability were 
observed, and no substantial risks are expected to occur following the repeated administration of 
P1101 doses ranging from 50 µg to 350 µg.  
In the development program in viral hepatitis, P1101 dose up to 450 μg was well-tolerated in 
subjects with chronic hepatitis C genotype 1, genotype 2, and chronic hepatitis B. P1101 showed 
comparable safety profiles to their active comparator, Pegasys. Almost all subjects reported AEs 
during treatment that were mostly mild or moderate. Grade 3 and 4 toxicities were uncommon and 
were managed effectively with dose reduction or discontinuation. The most common AEs were 
those that have been previously reported for other PEG IFNs, such as anemia, rash, leukopenia, 
pruritus, myalgia, insomnia, and neutropenia. No unexpected safety signal of P1101 up to 450 µg 
was noted in these studies. 
In the development program in PV, specifically in the PROUD-CONTINUATION-PV study, the 
dropout rate was low, and there were no new safety concerns observed with subjects receiving 500 
µg of P1101 in the maintenance period while the drug was effective in term of controlling elevated 
blood parameters. In fact, 40.18% subjects received the plateau dosage of 500 µg, and 60.53% 
subjects received the plateau dosages of 350 µg or higher. 

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The dose, used in the PV studies (PROUD-CONTI) and approved by the EMA will be used in this 
study. Treatment will continue beyond the one year of therapy, since PV therapy is chronic to keep 
the blood counts controlled and prevent long term disease complications (cardiovascular, 
transformations). 
5.7 
Justification of Study Target Subject Population 
The study will include patients with PV for whom the current standard therapy is difficult to apply. 
Specifically, it is planned to include younger patients considering the long-term treatment, patients 
who are classified as low risk of thrombosis but are considered to be candidates for cytoreductive 
therapy based on disease-related symptoms, etc., and patients who are intolerant of first-line 
therapy (hydroxyurea) as the standard therapy at present. 
IFN-α is established as the treatment of choice in both first-line and second-line settings for PV. 
This has been reflected by the European approval of P1101, with the indication “PV without 
symptomatic splenomegaly”. The medical and clinical rationale supports the use of P1101 in early 
stage of the disease, when the immune function is still preserved and long-lasting, immune 
mediated remission can be induced. Younger, early stage PV patients can also better tolerate P1101 
as known also for other representatives of the IFN-a class of drugs. 
6 STUDY OBJECTIVES 
6.1 
Primary Objective 
The primary objective is to demonstrate safety and efficacy of P1101 in terms of complete 
hematologic response (CHR) without phlebotomy with Japanese PV patients for whom the current 
standard therapy is difficult to apply. The primary endpoint “complete phlebotomy-free 
hematologic response (CHR)” is composed of freedom of phlebotomy with normal defined as a 
condition that meets the following hematological criteria, hematocrit (<45%), and normalization 
of WBC (≤10 x 109/L), and platelets (≤400 x 109/L) and require no phlebotomy at month 9 and 
month 12. 
6.2 
Secondary Objectives: 
The secondary objective is: 
- to demonstrate safety and efficacy of P1101 in terms of changes in Hct, WBC, PLT, spleen 
size, molecular and cytogenetic response from baseline, time to requiring no phlebotomy, 
numbers of phlebotomy required, time to response, duration of response maintenance, ratio of 
CHR rates of subjects with/without prior treatment with HU and Proportion of subjects without 
thrombotic events. 
- to assess the pharmacokinetics (PK) of P1101 and population PK (PPK) analysis 
- to assess the relationship between exposure and key efficacy and safety endpoint using 
exposure-response (E-R) analysis 
- to assess the immunogenicity of P1101 
7 STUDY ENDPOINTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the phlebotomy-free complete hematologic responder rate (CHR) 
at month 9 and month 12.  
The phlebotomy-free responder rate is defined as the proportion of patients with complete 
hematologic response (CHR) and with no phlebotomies during the previous 3 months. 
A responder in sense of a primary endpoint is a patient who has met all of the following criteria at 
month 9 and month 12: 
- Hematocrit <45% phlebotomy-free (absence of phlebotomy during the previous 3 months) 
- Platelet count ≤400 x 109/L, 

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- WBC count ≤10 x 109/L  
7.2 
Secondary Endpoints 
The secondary endpoints include: 
- Changes in Hct, WBC, PLT and spleen size from baseline 
- Time to requiring no phlebotomy 
- Time to first response 
- Duration of response maintenance 
- Proportion of subjects without thrombotic or hemorrhagic events 
- Change of JAK2 mutant allelic burden over time from baseline 
- PK of P1101 
7.3 
Exploratory Endpoint 
Bone marrow histological remission defined as the disappearance of hypercellularity, trilineage 
growth (panmyelosis) and absence of >grade 1 reticulin fibrosis (optional) 
7.4 
Safety Endpoints 
Incidence, causality, and severity of AEs, according to Common Terminology Criteria for Adverse 
Events (CTCAE; version 5.0) 
Incidence, causality, and severity of AEs of special interest (AESIs; e.g., cardiovascular events, 
hemorrhagic, thrombotic events, psychiatric events) 
Events leading to dose reduction or permanent treatment discontinuation 
7.5 
PPK and E-R Endpoints 
PK parameters of P1101, including (but not limited to) Cmin, Tmax, Cmax, and AUC0-t, will be derived 
using PPK analysis and the relationship between exposure and efficacy and safety endpoints will 
be examined using E-R analysis 
7.6 
Immunogenicity endpoints 
Proportion of subjects who are ADA positive and negative will be determined 
8 OVERVIEW OF STUDY DESIGN 
This is a Phase 2 open-label, multicenter, single arm study designed to evaluate the efficacy and 
safety and tolerability of P1101 in Japanese PV patients for 12 months of treatment for subjects 
with PV for whom the current standard therapy is difficult to apply. Specifically, it is planned to 
include younger patients considering the long-term treatment, patients who are classified as low 
risk of thrombosis but are considered to be candidates for cytoreductive therapy based on disease-
related symptoms, etc., and patients who are intolerant of first-line therapy (hydroxyurea) as the 
standard therapy at present. 
During the screening visit, after obtaining informed consent, screening evaluations will begin. 
Subject eligibility will be determined by the inclusion and exclusion criteria listed in Section 9. 
Subject visits will be scheduled every 2 weeks. A safety follow-up visit or end of study (EoS) visit 
will take place 28 days after the End of Treatment (EoT) visit.  
Efficacy evaluations, safety assessments, and PK and immunogenicity sampling will be performed 
according to the study flowcharts (Appendix 1). 
Evaluation of efficacy will include clinical laboratory assessments, allelic burden measurements 
of JAK2, spleen size measurements (palpation, sonography) and bone marrow sampling (optional). 
HADS questionnaire (see Appendix 8) will be applied at screening and at quarterly assessment 
visits at month 3, 6, 9 and 12. 

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Evaluation of safety will include assessing vital signs, clinical safety laboratory tests, physical 
examinations, ECG evaluation, heart ECHO, lung X-ray, ECOG performance status, ocular 
examination, and AEs.  
A urine pregnancy test must be performed within 7 days prior to the first administration of study 
drug and subsequently every 4 weeks for all women of childbearing potential, as well as for all 
women <2 years after the onset of menopause. 
Serial PK samples (n=4 per subject) will be collected at Week 0 and Week 28, at the following 
time points: pre-dose (0 hr), 48 (±24) hr, 96 (±24) hr, and 168 (±24) hr. Trough PK samples 
(mandatory) will be collected at every visit. 
Quantitative JAK2 allelic burden measurements will be done by a central laboratory. 
Total duration is approximately 14 months, with a screening period of 28 days, a treatment period 
of 12 months, and a follow-up period of 28 days. 
8.1 
Disease Progression/Withdrawal Criteria 
The reason(s) for a subject discontinuing from the study will be recorded in the electronic case 
report form (eCRF). A discontinuation occurs when an enrolled subject ceases participation in the 
study, regardless of the circumstances, prior to completion of the protocol planned schedule. The 
Investigator must determine the primary reason for discontinuation.  
Discontinuation from the study may occur for the following reasons:  
• Disease progression; 
For this study, disease progression will be defined as: 
- Death due to any cause 
- Development of secondary MF, as evidenced e.g. by bone marrow biopsy 
- Transformation into acute myeloid leukemia or myelodysplastic syndrome, as evidenced by 
bone marrow biopsy 
• Screening failure;  
• Withdrawal of patient consent; 
• Severe Noncompliance; 
• Worsening of the underlying disease in cases when the further participation (with dose adjustment) 
is not expected to provide sufficient medical care to the patient;  
• Study drug-related adverse event (AE) not recovering within the pre-specified period*; 
- pre-specified period*: 8 weeks after discontinuation of IMP administration 
• Medical condition unrelated to the underlying disease or study treatment (study drug-unrelated 
AE); 
• Lost to follow-up. 
The EoT visit will be performed at the time of study discontinuation.  
In case of early treatment discontinuation, the subject should be invited to attend the safety follow-
up visit (28 days after the EoT visit).  
Subjects who discontinue study drug due to a study drug-related AE or abnormal laboratory value 
must be followed at least once a week for 8 weeks (and subsequently at 2-week intervals) until 
resolution or stabilization of the event. If a subject has not recovered from any toxicity within 
8 weeks of prematurely discontinuing study drug, s/he must be discontinued from the study, but 
will continue to be followed for toxicity as described above. In this case, data will not be entered 
into the database but will be documented in the study log, which is stored at the site. 
9 STUDY POPULATION 

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Subjects with a diagnosis of PV who meet the inclusion criteria and do not meet the exclusion 
criteria will be eligible for participation in this study. 
9.1 
Inclusion Criteria 
1. Male or female patients ≥20 years old at the time of informed consent 
2. Patients diagnosed with PV according to the WHO 2008 or WHO 2016 criteria 
3. PV patients for whom the current standard of treatment is difficult to apply. Patients 
with a documented history of refractory to HU are excluded (see Appendix 6; modified 
ELN criteria based on "Barosi et al, 2010 ELN criteria", (Barosi et al. 2010)).  
- Younger patients (long-term treatment is anticipated) 
- Patients who are categorized as low risk, but cytoreduction is recommended due to disease-
related signs and symptoms (headache, dizziness, pruritus, night sweats, fatigue, 
erythromelalgia, vision disorders, scintillating scotoma, early satiety, abdominal distension). 
- Patients with HU intolerance (see Appendix 6; modified ELN criteria based on "Barosi et al, 
2010 ELN criteria", (Barosi et al. 2010)) 
4. Total HU treatment duration shorter than 3 years (cumulatively) at screening 
5. For cytoreduction naïve patients only: PV in need of cytoreductive treatment, defined 
by fulfilling as one or more of the following criteria at baseline: 
- at least one previous well documented major cardiovascular PV-related event in the medical 
history  
- poor tolerance of phlebotomy (defined as a phlebotomy/ procedure-related adverse event 
causing significant adverse impact on the patient and limiting ability to apply phlebotomy 
with the intention to keep Hct <45%) 
- frequent need of phlebotomy (more than one phlebotomy within last month prior entering the 
study) 
- platelet counts greater than 1000 x 109/L (for two measurements within the month prior 
treatment start) 
- leukocytosis (WBC >10 x 109/L for two measurements within the month prior treatment start) 
- manifestation of disease-related signs and symptoms (headache, dizziness, pruritus, night 
sweats, fatigue, erythromelalgia, vision disorders, scintillating scotoma, early satiety, 
abdominal distension) 
6. Adequate hepatic function defined as total bilirubin ≤1.5 x upper limit normal (ULN), 
international normalized ratio (INR) ≤1.5 x ULN, albumin >3.5 g/dL, alanine 
aminotransferase (ALT) ≤2.0 x ULN, aspartate aminotransferase (AST) ≤2.0 x ULN at 
screening 
7. Hemoglobin (HGB) ≥10 g/dL at screening 
8. Neutrophil count ≥1.5 x 109/L at screening 
9. Serum creatinine ≤1.5 x ULN at screening 
10. Hospital Anxiety and Depression Scale (HADS) score 0-7 on both subscales 
(Appendix 8). 
- (Patients with a borderline of HADS score (score > 7 but <10) or patients with necessity 
(expected benefits are higher than the risks) based on investigators' discretion are required to 
receive following assessment by psychiatric specialist to confirm the eligibility for IFNα 
therapy.) 

