Efficacy and Safety of P1101 in Polycythemia Vera Patients for Whom the Standard of Treatment is Difficult to Apply

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

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 10^9/L and leukocytes <10 x 10^9/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 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..

Inclusion Criteria:

1. Male or female patients ≥20 years old

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.)

   • 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

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 10^9/L (for two measurements within the month prior treatment start)
   • leukocytosis (WBC>10 x 10^9/L for two measurements within the month prior treatment start)

6. Adequate hepatic function defined as 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 10^9/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 (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.).

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

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

   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

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