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11. Males and females of childbearing potential, as well as all women <2 years after the 
onset of menopause, must agree to use an acceptable form of birth control until 28 days 
following the last dose of the study drug  
12. Written informed consent obtained from the patient or the patient’s legal representative, 
and ability for the patient to comply with the requirements of the study 
9.2 
Exclusion Criteria 
1. Patients with symptomatic splenomegaly 
2. Previous use of IFNα for any indication 
3. Any contraindications or hypersensitivity to interferon-alfa 
4. Co-morbidity with severe or serious conditions which may impact patient participation 
in the study in investigator’s opinion 
5. History of major organ transplantation 
6. Pregnant or lactating females (Breastfeeding women are not allowed to enter this study 
by discontinuing breastfeeding) 
7. Patients with any other medical conditions, which in the opinion of the Investigator 
would compromise the results of the study or may impair compliance with the 
requirements of the protocol, including but not limited to: 
7.1. History or presence of thyroid dysfunction (clinical symptoms of hyper- or hypo-
thyroidism) of the autoimmune origin, except late stages cases on the oral thyroid 
substitution therapy, where potential exacerbation under interferon therapy will 
not constitute any further harm to the patient 
7.2. Documented autoimmune disease (e.g., hepatitis, idiopathic thrombocytopenic 
purpura [ITP], scleroderma, psoriasis, or any autoimmune arthritis) 
7.3. Clinically relevant pulmonary infiltrates and pneumonitis at screening, patients 
with a history of interstitial pulmonary disease 
7.4. Active infections with systemic manifestations (e.g., bacterial, fungal, hepatitis B 
[HBV], hepatitis C [HCV], or human immunodeficiency virus [HIV]) at 
screening) 
7.5. Evidence of severe retinopathy (e.g., cytomegalovirus retinitis [CMV], macular 
degeneration) or clinically relevant ophthalmological disorder (due to diabetes 
mellitus or hypertension)  
7.6. Uncontrolled depression 
7.7. Previous suicide attempts or at any risk of suicide at screening 
8. Uncontrolled diabetes mellitus (HbA1c level of > 7% at screening) 
9. History of any malignancy within the past 5 years (except Stage 0 chronic lymphocytic 
leukemia [CLL], basal cell, squamous cell, and superficial melanoma believed to be 
cured) 
10. History of alcohol or drug abuse within the last year 
11. History or evidence of post polycythemia vera-myelofibrosis (PV-MF), essential 
thrombocythemia, or any non-PV MPN 
12. Presence of circulating blasts in the peripheral blood within the last 3 months 

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13. Use of any investigational drug(s), or investigational drug combinations <4 weeks 
prior to the first dose of study drug or not recovered from effects of prior administration 
of any investigational agent 
With regard to acetylsalicylic acid, which will be considered as the background treatment in the 
study unless contraindicated, the following contraindications are known for low-dose 
acetylsalicylic acid: active peptic ulceration or history of peptic ulceration, hemophilia, 
hypersensitivity to acetylsalicylic acid or any other nonsteroidal anti-inflammatory drugs 
(NSAIDs), including those in whom attacks of asthma, angioedema, urticaria, and rhinitis have 
been precipitated by acetylsalicylic acid or any other NSAID, and hypersensitivity to any of the 
other constituents. If any of the contraindications are observed, the patient may still participate in 
the study without being administered acetylsalicylic acid. 
9.3 
Justification of Inclusion/Exclusion Criteria 
9.3.1 
Justification of Inclusion Criteria 
Inclusion criterion 1 was designed to allow for the participation of subjects aged 20 years or older, 
since this study will be conducted in Japanese adults. 
Inclusion criterion 2 identifies the patient population to be enrolled to this study and is based on 
internationally accepted WHO diagnostic criteria guidelines. 
Since the 2016 version was actually widely used after 2017, both the 2008 and 2016 versions are 
applicable. 
Inclusion criterion 3 was established in consultation with the Pharmaceuticals and Medical Devices 
Agency (PMDA) and considers the group of patients for whom treatment with drug is desired. 
In general, the treatment of PV is long-term and is intended for inclusion in young people. 
Inclusion criterion 4 was set to include PV patients with a history of treatment with hydroxyurea 
for no more than 3 years because of concerns about the effect on efficacy and safety in PV patients 
with a long history of cytoreductive therapy with hydroxyurea and the possibly advanced disease 
status. 
Inclusion criterion 5 is for patients with PV who have not been treated with cytoreductive therapy. 
Current national treatment guidelines recommend phlebotomy and aspirin therapy for patients with 
PV at low risk of thrombosis, but no cytoreductive therapy. 
However, foreign NCCN guidelines consider the introduction of cytoreductive therapy in PV 
patients with low-risk for thrombosis who experiences frequent phlebotomy, worsening of disease-
related symptoms, or increased platelets or white blood cell counts. These PV patients are 
considered "the current standard of treatment is difficult to be applied". 
Inclusion criteria 6 and 9 are general criteria for liver function, renal function, and were set to 
minimize risks in subjects. 
Inclusion criteria 7 and 8 were set because they are expected to decrease red blood cell count and 
neutrophil count due to the cytopenic effects of drug. If these values are low at the time of screening, 
anaemia and susceptibility to infection are expected to occur. Therefore, these values were set. 
Inclusion criterion 10 was set to exclude subjects with psychiatric disorders based on the evaluation 
of HADS score, since interferon may exacerbate psychiatric disorders. 
Inclusion criterion 11 is general criteria for contraception during the study, and were set for 
subjects who can comply with the clinical trial procedures to ensure consistency of safety and data. 
Inclusion criteria 12 is implemented in accordance with the Guideline for Good Clinical Practice. 
Therefore, the inclusion criteria are set for subjects who can provide appropriate informed consent 
to participate in this clinical trial. 
9.3.2 
Justification of Exclusion Criteria 

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Exclusion criterion 1 was based on the indication "Besremi (trade name) is indicated as 
monotherapy in adults for the treatment of polycythemia vera without symptomatic splenomegaly" 
approved by the EMA on February 19th, 2019, and PV patients with symptomatic splenomegaly 
will be excluded in this study because they were not eligible for treatment according to the SmPC 
(EMA 2019). 
Exclusion criteria 2 and 3 were set to exclude patients who had previously been treated with 
interferon-alpha and those who were hypersensitive to interferon-alpha. 
This is because the above information may interfere with the assessment of the efficacy and/or 
safety of the drug in these patients. 
Exclusion criteria 4, 5, and 6 were set to exclude patients with conditions that could interfere with 
the efficacy and/or safety assessment of this drug. 
Exclusion criteria 7 (7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7.7), 8, 9, and 10 were set to exclude patients 
with complications such as autoimmune diseases, psychiatric disorders, ophthalmic diseases, 
diabetes mellitus, and cancer, and those with a history of such complications may be exacerbated 
by interferon therapy. 
Exclusion criterion 11 was set to exclude patients with myelofibrosis progressed from PV (post 
polycythemia vera myelofibrosis: PPV-MF), essential thrombocythemia, or non-PV 
myeloproliferative neoplasms (Myeloproliferative neoplasms). 
This is because the interpretation of the treatment outcome may be affected in patients other than 
those with PV. 
Exclusion criterion 12 was set because the presence of blasts in the peripheral blood may preclude 
the assessment of the efficacy and/or safety of this drug in these patients, who are considered to 
have progressed to profibrotic status in the bone marrow. 
Exclusion criterion 13 is a criterion for subjects who have recently participated in another clinical 
trial and/or received another investigational product. 
These subjects will be excluded because they could impair an accurate assessment of the causality 
of the AE. 
10 RANDOMIZATION AND BLINDING 
Not applicable – single arm study. 
11 ASSIGNMENT TO STUDY 
Screening numbers will be assigned by the Principal Investigator/designee at each study site as 
soon as the subject has signed the informed consent. Subjects who are screened and who do not 
meet all entry criteria are screen failures and will be entered into a screening log; data collected on 
screening failures will be entered in the clinical database. Once assigned, numbers for any 
screening failures subjects will not be re-used.  
12 STUDY DRUG 
12.1 Investigational Treatment 
Subjects who meet the inclusion criteria and who do not meet the exclusion criteria will be treated 
with investigational product P1101 (ropeginterferon alfa-2b). It will be administered 
subcutaneously every 2 weeks at the starting dose of 100 µg (Week 0). The dose will be elevated 
biweekly by 50 µg until 500 µg, or until response (as defined by primary endpoint) will be achieved. 
The dose then will remain fixed for the study duration. Dose adjustment to prior dose will be 
allowed if triggered by safety or tolerability. For transition phase from previous HU treatment to 
P1101 (for all patients on active HU), the rules as specified in the Appendix 7 will apply. 

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Due to the lack of experience of administration of the study drug over 300 μg in Japanese subjects, 
Sponsor introduce careful observation of all the subject after the administrations over 300 μg to 
ensure subjects safety and to respond quickly and appropriately in emergency situations. More 
specifically, all the subjects will be hospitalized for the first 2 days (incl. the date of administration) 
when they receive the study drug over 300 μg (350, 400, 450 and 500 μg). Two days after the 
administration, the subjects can be discharged if there is no evidence of clinically significant 
adverse reactions based on the assessment by the institutional Principal Investigatos at each site. 
All safety data up to Day 15 (from previous dose to next dose) will be collected and reviewed by 
Principal Investigators at each site, to determine if any of the criteria for stopping dose escalation 
has been met. Increase to the next higher planned dose level will only occur if the previous dose 
level was deemed to be safe and well-tolerated following review by Principal Investigator at each 
site. For the safety confirmation after administration of 500 μg, the time to dose increase to 500 μg 
should not exceed 32 weeks. In addition, as with the administration of 350 μg, 400 μg, and 450 μg, 
the Principal Investigators and sub-investigators at each medical institution assess that no drug-
related adverse events requiring dose reduction/interruption/discontinuation occur within 2 weeks 
after dose increase (by Day 15 after the next visit) according to the protocol criteria. If the safety 
profile of the 500 μg dosing level for the 5 subjects in the first 6 evaluable subjects is confirmed 
by Coordinating Principal Investigator, Principal Investigators at each site and Sponsor’s Medical 
Monitor, the observation based on the hospitalization for two days after administration will be 
deactivated and the rest of study subjects will receive the predefined higher dose level of the study 
drug (over 300 μg) without hospitalization. If two or more of the first six evaluable subjects fail to 
meet the criteria for tolerability, the Coordinating Principal Investigator, the Principal Investigators 
at each site and the sponsor's Medical Monitor will perform a comprehensive assessment of 
continuation of the study. 
12.2 Physical, Chemical, Pharmaceutical Properties, and Formulations 
The chemical name of P1101 is poly(oxy-1,2-ethanediyl), α-hydro-ω-methoxy-,1,1-diester with 
interferon α-2b [1-[1-[3,7-bis(carboxyamino) heptyl] proline]. 
P1101 is available as a solution containing P1101, sodium chloride, polysorbate 80, benzyl alcohol, 
sodium acetate anhydrous, acetic acid, sodium hydroxide, hydrochloride acid, and water for 
injection. The solution is colorless to light yellow. P1101 will be supplied in pre-filled syringes. 
The structural formula and amino acid sequence for P1101 is provided in Figure 12-1. 
 
Figure 12-1  P1101 Structural Formula and Amino Acid Sequence 

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Due to innovative pegylation technology, P1101 is composed of a single isoform. Recombinant 
IFNs as well as pegylated recombinant IFNs have been approved in several countries in various 
indications based on their antiviral, antiproliferative, and immunoregulatory properties.  
12.3 Packaging, Labeling and Storage 
The study drug will be labelled in the local language and comply with the legal requirements of 
each country. The study drug will include the following labeling: “For Clinical Trial Use Only,” 
“To be administered at a dose according to the physician’s instructions,” and “Keep out of reach 
of children.” The labels will include storage conditions for the study drug and the study drug 
number, but no information about the subject.  
Additionally, aspirin (aspirin) 75 to 150 mg per day as background therapy (provided locally) will 
be prescribed to all subjects (unless contraindicated). In this case, other prophylactic 
antithrombotic agents may be used. 
Table 12-1  Packaging and Labeling 
Study drugs 
Packaging  
P1101 
Pre-filled syringes with 500 µg per syringe  
P1101 pre-filled syringes will be shipped in cooled containers. Pre-filled syringes must be 
refrigerated immediately upon receipt to ensure optimal retention of physical and biochemical 
integrity and should remain refrigerated until just prior to use. Study drug should be stored by the 
study site at controlled room temperature of 2 to 8ºC. Temperature logs must be maintained to 
ensure proper storage conditions. Do not freeze or shake the pre-filled syringes. Do not use 
medication beyond the expiration date stamped on the PFS. PFS must be kept in their outer carton 
to protect them from the light. 
If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below the 
2ºC to 8ºC range, this should be reported to the Sponsor/designee and captured as a temperature 
excursion. Additional details on study drug storage requirements and related information will be 
provided in the pharmacy manual.  
12.4 Supply of Study Drug at Site 
The Sponsor/designee will ship the study drug to the investigational sites. The initial study drug 
shipment will be authorized by the Sponsor/designee after all required regulatory documentation 
for a particular site has been received. Subsequent study drug shipments will be made after site 
request for resupply. Details will be included in the pharmacy manual. 
The study drug must be received by the study pharmacist or designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the study 
pharmacist and designated assistants have access. Upon receipt, the study drug should be stored 
according to the instructions specified on the drug labels. All drug product must be accounted for 
in accordance with the standard practice at each study center and in compliance with applicable 
regulations. The site must use an appropriate dispensing log/accountability form provided by the 
sponsor, or an acceptable substitute approved by the sponsor. Each time study medication is 
dispensed for a subject, the following information must be recorded: the subject’s unique 
identifying number, the dose strength, the number of units (syringe) with the corresponding lot 
number, and the initials of the person dispensing the drug. These logs are to be maintained by the 
study pharmacist in the pharmacy throughout the duration of the study and will be periodically 
verified by a representative of the sponsor. 
12.5 Dosage and Dosing Schedule 
P1101 will be administered SC during the study visits every 2 weeks. Subjects will receive an 
initial dose of 100 µg at Week 0, 150 µg at Week 2, and then 200 µg at Week 4, etc., i.e. dose 
escalation by 50 µg biweekly until 500 µg, or until response will be achieved.  The dose can be 
further adjusted to prior dose for safety and tolerability reasons, but should preferably remain fixed 
for the treatment period.  

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The study drug should be administered SC into the abdominal skin around but not within 5 cm of 
the navel. If the abdomen appears inappropriate or unfavorable for injection according to the 
Investigator’s judgment, study drug can be injected SC into the thigh. At the time of dispensing, 
the person administering the study drug will note the date and time of administration, both of which 
are then to be documented into the subject’s eCRF. 
A standardized dosing paradigm will be used to determine dose adjustments for safety and 
tolerability so that each subject will receive their most appropriate dose (Section 12.5.2). 
12.5.1 
Aspirin 
All subjects should receive low-dose aspirin (75-150 mg/day) as background therapy unless 
medically contraindicated. In this case, other prophylactic antithrombotic agents may be used. 
Higher doses of aspirin (>150 mg/day) should not be used except when medically indicated. 
12.5.2 
Dose Reduction and Dose Interruption 
Dose reduction or interruption for P1101 are recommended in subjects experiencing AEs until the 
AE abates. If intolerance persists after dose reduction or interruption, therapy should be 
discontinued. These dose changes must be recorded on the Dosage Administration Record and 
Adverse Event eCRF page. 
Dose reduction of the study drugs should be driven exclusively by the safety and tolerability of the 
drugs under study. If a certain dose is poorly-tolerated and drug-related toxicities arise, the dose 
has to be reduced to the prior dose, or interrupted, following the scenarios below: 
If a subject has a severe (Grade 3 or 4) toxicity, or a drop in absolute neutrophil count (ANC) to 
below 0.5 × 109/L, temporary interruption has to be implemented until recovery to the condition, 
which allows treatment continuation (e.g., Grade 1 mild intensity). Treatment re-initiation has to 
occur from the prior lower dose than those that caused the toxicity. For example, if Grade 3 AE 
occurs at 500 µg, treatment re-initiation will occur with 450 µg.  
If a subject has a Grade 2 toxicity, or a drop in ANC to below 0.75 × 109/L but higher than 0.5 × 
109/L, dose decrease without treatment interruption should be considered.  
Grade 1 toxicity should not lead to dose reduction or interruption. 
Dose re-escalation may be omitted in those subjects who do not recover from previous toxicity.   
13 COMPLIANCE 
P1101 will be supplied by the Sponsor. The study drug is to be prescribed only by the Principal 
Investigator or the designee. Under no circumstances will the Principal Investigator allow the study 
drug to be used in any settings other than those specified and directed by this protocol. 
The Principal Investigator or designee is responsible for ensuring that all drug supplies are kept 
under lock and key, with access limited to the study team. The Investigator or designated study 
personnel will maintain accountability of all study drugs received, dispensed, and returned. Drug 
supplies for each subject will be inventoried and accounted for throughout the study. The 
pharmacist/designated person must maintain accurate records of the receipt of all study drugs 
shipped by the Sponsor, including date received, lot number, expiration date, amount received, and 
the disposition of all study drugs. If any damage in the clinical drug supply shipments occurs, the 
Investigator should contact the Sponsor/designee immediately. The inventory will be made 
available to the monitor to verify drug accountability during the study. 
Compliance with the dosing regimens will be calculated by the Sponsor based on the drug 
accountability documented by the site staff and monitored by the Sponsor/designee (injection 
counts).  
Drug administration will also be recorded in each subject’s eCRF. An accountability log will be 
kept, indicating disposition of study drug; this log will be kept in the On-Site Study File. 
14 PRIOR AND CONCOMITANT THERAPY 

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All medications (i.e., over-the-counter drugs and blood products) taken within 3 months (12 weeks) 
prior to the administration of the study drug, as well as, all concurrent therapies will be recorded 
in the relevant eCRF pages. All prior nondrug therapies, as well as, all surgeries will be recorded 
in the relevant eCRF pages. Dose, route, unit frequency of administration, indication for 
administration, and dates of medication will be captured. Any concomitant medications or changes 
thereof must be recorded at each visit. If the change influences the subjects’ eligibility to continue 
in the trial, the Sponsor must be informed. 
14.1 Allowed Concomitant Therapy 
All subjects should receive low-dose aspirin (75-150 mg/day), unless medically contraindicated. 
In this case, other prophylactic antithrombotic agents may be used. 
Paracetamol (acetaminophen), chlorphenamine (chlorpheniramine), and other antihistamines 
(used as monotherapy or combination preparations) can be used according to local clinical practice, 
for the prevention and treatment of injection site reactions associated with peg-interferon.  
Moreover, paracetamol (e.g., 500 mg by mouth) or an appropriate dose of another NSAID is 
recommended to be administered 8 to 10 hours, 24 hours, and 48 hours after the first administration 
of P1101 in order to avoid potential flu-like symptoms. No prophylaxis will be administered until 
Visit 2 in order to assess the necessity of prophylaxis and to assess the true rate of IFN-induced 
flu-like symptoms.  
Anti-coagulation therapy: subjects who experience thromboembolic events during the study 
treatment are permitted to receive full-dose anticoagulants and remain on the study drug based on 
the judgement of the treating Investigator, except for severe thromboembolic events. All details 
regarding anticoagulant treatment should be collected and recorded in the Concomitant eCRF page. 
Details regarding discontinuation due to severe thromboembolic events should be reported on the 
AEs and discontinuation eCRF page. Severe thromboembolic events are defined as Grade 3 and 
related AEs. On the Discontinuation eCRF page, the reason for discontinuation would be 
thromboembolic event.  
Phlebotomy is performed aiming at a hematocrit < 45%. When the hematocrit value is 45% or 
higher, phlebotomy is performed. The volume of phlebotomy per procedure should be 200 to 400 
mL per one phlebotomy while monitoring the circulatory dynamics such as blood pressure and 
pulse. In the elderly and patients with cardiovascular disorders, a small volume (100 to 200 mL) 
should be considered to avoid rapid changes in hemodynamics. 
14.2 Prohibited Concomitant Therapy 
Except for the investigational and reference drugs, no other cytoreductive (i.e., leading to decrease 
of cell counts in peripheral blood) therapy, JAK inhibitors, nor any other drugs leading to a 
decrease of peripheral blood cell counts are allowed in this study. Investigational medications, 
other than the study drugs used in this study, are not allowed in this study.  
In addition, interstitial pneumonitis associated with the concomitant use of interferon-α 
preparations and Sho-sai-ko-to (or xiao-chai-hu-tang, herbal medicine) has been reported as safety 
data common to interferon-α 2a and interferon-α 2b products. Therefore, the concomitant use of 
Sho-sai-ko-to is contraindicated from a safety standpoint. 
The contraindicated concomitant therapy period is set as from obtaining informed consent to the 
safety follow-up visit after completion of the administration period. 
14.3 Contraception Use 
Females of childbearing potential will be required to use oral, injectable, or implanted 
contraceptives. Use of hormonal contraception will be determined by the Investigator, taking into 
account the therapy used, the manufacturer’s instructions, labeling, and accepted medical practice. 
Male subjects will use an appropriate method of contraception, such as vasectomy (confirmed to 
be azoospermia) or condom use. 
In this study, contraception is required from the start of the study to 28 days after the last dose of 
the investigational product, regardless of gender. 

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15 STUDY EVALUATIONS 
15.1 Study Procedures by Visit 
15.1.1 
Overview 
The study is divided into 2 phases with associated evaluations and procedures that must be 
performed at specific time points, as described in the following sections. The study flowchart 
(Appendix 1) summarizes the frequency and timing of study events. 
As soon as the subject is considered for this study, and prior to any other study procedures, the 
subject will have the nature of the study explained to them, and will be asked to give written 
informed consent. Informed consent must be obtained prior to any procedures during the course of 
a clinical trial.  
Subjects who are prematurely discontinued from the study should attend the safety follow-up visit 
28 days after the last study drug administration. 
15.1.2 
Screening (-28 days/-1 day) 
Subjects who might meet the inclusion criteria will be contacted and asked for their interest in 
participating in the study. If they agree to participate in the study, all subjects must provide written 
informed consent before any study-specific assessments or procedures are performed. 
Subjects who are considered for study entry but fail to meet one or more of the eligibility criteria 
should not be reported in the eCRF. A detailed reason for ineligibility should be reported in the 
screening log.  
An eCRF should be completed for all subjects fulfilling all of the entry criteria. 
The site notifies the Sponsor when a subject eligible according to all inclusion and exclusion 
criteria is to be enrolled into the study. Study entry (enrollment) is defined by the subject’s, or their 
legally authorized representative’s, signature on the informed consent form. All subjects enrolled 
will be assigned a subject ID number. 
The following assessments will be completed according to the study flowchart (Appendix 1). 
- Informed consent - verification of personally signed and dated informed consent of the subject, 
or their legally authorized representative, prior to any study-related examinations performed 
- Inclusion and exclusion criteria - Subjects who meet all inclusion criteria and none of the 
exclusion criteria will be invited to participate in the study 
- Demographic information (e.g., age, sex, and race) will be recorded at screening in the 
appropriate eCRF. Relevant medical history, including history of prior and current disease(s), 
and information regarding underlying diseases will also be recorded at screening. Included will 
be the usage of any and all drugs used to treat PV. 
- Standard 12-lead ECG  
- A urine pregnancy test must be performed within 7 days prior to the first administration of 
study drug and subsequently every 4 weeks for all women of childbearing potential (no 
hysterectomy or bilateral oophorectomy, or at least 12 consecutive months without 
spontaneous menopause [i.e., menstruation occurred sometime in the past 12 consecutive 
months], or amenorrhea due to medical treatment such as antineoplastic drugs) as well as for 
all women <2 years from the onset of presumed menopause (the time point of completion of 
the last menstruation was considered as menopause, when the next menstruation has not started 
for more than 2 years) 
- Complete physical examination  
- Vital signs (pulse rate, blood pressure, and body temperature) 
- Blood chemistry 
- Blood coagulation 

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- Serology to exclude systemic infections; the tests commonly used in the local setting for 
diagnosing current infections (with HIV and HCV, as well as hepatitis B surface antigen 
[HBsAg] to detect HBV infection) are to be performed for eligibility assessment purposes  
- Hematology 
- Autoimmune markers (blood) 
- Urine test 
- Urine beta 2 microglobulin test 
- ECOG performance status  
- Spleen size measurement: Spleen size will be measured by palpation and, for palpable spleen, 
subsequently by ultrasound with local review of the images 
- Genetic test sample including JAK-2 allelic burden (data collected according to WHO criteria) 
- Bone marrow sampling (optional). Bone marrow biopsy collected within 6 months of 
Screening could be used to replace the Screening sample. If a sample was taken within 6 
months, but since then the patient was treated with HU and failed, the sample needs to be 
retaken. 
- AEs 
- Concomitant treatment 
- Ocular examination 
- Lung X-ray: Will be accepted if they are not older than 12 weeks prior to the date of the 
screening visit 
- Heart ECHO: Will be accepted if they are not older than 12 weeks prior to the date of the 
screening visit  
- HADS (Appendix 8) 
- After having successfully completed the screening period and if found eligible for the study, 
the subjects will receive the study treatment. 
15.1.3 
Treatment Period Week 0 to Week 52 
The first dose of study drug will be administered at 0 hours on Day 1. 
All assessments, including local laboratory samples, are to be completed prior to the study drug 
administration at each visit.  
Note: If hematology and/or blood chemistry are done within 7 days prior to Visit 1, they do not 
have to be repeated. 
Please refer to the study flowchart and others (Appendix 1, Appendix 2, Appendix 3) for specific 
assessments at each visit.  
15.1.4 
Safety Follow-up or End of Study Visit 
Subjects who discontinue study drug prematurely will return for a follow-up visit 28 days after the 
last dose. Please refer to the study flowchart and others (Appendix 1, Appendix 2, Appendix 3) for 
visit-specific assessments.  
If subjects will participate in extension study of A19-201, safety follow-up will not be performed. 
Subjects who discontinue study drug due to a suspected study drug-related AE must be followed 
at least once a week for 8 weeks and subsequently at 2-week intervals until resolution or 
stabilization of the event.  
If a subject has not recovered from any toxicity within 8 weeks of prematurely discontinuing study 
drug, s/he must be discontinued from the study, but will continue to be followed for toxicity as 
described above. 

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Subjects who discontinue study drug due to a severe thromboembolic event will have an AE 
reported as the reason for discontinuation, and “severe thromboembolic event” indicated in the 
specific field.  
If a subject has not recovered from any toxicity within 8 weeks of prematurely discontinuing study 
drug, s/he must be discontinued from the study, but will continue to be followed for toxicity as 
described above. In this case, data may not be entered into the database but will be documented in 
the study log, and stored at the site.   
There may be a post-study care opportunity for study subjects who benefit from P1101 therapy. 
Further details will be provided as a separate protocol or amendment to this protocol at a later stage. 
15.2 Pharmacokinetic and Immunogenicity Evaluations 
Pharmacokinetic Evaluation 
• The PK samples will be collected for population PK analysis of P1101.  
• Serial PK samples (n=4 per subject) will be collected at Week 0 and Week 28, at the following 
time points: pre-dose (0 hr), 48 (±24) hr, 96 (±24) hr, and 168 (±24) hr.  At Weeks 0 and 24, 
subjects must administer their P1101 dose in the clinic. 
• Trough PK samples will be collected at every visit. 
• The PK sampling schedule is provided in Appendix 2. The actual date and time of dose and PK 
sample collection must be recorded on the CRF. 
• All P1101 treated subjects will have their blood samples collected for the analysis of serum 
concentrations of P1101 according to the study flowchart (Appendix 1, Appendix 2). Population 
PK/PD models will be updated with the PK and PD data from Week 0 to Week 12 of the first 15 
subjects in the P1101 arm. 
• Detailed instructions will be provided in a laboratory manual and stored in the investigator site 
file. 
Immunogenicity Evaluation 
• The immunogenicity samples will be collected for anti-drug antibody assessment for P1101.  
• Blood samples will be collected from the subject confirmed positive for P1101 ADA at EoS visit 
every three months until ADAs return to baseline levels or up to 12 months. 
• The immunogenicity sampling schedule is provided in Appendix 3. The actual date and time of 
dose and immunogenicity sample collection must be recorded on the CRF. 
• All P1101 treated subjects will have their blood samples collected for the analysis of serum anti-
drug antibody against P1101 according to the study flowchart (Appendix 3).  
• Detailed instructions will be provided in a laboratory manual and stored in the investigator site 
file. 
15.3 Assessment of Efficacy 
15.3.1 
Efficacy Measurements and Time Points 
15.3.1.1 Primary Efficacy Measurements – Peripheral Blood Count Remission 
The primary efficacy endpoint is the phlebotomy-free complete hematologic responder rate (CHR) 
at month 9 and month 12.  
The phlebotomy-free responder rate is defined as the proportion of patients with complete 
hematologic response (CHR) and with no phlebotomies during the previous 3 months. 
A responder in sense of a primary endpoint is a patient who has met all of the following criteria at 
month 9 and month 12: 
- • Hematocrit <45% phlebotomy-free (absence of phlebotomy during the previous 3 months) 

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- • Platelet count ≤ 400 x 109/L, 
- • WBC count ≤ 10 x 109/L 
Scheduled hematological assessments will occur as indicated in Appendix 1. Samples for 
hematology assessments will be prepared using standard procedures. For the hematologic 
parameters of Hct, platelets and WBCs, central laboratory assessments at Weeks 0, 12, 24, 36, and 
52 will be used for determination of responder. Detailed specifications for hematology sample 
handling, shipping, and processing will be provided in a laboratory manual. 
15.3.1.2 Other Efficacy Measurements 
There will be disease response assessments at Weeks 0, 12, 24, 36, and 52 of treatment with P1101. 
During these times, changes in Hct, WBC, PLT, spleen size, molecular response from baseline, 
time to requiring no phlebotomy, numbers of phlebotomy required, time to response, duration of 
response maintenance, ratio of CHR rates of subjects with/without prior treatment with HU and 
Proportion of subjects without thrombotic events will be assessed. 
15.3.1.3 Genetic Assessment of JAK2 
Genetic assessments will consist of screening tests for PV diagnosis purposes and quantitative 
JAK2 measurements at screening, Weeks 0, 12, 24, 36 and 52 (central laboratory). Change of JAK2 
allelic burden over time will be assessed (by ELN 2013 criteria; (Barosi et al. 2013) ). 
Whole blood samples, collected from all subjects prior to study drug administration, will be 
centrally assessed. Detailed instructions for sample handling, labeling, and storage will be provided 
in the laboratory manual.  
Handling of samples for JAK2 mutation assessment and disclosure of assay results to subjects are 
as follows. 
- Storage period, storage method and disposal of samples 
DNA samples are extracted from whole blood at a central laboratory and stored in a locked 
and manageable refrigerator. 
The DNA samples are handed over to the company handing industrial waste as industrial 
wastes 6 months after the end of the determination. 
- Volume of blood samples collected 
Three mL of whole blood is collected from vein at each sampling 
- Disclosure plan of genetic test results to subjects and the reason 
The genetic test results will be disclosed to the subject or the subject's legally acceptable 
representative, only if the subject or the subject's legally acceptable representative desire to 
know the results. 
- Handling of blood samples if the consent is withdrawn the use of blood samples during the 
study 
If a subject withdraws consent to the genetic mutation test during the study period, the 
genetic test will be discontinued, and the sample will be discarded.  
15.3.1.4 Spleen Size Assessment 
Spleen size will be measured by ultrasound. The captured images are recorded and assessed, 
according to the clinic’s routine criteria. Detailed instructions for procedures will be provided in 
the laboratory manual. 
15.3.1.5 Hospital Anxiety and Depression Scale (HADS) 

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The Hospital Anxiety and Depression Scale (HADS) will be used. HADS is a self-report 
questionnaire commonly used by doctors and therapists to assess levels of anxiety and depression 
in patients. The HADS comprises 14 statements which the patient rates based on their experience 
over the past week. Each question has 4 possible responses. Responses are scored on a scale from 
3 to 0. The maximum score is 21 for depression and 21 for anxiety. A score of 11 or higher indicates 
the probable presence of mood disorder, with a score of 8 to 10 being just suggestive of the 
presence of the respective state. The HADS is divided into four ranges: normal (0-7), mild (8-10), 
moderate (11-15) and severe (16-21) (Snaith 2003). HADS was found to perform well in assessing 
the symptom severity and identifying cases of anxiety disorders and depression in both somatic, 
psychiatric and primary care patients and in the general population (Bjelland et al. 2002). HADS 
is being used and confirmed to be a valid tool for assessment of psychiatric side effects of 
interferon alpha (Kraus et al. 2005). Furthermore, the HADS can be administered by non-
psychiatrist physicians (Olsson, Mykletun, and Dahl 2005). For HADS see Appendix 8. 
15.3.2 
Assessment of Safety 
Assessment of safety will be determined by vital signs, clinical laboratory tests, physical 
examinations, ECGs, heart ECHOs, lung X-rays, ECOG performance status, ocular examinations, 
and AEs. 
15.3.3 
Subject Demographics and Medical History 
Demographic information (e.g., age, sex, race) will be recorded at screening in the appropriate 
eCRF. Relevant medical history, including history of prior and current disease(s), and information 
regarding underlying diseases will also be recorded at screening. Included will be the usage of any 
and all drugs used to treat PV. 
At screening, in-depth medical history data will be collected, including thrombosis/hemorrhage 
history, JAK2 mutation status, acquired von Willebrand disease in the past, presence of 
progressive/symptomatic splenomegaly, symptomatic thrombocytosis, progressive leukocytosis, 
progressive disease-related symptoms, and vasomotor/microvascular disturbances not responsive 
to aspirin. 
15.3.4 
Physical Examination 
Information about the physical examination must be present in the source documentation at the 
study site. The physical examination will include general status, lungs, cardiovascular system, 
abdomen, musculoskeletal system, skin, lymph nodes, and central nervous system. Any significant 
findings associated with clinical signs or symptoms, or requiring therapy before the screening visit 
should be recorded. Clinically significant findings made after the start of the study drug that meet 
the definition of an AE must be recorded as AEs. 
15.3.5 
Vital Signs 
Body temperature, blood pressure, and pulse rate will be measured after resting in a supine position 
for 5 minutes at all visits. 
15.3.6 
Electrocardiograms 
In accordance with the study flowchart (Appendix 1), standard 12-lead ECGs will be performed at 
screening, and prior to study drug administration (0 hr) at Weeks 0, 2, 4, 12, 24, 28, 36, and 52 , 
as well as at early withdrawal and the safety follow-up visit. At Weeks 0 and 28, an additional 
ECG assessment will be performed at 96 (±24) hr after study drug administration. The ECG should 
be performed following the subject is in a supine position for 5 minutes and prior to the collection 
of any PK samples. 
The QT/QTcF interval will be determined from at least 3 to 5 cardiac cycles (heart beats). 
Any abnormal findings assessed by the Investigator as clinically significant should be recorded in 
the relevant eCRF modules (e.g., AE, medical history). 

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15.3.7 
Bone Marrow Assessment 
Bone marrow sampling is optional. However, if bone marrow is collected, the following process 
will be followed. The bone marrow samples should be centrally assessed. Two bone marrow 
samplings (one at the first study drug dose [Week 0] and one at Week 52) will be taken and sent 
for central evaluation. 
The definition of bone marrow histological remission is disappearance of hypercellularity, 
trilineage growth (panmyelosis) and absence of > grade 1 reticulin fibrosis. 
15.3.8 
Ocular Examination 
All subjects will have an ocular examination at screening and at the EoT visit. The examination 
will consist of visual acuity assessment, slit lamp examination, tonometry, and fundus examination. 
Clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension) at 
screening will be an exclusion criterion. In addition to scheduled examinations, an ophthalmologist 
consultation is mandatory for all subjects reporting worsening vision or visual symptoms. P1101 
treatment will be discontinued in subjects who develop a new ophthalmologic disorder during the 
study. 
15.3.9 
Lung X-Ray and Heart ECHO 
All subjects will have a lung X-ray and heart ECHO at screening and at the EoT visit. For screening, 
lung X-rays will be accepted which are not older than 12 weeks prior to the date of screening visit. 
In case of premature discontinuation, no X-ray examination (but the heart ECHO only) will be 
performed (to reduce the burden from exposure to radiation) unless necessary for safety follow-up 
purposes.  
Subjects with clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening 
will not be eligible for the study. In cases of persistent or unexplained pulmonary infiltrates or 
pulmonary function impairment, treatment will be discontinued as a precautionary measure if 
deemed necessary in the judgement of the Investigator or sponsor. 
15.3.10 ECOG Performance Status 
The ECOG Performance Status are scales and criteria used by doctors and researchers to assess 
how a subject's disease is progressing, assess how the disease affects the daily living abilities of 
the subject, and determine appropriate treatment and prognosis.  
The performance status will be assessed according to the ECOG performance status scale as noted 
in Appendix 4. The ECOG performance status is graded on a 6-point scale (range 0 to 5): 
0=Asymptomatic (fully active, able to carry on all pre-disease activities without restriction); 
1=Symptomatic but completely ambulatory (restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office 
work); 2=Symptomatic, <50% in bed during the day (ambulatory and capable of all self-care but 
unable to carry out any work activities. Up and about more than 50% of waking hours); 
3=Symptomatic, >50% in bed, but not bedbound (capable of only limited self-care, confined to 
bed or chair 50% or more of waking hours); 4=Bedbound (completely disabled, cannot carry on 
any self-care, totally confined to bed or chair); and 5=Death. 
In accordance with the study flowchart (Appendix 1), the ECOG will be performed at screening, 
and Weeks 0, 12, 24, 36, and 52 following first study drug administration, as well as at early 
withdrawal/EoT and the safety follow-up visit. 
15.3.11 Adverse Events 
Information regarding occurrence of AEs will be captured throughout the study. Duration (start 
and stop dates and times), seriousness, severity/grade, outcome, concomitant medication use, 
action taken, and relation to study drug will be recorded in the eCRF. For more information on 
safety reporting, see Section 16. 

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15.3.12 Laboratory Evaluations 
Table 15-1 presents the list of clinical laboratory measurements that will be performed. A local 
laboratory will be used for analysis of all specimens. Hematology specimens for baseline (Visit 1) 
and Months 3, 6, 9, and 12 will also be evaluated by the central laboratory. Details on the collection, 
shipment of samples, and reporting of results will be provided to Investigators in the laboratory 
manual. For the schedule of the laboratory assessments, refer to Appendix 1, Appendix 2 and 
Appendix 3. 
 
Table 15-1  Clinical Laboratory Measurements 
Hematology Panel 
Blood Chemistry Panel 
Others 
HGB 
HCT 
Red blood cell (RBC) count 
Platelet count 
White blood cell (WBC) count 
WBC differential 
(neutrophils, lymphocytes, 
monocytes, eosinophils, 
basophils and reticulocytes) 
MCV 
ALT, AST 
Gamma-glutamyl transferase 
(GGT) 
NT-proBNP or BNP 
Alkaline phosphatase (ALP) 
Amylase 
Lipase 
Total bilirubin 
Albumin  
Total protein 
Electrolytes (Potassium, Sodium, 
Calcium, Chloride) 
Lactate dehydrogenase (LDH) 
Blood urea nitrogen (BUN)  
Creatinine 
 
Glucose  
Iron 
Transferrin 
Thyroid stimulating hormone 
(TSH), FT4 
Uric acid 
Low-density lipoprotein (LDL) 
High-density lipoprotein (HDL) 
Total cholesterol 
Triglycerides 
Coagulation tests: PT-INR, aPTT, 
Fibrinogen 
Urinalysis (pH, blood, protein, 
glucose, WBC, nitrite) 
Urine beta 2 microglobulin 
Pregnancy test (urine)  
Serology: HBsAg, HCV antibody, 
HIV antibody 
Autoimmune markers: Antinuclear 
antibodies, TgAb, TPOAb 
Genetic test: JAK-2 
 
Increases in liver enzyme levels in blood serum have been observed in subjects treated with 
pegylated IFNs. Therefore, liver enzyme levels (ALT, AST, and GGT) and total bilirubin will be 
measured at screening and subsequently, every 2 weeks in the treatment period of the trial, as well 
as at early withdrawal/EoT and the safety follow-up visit (if applicable). If the increase of liver 
enzyme levels is progressive and clinically significant, despite dose reduction, or is accompanied 
by increased total bilirubin, the subject will be withdrawn from the study.  
Immunogenicity assessment of anti-P1101 antibodies (anti-drug antibodies; ADA) will be 
measured before the first dose (Week 0), 7 days (168 (±24) hr) after the initial P1101 dose, Week 
4, 12, 24, 36, and at End of Treatment (EoT; Week 52), and at the EoS/Follow-up visit (28 days 
after the final P1101 drug administration at the EoT visit). Presence of anti-PEG antibodies will 
be measured. A multi-tiered ADA testing approach will include assays for the following: anti-
P1101 binding antibodies and a confirmatory assay, antibody titers, and P1101 neutralizing 
antibodies. Blood samples will be collected from the subject confirmed positive for P1101 ADA 
at EoS visit every three months (Week 64, 76, and 88) until ADAs return to baseline levels or up 
to 12 months (Week 104). (Appendix 3) 
15.4 Appropriateness of Measurements 
Platelets and WBCs at baseline (Visit 1), Months 3, 6, 9, and 12 will be evaluated by a central 
laboratory.  

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Quantitative JAK2 allelic burden measurements will be also done by a central laboratory, every 3 
months including baseline (Visit 1; Day 0). 
16 SAFETY REPORTING 
Clinical events occurring before starting study treatment but after signing the informed consent are 
recorded on the Medical History/Current Medical Conditions eCRF page. 
16.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. All AEs occurring during the course of the clinical trial (i.e., from signing the 
informed consent form onwards through the treatment phase until the safety follow-up visit) will 
be collected, documented, and reported by the Investigator. Details on AE collection will be 
available in the eCRF collection guideline. 
All AEs, serious and non-serious, will be fully documented on the appropriate eCRFs. For each 
AE, the Investigator will provide the onset, end, intensity, treatment required, outcome, seriousness, 
and action taken with the study drug. The Investigator will determine the relationship of the 
investigational drug to all AEs and record it in the eCRF. When assessing whether an AE is 
causally related to the study drug, the Investigator should consult the IB and use his/her clinical 
judgement and the subject’s underlying disease before rendering an assessment. 
All collected AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA). AEs and laboratory parameters will be graded according to CTCAE Version 5.0, 
(http://ctep.cancer.gov). 
Adverse event monitoring should be continued until the safety follow-up visit/EoS or until AE 
resolution/stabilization, whichever occurs first. Safety follow-up visit is 28 days after end of 
treatment visit. AEs will be regarded as treatment-emergent if the time of onset or worsening is 
after or on the first intake of study drug. 
Disease progression of PV should not be regarded or reported as an AE unless it is associated with 
a separate AE. Relationship will be assessed with not related, unlikely related, possibly related, 
probably and definitely related. Action taken will be described as dose increased, dose not changed, 
dose reduced, drug interrupted, drug withdrawn, and unknown.  
16.2 Abnormal Clinical Laboratory Test Results 
All clinically significant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline or to a level deemed acceptable by the 
Investigator and the Sponsor’s clinical monitor (or his/her designated representative), or until the 
abnormality is explained by an appropriate diagnosis. Clinically significant abnormal laboratory 
tests that result in a change in study drug dosage, discontinuation of the drug, or require 
intervention or diagnostic evaluation to assess the risk to the subject, or are otherwise clinically 
relevant, should be recorded as AEs in the eCRF. Clinical diagnosis should be provided whenever 
possible. If no clinical diagnosis is available, the increase/decrease in the laboratory parameter may 
be recorded as an AE term. When an abnormal laboratory or test result corresponds to a 
sign/symptom of an already reported AE, it is not necessary to separately record the laboratory/test 
result as an additional event. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs. 
A Grade 3 or 4 event (severe), as per CTCAE, does not automatically indicate an SAE unless it 
meets the definition of serious as defined in the protocol and/or as per Investigator’s discretion. A 
dose modification or medication for the laboratory abnormality may be required by the protocol in 
Section 12.5.2 and should not contribute to the designation of a laboratory parameter abnormality 
as an SAE. 
16.3 Abnormal Physical Examination Findings 

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Clinically significant changes, in the judgment of the Investigator, in physical examination 
findings (abnormalities) will be recorded as AEs and followed up until resolved or considered 
stable. Physical examination AEs should be followed up and reported in the same way as for the 
laboratory findings. Clinical diagnosis should be provided whenever possible. If no clinical 
diagnosis is available, the finding may be recorded as an AE term. 
16.4 Pregnancy 
In female subjects of childbearing potential, as well as all women <2 years after the onset of 
menopause, appropriate contraceptive measures are mandatory during the study (e.g., barrier 
method such as condoms or diaphragms; intrauterine devices; surgical methods; contraceptives of 
hormone preparations alone or in combination; or sexual abstinence). 
Male subjects will use an appropriate method of contraception, such as vasectomy (confirmed to 
be azoospermia) or condom use. 
In this study, contraception is required from the start of the study to 28 days after the last dose of 
the investigational product, regardless of gender. 
Pregnancy itself is not an AE, but pregnancy-related AEs should be captured for study subjects 
and female partners of male study subjects who may become pregnant during the study. 
Pregnancies should be reported and followed up within the timelines specified for SAEs. Relevant 
risk factors as well as outcome should be recorded. Subjects should be advised to discontinue study 
treatment at the first suspicion of pregnancy. 
16.5 Adverse Events of Special Interest 
According to the Council for International Organizations of Medical Sciences (CIOMS VI) 
definition, an AESI is one of scientific and medical concern specific to the Sponsor’s product or 
program, for which ongoing monitoring and rapid communication by the Investigator to the 
Sponsor can be appropriate. Such an event (serious or non-serious) might warrant further 
investigation in order to characterize and understand it.  
Such events should be reported within the timelines and according to the procedures defined for 
SAEs. 
Protocol-specific AESIs, e.g., psychiatric AEs, will be described in the statistical analysis plan 
(SAP). For cardiovascular disease-related AESIs, the diagnostic criteria are pre-specified in 
Appendix 5 of this protocol with conditions to ensure adherence to the diagnostic criteria standards 
across all centers in the study.  
16.6 Serious Adverse Events 
Information about all SAEs will be collected and recorded on the AE eCRF page. To ensure subject 
safety, each SAE must also be reported to the Sponsor within 24 hours of learning of its occurrence. 
All SAE will be followed until resolution or up to 30 days following the last infusion / last dose of 
study drug. An SAE is defined in general as an untoward (unfavorable) event that is serious and 
has the following outcome(s): 
- Death 
- Life-threatening: The study subject’s life was in an immediate danger due to the event. 
- Hospitalization: The study subject had to be hospitalized due to the event. 
- Prolongation of hospitalization: The existing hospital stay had to be prolonged due to the 
event. 
- Persistent/significant disability/incapacity: The event resulted in persistent/ significant 
disability/incapacity having caused long-term changes (either anatomical, physiological, or 
psychic) affecting the study subject’s life. 
- Congenital anomaly/birth defect: Any abnormalities in features or functions of the offspring 
of the study subject who has been exposed to study drug treatment during pregnancy. 

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- Important medical event: The event is considered medically significant, but none of the above 
categories are applicable (e.g., the study subject required medical intervention to prevent the 
event to become life-threatening). Important medical events are those which may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed above. 
Hospitalizations occurring under the following circumstances are not considered SAEs: admission 
to a hospice for respite care; hospitalizations planned before entry into the clinical study; 
hospitalization for elective treatment of a condition unrelated to the studied indication or its 
treatment; hospitalization on an emergency, out-subject basis that does not result in admission 
(unless fulfilling the criteria above); hospitalization as a part of the normal treatment or monitoring 
of the studied indication; and hospitalization not associated with any deterioration in condition. 
16.7 Instructions for Expedited Notification of Serious Adverse Events 
16.7.1 
Reporting Responsibility 
Any SAE occurring in a subject after providing informed consent and until completion of the last 
visit for subjects, e.g., completing EoS form must be reported to the sponsor. The period after 
discontinuing study drug may be extended if there is a strong suspicion that the drug has not yet 
been eliminated. All SAEs must also be reported for the period in which the study protocol 
interferes with the standard medical treatment given to a subject. 
Each SAE must be reported by the Investigator to the Sponsor within 24 hours of learning of its 
occurrence, even if it is not considered to be treatment-related. Follow-up information about a 
previously reported SAE must also be reported to the Safety Desk within 24 hours of receiving it. 
The Safety Desk may contact the Investigator to obtain further information on a reported SAE. If 
warranted, an Investigator alert may be issued, to inform all Investigators involved in any study 
with the same drug that this SAE has been reported. 
16.7.2 
Reporting Procedures 
If the investigator becomes aware of a serious adverse event or malfunction of device, the 
investigator must report it to the point of contact described in “4) Contact Information for serious 
adverse event” in the Attachment 1 of the protocol by telephone, fax or e-mail, etc. within 24 hours. 
If additional information such as follow-up information is collected, it should be reported 
immediately to the sponsor. All the reports will be filed in the Trial Master File.  
 
17 STATISTICAL ANALYSIS 
17.1 General Consideration 
Categorical variables will be summarized using frequency counts and percentages. Percentages 
will be presented to 1 decimal point, unless otherwise specified. Continuous variables will be 
summarized by total number (n), mean, standard deviation, median, minimum, and maximum. 
17.2 Sample Size Estimation 
Sample size is calculated, based on the following assumptions; 
- The target population of the Japanese local study: Japanese PV patients for whom the current 
standard of treatment is difficult to apply. 
- Study design: P1101 single arm no controlled study (previous proposal was designed as a 
historical control study using PROUD-PV study). 
- Primary study objective: To evaluate the safety and efficacy of P1101 for Japanese PV 
patients for whom the current standard of treatment is difficult to apply. 
- Primary efficacy variable: Complete Hematological Response (CHR) 

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- Study period and evaluation visits: 3 month, 6 month, 9 month and 12 months. The safety 
follow-up will be continued to 12 months and the major efficacy data will be obtained at 12 
months. 
- The primary analysis of the primary endpoint: The lower limit of the 95% confidence interval 
of CHR rate is greater than 11%, and also the slope of the linear regression model of the CHR 
rate time course is greater than 0 (positive trend):  
- The rationale: the natural healing rate (placebo response) of CHR rate of PV patients is 0%, 
thus if the lower limit of 95% confidence interval of the CHR rate exceed 11%, the efficacy 
of P1101 can be confirmed. The rationale to set the CHR rate limit as 11% is, (1) 11% is the 
minimum CHR rate value of P1101 obtained in the PROUD-PV study, (2) and the trend of 
the CHR rate is positive, thus 11% can be considered as a limit of the acceptable clinical risks. 
- Assuming the above conditions, the power of the study at 9 months will be about 85% with 
25 cases (CHR rate of the PROUD-PV study at 3, 6, 9, and 12 months are 11%, 27%, 36% 
and 43%, respectively). Considering the uncertainty of maximum 5 patients who are different 
background from PROUD-PV, a total of 30 cases will be reasonable to evaluate both efficacy 
and safety. 
17.3 Populations for Analysis 
17.3.1 
Enrolled Population 
The enrolled population will include subjects who signed informed consent form.  
17.3.2 
Intent-to-Treat (ITT) Population 
The intent-to-treat (ITT) population will include all treated subjects. Analysis based on ITT 
population will be based on the treatment to which they are treated.  
17.3.3 
Per Protocol Population (PPP) 
The PPP will consist of subjects included in the ITT who are exposed to treatment and have all 
measurements needed for assessment of the primary endpoint for at least 1 post-baseline visit, and 
do not have a major protocol deviation.  
17.3.4 
Protocol Deviations 
The following are considered potential protocol deviations: 
- No diagnosis of PV. 
- Prior therapy does not match with protocol requirements in terms of types of previous therapy 
regimens. 
- No baseline spleen size measurement in the protocol-specified time windows. 
- Subjects who take <80% of the prescribed dose over the total duration of study drug dosing 
as calculated by the Sponsor based on the drug accountability documented by the site staff 
and monitored by the Sponsor/designee. 
Other observations made during the study will also be considered. All potential protocol deviations 
will be reviewed prior to any interim analysis or database lock. For every potential protocol 
deviation, a general decision will be made whether to regard it as major or minor, and approved 
by the Sponsor before database lock. The PPP will be used for efficacy sensitivity analysis. 
17.3.5 
Safety Population 
The Safety Population will include all subjects who have received at least one dose of study drug. 
For analysis, it will assign subjects to the treatment actually received. 
17.4 Efficacy Endpoints Analysis 

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17.4.1 
Primary Efficacy Endpoint Analysis 
This study will enroll 30 Japanese PV subjects and collect laboratory and clinical data on each 
subject every 3 months after baseline through 12 months. Primary endpoint analysis will be based 
on all the evaluable subjects. For each subject at each time point of 3 months, response will be 
assessed. 
The primary efficacy endpoint is the phlebotomy-free complete hematologic responder rate (CHR) 
at month 9 and month 12.  
The phlebotomy-free responder rate is defined as the proportion of patients with complete 
hematologic response (CHR) and with no phlebotomies during the previous 3 months. 
A responder in sense of a primary endpoint is a patient who has met all of the following criteria at 
month 9 and month 12: 
- Hematocrit <45% phlebotomy-free (absence of phlebotomy during the previous 3 months) 
- Platelet count ≤400 x 109/L, 
- WBC count ≤10 x 109/L,  
17.4.2 
Secondary Efficacy Endpoints Analyses 
The secondary efficacy endpoints are for providing additional supportive evidence of efficacy of 
the treatment.  
- Changes in Hct, WBC, PLT and spleen size from baseline 
- Time to requiring no phlebotomy  
- Numbers of phlebotomy 
- Time to first peripheral blood count response: Cox regression will be performed with 
treatment, age and baseline factors as the covariates. 
- Duration of peripheral blood count response maintenance: Only subjects with response will 
be included. Mean duration of response will be compared between the two arms using 
appropriate parametric t-test or non-parametric rank-based test. 
- Change from baseline of JAK2 allelic burden over time: Longitudinal evaluation using 
repeated measures will be performed. 
- Spleen size measurements by sonography will be summarized by scheduled time points, as 
appropriate. 
- Difference in CHR rate between subject with or without of treatment with HU 
- Proportion of subjects without thrombotic or hemorrhagic events 
Frequencies of disease-related symptoms will be presented in frequency table and compared 
between treatment arms using chi-square test (or logistic regression with the same factors as used 
in the primary endpoint analysis). 
Additional analyses to those proposed below that may be performed after the completion of the 
clinical study report (CSR) will be documented in separate reports. These analyses may include 
but are not limited to the meta-analysis of data from this study combined with data from other 
studies, or the analysis of biomarkers generated from samples collected during the study but 
analyzed after database lock and completion of the CSR. In addition, the relationship between 
biomarker endpoints and safety and efficacy endpoints may be explored. Such data analysis will 
be described in the SAP.  
17.5 Exploratory Analysis 
The exploratory analysis consists of bone marrow histological remission. Bone marrow 
histological remission defined as the disappearance of hypercellularity, trilineage growth 
(panmyelosis) and absence of >grade 1 reticulin fibrosis (optional).  

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17.6 PPK, E-R, and Immunogenicity Endpoints Analyses  
• PPK Analysis 
• PK analyses will be performed using the PPK approach and summarized in a separate report 
where PK parameters, including but not limited to AUC, Cmax, Tmax, and half-life, will be 
summarized with mean, median, SD, and 95% confidence intervals. The effects of covariates on 
the PK of P1101 will be investigated. 
• E-R Analysis 
• The relationship between exposure and key efficacy and safety endpoints will be explored using 
E-R analysis. The effects of covariates on E-R will be investigated. 
• Immunogenicity Analysis 
• The proportion of subjects who are positive or negative to anti-P1101 antibody will be 
summarized. 
17.7 Safety Endpoints Analysis 
Safety data, including ECOG performance status, vital signs, ECGs, heart ECHOs, clinical 
laboratory tests, physical examinations, lung X-rays, AEs, and ocular examinations, will be 
summarized by treatment arms and scheduled visits, as appropriate. Change from baseline will be 
included in summary tables for laboratory, ECG, and vital sign parameters. AEs will be coded by 
MedDRA and then summarized by system organ class and preferred term for each treatment.  
17.8 Handling of Missing Data  
Missing data will not be imputed, unless otherwise specified. See details in the SAP on the general 
issue of handling intercurrent events and sensitivity analysis for the primary endpoint. 
 
18 ETHICAL AND REGULATORY ASPECTS 
18.1 Ethics and Good Clinical Practice 
This study will be conducted in accordance with the ethical principles laid down in the Declaration 
of Helsinki. The study protocol and any subsequent amendment(s) will be submitted for approval 
to an Institutional Review Board (IRB). The study will be conducted in compliance with the 
protocol, Good Clinical Practice (GCP) regulations and applicable regulatory requirements. The 
regulatory application or submission for regulatory approval will be made by the Sponsor or its 
delegate as required by national law.  
18.2 Institutional Review Board 
Before implementing this study, the proposed informed consent, and other information given to 
subjects must be reviewed by an IRB, and a signed/subscribed and dated statement that the 
informed consent have been approved by the IRB must be given to Sponsor before study initiation. 
The IRB membership roster must be provided to the Sponsor. The IRB will review any 
amendments to the protocol that require formal review and approval. The IRB may be notified for 
all other amendments (i.e., administrative changes) in accordance with applicable regulatory 
requirements. 
18.3 Subject Information and Informed Consent 
The Investigator (or a properly trained specialty physician, allocated with this task by the 
Investigator), should obtain a freely given written consent from each subject after an appropriate 
explanation of the aims, methods, anticipated benefits, potential hazards and any other aspect of 
the study that is relevant to the subject's decision to participate. The informed consent form must 
be signed, with name and date noted by the subject or their legally authorized representative, if 
applicable, before the subject is exposed to any study-related procedures, including screening tests 
for eligibility.  

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The Investigator will explain that the subject is completely free to refuse to enter the study or to 
withdraw from the study at any time, without any consequences to their current or future care and 
without the need to justify their decision.  
Each subject will be informed that his/her source records may be reviewed by the study monitor, 
IRB, or a regulatory authority inspector, in accordance with applicable regulations, and that these 
persons are bound by confidentiality obligations. 
18.4 Confidentiality 
The Investigator will ensure that the confidentiality of the subjects' data will be preserved. In the 
eCRF or any other documents submitted to the Sponsor, the subjects will not be identified by their 
names, but by an identification system.  
The Investigator will maintain documents not meant for submission to the Sponsor, e.g., the 
confidential subject identification code and the signed informed consent forms, in strict confidence.  
Each subject will be informed that a monitor or a regulatory authority inspector, in accordance 
with applicable regulatory requirements, may review portions of their source records and source 
data related to the study. Data protection and confidentiality will be handled in compliance with 
applicable local, regional, and/or international requirements. 
 
19 QUALITY CONTROL AND QUALITY ASSURANCE 
19.1 Source Data and Records 
Source data are defined as all the information related to clinical findings, observations, or other 
activities in the study, added to the original records allowing reconstruction and evaluation of the 
study.  
The Investigator will maintain adequate source records (e.g., files for each enrolled subject). 
Source records should be preserved for the maximum period of time required by applicable 
regulations.  
All data entered in the eCRF must be supported by source data in the subjects’ records.  
The Investigator will permit trial-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s) by local and/or regional regulatory authorities, as applicable, by providing direct 
access to source data/records.  
The Investigator may authorize site staff (e.g., co-Investigators, nurses) to enter study data into the 
eCRF.  
19.2 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all trial-related source 
data/records, verify the adherence to the protocol and the completeness, correctness, and accuracy 
of all eCRF entries compared to source data. The Investigator will cooperate with the monitor to 
ensure that any discrepancies identified are resolved.  
The monitor must be given direct access to source documents (original documents, data, and 
records). Direct access includes permission to examine, analyze, verify, and reproduce any records 
and reports that are important to the evaluation of the trial. Source data will be available for all 
data in the eCRFs, including all laboratory results. Data, which will be continuously monitored 
during drug administration, will be entered into the eCRF periodically.  
19.3 Confidentiality of Subjects´ Data 
The Investigator will ensure that the subject's anonymity will be preserved. On eCRFs or any other 
documents submitted to the Sponsor, the subjects will not be identified by their names, but by a 
unique subject number. Documents that are not intended for submission to the Sponsor, i.e., the 
original consent forms and source records, will be maintained by the Investigator in strict 
confidence and in accordance with regulatory requirements. 

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20 DATA HANDLING AND RECORDKEEPING 
20.1 Responsibilities of Investigators 
The Investigator is accountable for the conduct of the trial at the site. If any responsibilities are 
delegated, the Investigator should maintain a list of appropriately qualified persons to whom he/she 
has delegated significant trial-related duties.  
20.2 Case Report Forms 
Electronic Case Report Forms (eCRF) are supplied by the CRO and should be handled in 
accordance with instructions from the Sponsor. Only the Sponsor approved version of the eCRF 
should be used for recording study data. 
The Investigator is responsible for maintaining adequate and accurate medical records from which 
accurate information is recorded to eCRFs, which have been designed to record all observations 
and other data pertinent to the clinical investigation. 
eCRFs should be completed by the Investigator or delegate as stated in the site delegation log for 
all subjects who have signed informed consent. 
The Investigator should complete the relevant eCRF pages as soon as possible after each visit 
observation or clinical laboratory test. 
All data sent to the Sponsor must be endorsed by the Investigator. 
The Study Monitor should verify the contents against the source data. If the data are unclear or 
contradictory, queries are sent for corrections or verification of data. 
20.3 Changes to Case Report Form Data 
Errors occurring in eCRFs will be modified by the Investigator or designee, and all changes will 
be tracked in the audit trail. 
20.4 Recording, Access, and Retention of Source Data and Study Documents 
Source data to be reviewed during this study will include, but is not limited to: subject's medical 
file, subject ID code list, subject diary cards, original laboratory reports, and histology and 
pathology reports, investigational medicinal product inventory, 12-lead ECG printouts and 
echocardiograph reports. 
All key data must be recorded in the subject's medical records. Original printouts of data that were 
generated by technical equipment, for example 12-lead ECG trace, must be labelled with the date 
that they were printed by the machine, and the subjects' unique identification number. The medical 
evaluation of such records should be documented as necessary and signed and dated. 
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB, and auditors to inspect facilities and records 
relevant to this study. 
The Study Monitor (and auditors, IRB or regulatory inspectors) may check the CRF entries against 
the source documents. The consent form includes a statement by which the subject agrees to the 
monitor/auditor from the Sponsor or its representatives, national or local regulatory authorities or 
the IRB having access to source data (e.g., subject's medical file, appointment books, original 
laboratory reports, X-rays etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the 
Pharmaceuticals Medical Devices Agency, Japan [PMDA], U.S. Food and Drug Administration 
[FDA], European Medicines Evaluation Agency [EMEA], UK Medicines and Healthcare products 
Regulatory Agency [MHRA]) or an auditor. 

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Essential documents must be maintained according to J-GCP requirements and may not be 
destroyed without written permission from the Sponsor. The Investigator is required to arrange 
within the study site, that designated essential documents will be retained for the period as 
specified in GCP and local regulatory requirements. The head of the study site will designate an 
archive manager for each type of record to ensure appropriate archiving. The Investigator will be 
provided with an Investigator Site File at the start of the study. This file contains all relevant 
documents necessary for the conduct of the study. This file must be safely archived after 
termination of the study. It is the responsibility of the Investigator or the Head of the Medical 
Institution to ensure that the subject identification sheets (records stipulated in GCP Ordinance, 
Article 41 Paragraphs 1 and 2) are stored for at least 15 years  (or 2 years after the last Marketing 
Authorization Application granted for the investigational medicinal product, whichever is longest) 
beyond the end of the clinical study. All original subject files must be stored for the longest possible 
time permitted by the regulations at the hospital, research institute, or practice in question. If 
archiving can no longer be maintained at the site, the Investigator will notify the Sponsor. 
 
21 CHANGES IN THE CONDUCT OF THE STUDY  
21.1 Protocol Amendments 
Any prospective change to the protocol will be submitted to the IRB and to the competent authority 
in every country, as required, and should be approved before its implementation.  
21.2 Premature Study Termination 
Both an Investigator and the Sponsor reserve the right to terminate the study at any time. If this 
becomes necessary, the procedures will be arranged on an individual study basis after review and 
consultation by both parties. In terminating the study, the Sponsor and the Investigator will ensure 
that adequate consideration is given to the protection of the subjects interests. Furthermore, the 
Investigator should promptly inform the IRB and provide a detailed written explanation that 
includes the reasons for study termination. The relevant regulatory authorities should be informed 
according to applicable regulatory requirements. 
21.3 Publication of Results 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor prior to submission. 
This allows the Sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the Investigator.  
In accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual center data. In this 
case, a coordinating investigator will be designated by mutual agreement. Any formal publication 
of the study in which input of the Sponsor’s personnel exceeded that of conventional monitoring 
will be considered as a joint publication by the Investigator and the appropriate Sponsor personnel. 
In general, the maximum number of authors allowed on any abstract/publication will be used. All 
screening investigators will be added to the main publication as a group.  
 
22 LIABILITIES AND INSURANCE 
In case of any damage or injury occurring to a subject in association with the trial medication or 
the participation in the study, PharmaEssentia Corporation, will maintain an insurance policy that 
meets local regulatory requirements. The Investigator is responsible for administering/dispensing 
the study drug according to this protocol, and for its secure storage and safe handling throughout 
the study.  
 
 

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23 REFERENCES 
 
Barbui, T., G. Barosi, G. Birgegard, F. Cervantes, G. Finazzi, M. Griesshammer, C. 
Harrison, H. C. Hasselbalch, R. Hehlmann, R. Hoffman, J. J. Kiladjian, N. Kroger, R. 
Mesa, M. F. McMullin, A. Pardanani, F. Passamonti, A. M. Vannucchi, A. Reiter, R. T. 
Silver, S. Verstovsek, and A. Tefferi. 2011. 'Philadelphia-negative classical 
myeloproliferative neoplasms: critical concepts and management recommendations from 
European LeukemiaNet', J Clin Oncol, 29: 761-70. 
Barosi, G., G. Birgegard, G. Finazzi, M. Griesshammer, C. Harrison, H. Hasselbalch, J. J. 
Kiladijan, E. Lengfelder, R. Mesa, M. F. Mc Mullin, F. Passamonti, J. T. Reilly, A. M. 
Vannucchi, and T. Barbui. 2010. 'A unified definition of clinical resistance and intolerance 
to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a 
European LeukemiaNet (ELN) consensus process', Br J Haematol, 148: 961-3. 
Barosi, G., R. Mesa, G. Finazzi, C. Harrison, J. J. Kiladjian, E. Lengfelder, M. F. 
McMullin, F. Passamonti, A. M. Vannucchi, C. Besses, H. Gisslinger, J. Samuelsson, S. 
Verstovsek, R. Hoffman, A. Pardanani, F. Cervantes, A. Tefferi, and T. Barbui. 2013. 
'Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN 
and IWG-MRT consensus project', Blood, 121: 4778-81. 
Bjelland, I., A. A. Dahl, T. T. Haug, and D. Neckelmann. 2002. 'The validity of the 
Hospital Anxiety and Depression Scale. An updated literature review', J Psychosom Res, 
52: 69-77. 
Choi, C. W., S. M. Bang, S. Jang, C. W. Jung, H. J. Kim, H. Y. Kim, S. J. Kim, Y. K. Kim, 
J. Park, and J. H. Won. 2015. 'Guidelines for the management of myeloproliferative 
neoplasms', Korean J Intern Med, 30: 771-88. 
EMA. 2015. "Jakavi-H-C-2464-II-0016-EPAR-Assessment-Report-Variation_en.". 
EMA. 2019. "Besremi : EPAR - Product information.". 
Griesshammer, M., H. Gisslinger, and R. Mesa. 2015. 'Current and future treatment 
options for polycythemia vera', Ann Hematol, 94: 901-10. 
Kraus, M. R., A. Schafer, H. Csef, and M. Scheurlen. 2005. 'Psychiatric side effects of 
pegylated interferon alfa-2b as compared to conventional interferon alfa-2b in patients 
with chronic hepatitis C', World J Gastroenterol, 11: 1769-74. 
Moulard, O., J. Mehta, J. Fryzek, R. Olivares, U. Iqbal, and R. A. Mesa. 2014. 
'Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the 
European Union', Eur J Haematol, 92: 289-97. 
Oken, M. M., R. H. Creech, D. C. Tormey, J. Horton, T. E. Davis, E. T. McFadden, and 
P. P. Carbone. 1982. 'Toxicity and response criteria of the Eastern Cooperative Oncology 
Group', Am J Clin Oncol, 5: 649-55. 
Olsson, I., A. Mykletun, and A. A. Dahl. 2005. 'The Hospital Anxiety and Depression 
Rating Scale: a cross-sectional study of psychometrics and case finding abilities in general 
practice', BMC Psychiatry, 5: 46. 
Snaith, R. P. 2003. 'The Hospital Anxiety And Depression Scale', Health Qual Life 
Outcomes, 1: 29. 

PharmaEssentia Japan 
 
Page 54 
Protocol P1101 in Japanese PV (A19-201) 
 
November 29th, 2019 
Stein, B. L., S. T. Oh, D. Berenzon, G. S. Hobbs, M. Kremyanskaya, R. K. Rampal, C. N. 
Abboud, K. Adler, M. L. Heaney, E. J. Jabbour, R. S. Komrokji, A. R. Moliterno, E. K. 
Ritchie, L. Rice, J. Mascarenhas, and R. Hoffman. 2015. 'Polycythemia Vera: An 
Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F', 
J Clin Oncol, 33: 3953-60. 
Tefferi, A., and T. Barbui. 2015. 'Essential Thrombocythemia and Polycythemia Vera: 
Focus on Clinical Practice', Mayo Clin Proc, 90: 1283-93. 
Tefferi, A., and A. Pardanani. 2015. 'Myeloproliferative Neoplasms: A Contemporary 
Review', JAMA Oncol, 1: 97-105. 
Titmarsh, G. J., A. S. Duncombe, M. F. McMullin, M. O'Rorke, R. Mesa, F. De Vocht, S. 
Horan, L. Fritschi, M. Clarke, and L. A. Anderson. 2014. 'How common are 
myeloproliferative neoplasms? A systematic review and meta-analysis', Am J Hematol, 
89: 581-7. 
Vannucchi, A. M. 2014. 'How I treat polycythemia vera', Blood, 124: 3212-20. 
Vannucchi, A. M., T. Barbui, F. Cervantes, C. Harrison, J. J. Kiladjian, N. Kroger, J. 
Thiele, 
and 
C. 
Buske. 
2015. 
'Philadelphia 
chromosome-negative 
chronic 
myeloproliferative neoplasms: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up', Ann Oncol, 26 Suppl 5: v85-99. 
Vannucchi, A. M., P. Guglielmelli, L. Pieri, E. Antonioli, and A. Bosi. 2009. 'Treatment 
options for essential thrombocythemia and polycythemia vera', Expert Rev Hematol, 2: 
41-55. 
 
 
 
 

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24 APPENDICES 
 
 

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24.1 Appendix 1. Study Flowchart 
 
 
 
 
Screening  
Treatment phase  
 
End of Treatment 
End of Study 
(Safety follow-up 
visit) 
every 2 weeks, except 
visits 
co-incident to the 
Assessment visits 
Assessment visits - every 12 
weeks (month 3, 6 and 9) 
Month 12 / Premature 
discontinuation visit 
28 days after the 
EoT visit 
Informed consent 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
Demographics & medical history 
X 
 
 
 
 
Pregnancy test (urine) 
X 
X (Every 4 weeks from 
Week 0) 
X 
X 
X 
Heart ECHO standard  
X 
 
 
X 
X  (cases with early 
termination only) 
12-lead ECG 
X 
Week 0, Week 0 +96 h 
Week 2, 
Week 4, 
Week 28, Week 28 + 96 h 
X 
X 
X 
Physical examination 
X 
X 
X 
X 
X 

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Protocol P1101 in Japanese PV (A19-201) 
 
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Vital signs 
X 
X 
X 
X 
X 
Blood chemistry small panel 
X 
X 
X 
X 
X 
Blood chemistry large panel 
X 
 
X 
X 
 
Coagulation (blood) 
X 
 
X 
X 
X 
Virology (blood) 
X 
 
 
 
 
Hemoglobin A1c HbA1c) 
X 
 
 
 
 
Hematology small panel 
X 
X 
X 
X 
X 
Hematology large panel 
X 
 
X 
X 
 
Immunological parameters (blood) 
X 
 
X 
X 
X 
Urine test 
X 
X 
X 
X 
X 
Urine beta 2 microglobulin test  
X 
 
 
X 
 
ECOG performance status 
X 
Week 0 only 
X 
X 
X 
Spleen size measurement 
X 
Week 0 only 
X 
X 
 
Genetic and mutation test sample (incl. 
JAK2 allelic burden) (blood) 
X 
Week 0 only 
X 
X 
 
Bone marrow sampling (OPTIONAL) 
X 
 
 
X 
 
P1101 administration 
 
X 
X 
 
 
Adverse events  
X 
X 
X 
X 
X 

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Protocol P1101 in Japanese PV (A19-201) 
 
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Concomitant treatment 
X 
X 
X 
X 
X 
Immunogenicity (blood) 
 
Week 0 and Week 4 
(Week 0: 0 hr. and 168 
hr.) 
(Week 4: 0 hr.) see 
Appendix 3 
X 
X 
X 
PK (blood) 
 
X (Trough value at every 
dosing) 
(4 sampling points per 
visit at Week 0 and Week 
28, see Appendix 2) 
 
X 
X 
X 
HADS 
X 
 
X 
X 
X 
Ocular examination 
X 
 
 
X 
 
Lung X-ray 
X 
 
 
X 
 

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Protocol P1101 in Japanese PV (A19-201) 
 
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Vital signs: 
Pulse rate, blood pressure and body temperature. 
Blood chemistry small panel: 
BUN, ALT, AST, GGT, LDH, total bilirubin.  
Blood chemistry large panel: 
NT-proBNP or BNP, Na+, K+, Ca++, Cl-, uric acid, blood glucose, alkaline phosphatase, amylase, lipase, creatinine, total protein, 
albumin, LDL, HDL, cholesterol, triglycerides, serum iron, transferrin, TSH and fT4. 
Coagulation (Blood): 
PT-INR, aPTT and fibrinogen. 
Virology: 
Serology: HBsAg, HCV antibody, HIV antibody 
Hematology small panel: 
Hemoglobin, hematocrit, platelet count, RBC, WBC. 
Hematology large panel: 
WBC differential (neutrophils, lymphocytes, monocytes, eosinophils, basophils and reticulocytes), MCV  
Immunological parameters: 
ANA, TgAb (autoantibodies to thyroglobulin), TPOAb (autoantibodies to thyroid peroxidase). 
Urinalysis: 
pH, blood, protein, glucose, WBC, nitrite 
Spleen size measurement:  
ultrasound 
Lung X-ray: 
For screening, X-rays will be accepted which are not older than 12 weeks prior to the date of screening visit. In case of premature 
discontinuation, no X-ray examination will be performed (to reduce the burden from exposure to radiation) unless necessary for 
safety follow-up purposes. 
Necessity of Lab examination at Week 0: Week 0 tests can be omitted if the difference in the dates between screening and Week 0 is 7 days or less. 
 

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Protocol P1101 in Japanese PV (A19-201) 
 
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24.2 Appendix 2. Pharmacokinetic Sampling Schedule 
Scheme 
PK Sample Collection Times Relative to 
Dosing a 
Sample 
Window 
Visit 1 
(Week 0) 
Visit 15 
(Week 28) 
4 
(4 samples 
per visit) 
1 
0 
0 
2 
48 (± 24) 
48 (± 24) 
3 
96 (± 24) 
96 (± 24) 
4 
168 (± 24) 
168 (± 24) 
aSince dosing is every 2 weeks, Day 1/Week 0 is the dosing day (first day of the dosing interval) and the trough sample will be 
collected before dosing. Trough samples will be collected at every visit, and ANY dose amount change thereafter. 
  
24.3 Appendix 3. Immunogenecity Sampling  
Scheme 
Immunogenecity Sample Collection Times Relative to Dosinga 
Visit 1 
(Week 
0) 
Visit 3 
(Week 
4) 
Visit 7 
(Week 
12) 
Visit 13 
(Week 
24) 
Visit 19 
(Week 
36) 
Visit 27 
(Week 
52) 
EoS 
(Week 
56) 
Week 
64, 76, 
88, 
and 
104a 
 
0 
0 
0 
0 
0 
0 
0 
0 
 
168 
(± 24) 
 
 
 
 
 
 
 
aImmunogenicity assessment of anti-P1101 antibodies (anti-drug antibodies; ADA) will be measured at before the first dose (Week 
0), 7 days (168 (±24) hr) after the initial P1101 dose, Week 4, 12, 24, 36, and at End of Treatment (EoT; Week 52), and at the 
EoS/Follow-up visit (28 days after the final P1101 drug administration at the EoT visit). Blood samples will be collected from the 
subject confirmed positive for P1101 ADA at EoS visit every three months until ADAs return to baseline levels or up to 12 months. 
 
24.4 Appendix 4. ECOG Performance Status 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: (Oken et al. 1982) 
 
 

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24.5 Appendix 5. Diagnosis of the PV-Related Cardiovascular Complications as Adverse 
Events of Special Interest  
 
These criteria are to be used for the diagnosis of cardiovascular PV-related events as AEs of special 
interest (as per Section 16.5). 
ARTERIAL 
 
Event  
Definition/Diagnostic findings  
Stroke  
A new focal neurologic deficit of presumed 
vascular origin which persists for >24 hours or 
results in death within 24 hours.  
Diagnostic are the following procedures: CT, 
magnetic 
resonance 
imaging 
(MRI), 
angiography, and transcranial Doppler.  
Cerebrovascular event such as a major transient 
ischemic attack  
Cerebral circulatory disturbance caused by the 
changes in the blood supply to a particular area 
of the brain resulting in transient neurologic 
dysfunction that persists, by definition, for >60 
min and <24 hours.  
Diagnostic is a neurological examination.  
Myocardial infarction  
Comprising non-ST-segment elevation MIs 
identified by blood tests and typical MIs with 
additional ECG changes such as ST-segment 
elevation.  
Unstable Angina  
Acute 
coronary 
syndromes 
(including 
Prinzmetal's angina) which have to be treated as 
an emergency.  
Acute peripheral arterial occlusive diseases  
Acute limb ischemia confirmed by, e.g., ankle-
brachial index, color duplex sonography, and 
digital subtraction angiography. Severity of the 
event 
requires 
either 
immediate 
surgical 
intervention or interventional revascularization.  
Other major arterial events  
Arterial events other than the events mentioned 
above, which led to hospitalization, were 
permanently disabling or life-threatening.  
VENOUS  
Pulmonary infarction (pulmonary embolism)  
Confirmed by plasma D-dimer measurement, 
lower limb compression ultrasound, V/Q lung 
scintigraphy, 
spiral 
CT 
and 
pulmonary 
angiography.  
Splanchnic 
vein 
thrombosis 
(mesenteric 
infarction)  
Confirmed by CT scan, MRI, and/or duplex 
ultrasonography of the visceral system.  
Portal  
Confirmed 
by 
Doppler 
ultrasonography, 
magnetic resonance  
 
 
 

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24.6 Appendix 6. HU resistance and intolerance criteria according to ELN (Barosi et al. 
2010). 
1. Need for phlebotomy to keep haematocrit <45% after 3 months of at least 2 g/day of 
Hydroxycarbamide, OR 
2. Uncontrolled myeloproliferation, i.e. platelet count >400 G/L AND white blood cell count 
>10G/L after 3 months of at least 2 g/day of Hydroxycarbamide, OR 
3. Failure to reduce massive* splenomegaly by more than 50% as measured by palpation, OR 
failure to completely relieve symptoms related to splenomegaly, after 3 months of at least 
2 g/day of Hydroxycarbamide, OR 
4. Absolute neutrophil count <1 G/LOR platelet count <100G/L or haemoglobin <100 g/l at 
the lowest dose of Hydroxycarbamide required to achieve a complete or partial clinico-
haematological response, OR 
5. Presence of leg ulcers or other unacceptable Hydroxycarbamide-related non-
haematological toxicities, such as mucocutaneous manifestations, gastrointestinal 
symptoms, pneumonitis or fever at any dose of Hydroxycarbamide 
 
24.7 Appendix 7. Transition phase from previous HU treatment to P1101 (for all patients 
on active HU  
Transition phase is the initial part of the dose finding for the patients concurrently receiving HU at the time 
of screening but transferred to P1101. 
The following scheme will be applied: 
HU weekly dose  
P1101 dose  
Week 1-2  
100% of the dose at baseline  
50 mcg 
Week 3-12 
Earliest possible HU 
discontinuation is being 
encouraged  
Every two weeks, decrease the HU 
level 250-500 mg 
Every two weeks, increase the P1101 
level by 50 mcg 
By week 13 onwards  
discontinued  
Monotherapy with dose, allowing CHR  
 
 

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24.8 Appendix 8. Hospital Anxiety and Depression Scale 
(A stays for anxiety, D stays for depression) 

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A 
1. I feel tense or ‘wound up’ 
3 Most of the time 
2 
A lot of the time 
1 
From time to time, occasionally 
0 
Not at all 
D 
2. I still enjoy the things I used to enjoy 
0 Definitely as much 
1 
Not quite so much 
2 
Only a little 
3 
Hardly at all 
A 
3. I get a sort of frightened feeling as if something awful is about to happen 
3 Very definitely and quite badly 
2 
Yes, but not too badly 
1 
A little, but it doesn’t worry me 
0 
Not at all 
D 
4. I can laugh and see the funny side of things 
0 As much as I always could 
1 
Not quite so much now 
2 
Definitely not so much now 
3 
Not at all 
A 
5. Worrying thoughts go through my mind 
3 A great deal of the time 
2 
A lot of the time 
1 
Not too often 
0 
Very little 
D 
6. I feel cheerful 
3 Never 
2 
Not often 
1 
Sometimes 
0 
Most of the time 
A 
7. I can sit at ease and feel relaxed 
0 Definitely 
1 
Usually 
2 
Not often 
3 
Not at all 
D 
8. I feel as if I am slowed down 
3 Nearly all the time 
2 
Very often 
1 
Sometimes 
0 
Not at all 
A 
9. I get a sort of frightened feeling like ‘butterflies’ in the stomach 
0 Not at all 
1 
Occasionally 
2 
Quite often 
3 
Very often 
D 
10. I have lost interest in my appearance 
3 Definitely 
2 
I don’t take as much care as I should 
1 
I may not take quite as much care 
0 
I take just as much care as ever 
A 
11. I feel restless as if I have to be on the move 
3 Very much indeed 
2 
Quite a lot 
1 
Not very much 
0 
Not at all 
D 
12. I look forward with enjoyment to things 
0 As much as I ever did 
1 
Rather less than I used to 
2 
Definitely less than I used to 
3 
Hardly at all 
13. I get sudden feelings of panic 

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Protocol P1101 in Japanese PV (A19-201) 
 
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A 
3 Very often indeed 
2 
Quite often 
1 
Not very often 
0 
Not at all 
D 
14. I can enjoy a good book or radio or television programme 
0 Often 
1 
Sometimes 
2 
Not often 
3 
Very seldom 
 
Anxiety Subscale:   questions 1, 3, 5, 7, 9, 11, 13 
Depression Subscale:  questions 2, 4, 6, 8, 10, 12, 14 
 
HADS copyright © R.P. Snaith and A.S. Zigmond, 1983, 1992, 1994. 
Record form items originally published in Acta Psychiatrica Scandinavica 67, 361–70, copyright © Munksgaard International 
Publishers Ltd, Copenhagen, 1983. 
This edition first published in 1994 by nferNelson Publishing Company Ltd (now GL Assessment Ltd), 
389 Chiswick High Road, London W4 4AL 
GL Assessment Ltd is part of GL Education