Inclusion Criteria:
* Subject is ≥ 18 years of age at the time of signing the informed consent form (ICF).
* Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
* Subjects must have been diagnosed with PV per WHO 2016 or WHO 2022 criteria within 12 months of enrollment and must not have received prior cytoreductive therapy other than hydroxyurea for \<6 months.54,55 Patients on hydroxyurea at the time of enrollment should discontinue hydroxyurea upon initiation of ropeg-IFN. If during the titration phase, the WBC and/or platelet counts increase to clinically significant levels, the Investigator can consider additional therapies as clinically appropriate. This transition approach has been evaluated in the ECLIPSE-PV study (NCT05481151).
* Prior treatment with aspirin and phlebotomy is permitted and should be continued per standard practice during the trial.
* Subjects with both high-risk and low-risk PV per European LeukemiaNet 2018 criteria are eligible for enrollment except for subjects with known PV-related thromboembolic complications other than DVT/PE more than 6 months prior to enrollment.
* Subjects must have a JAK2V617F allele burden of \>20% at enrollment.
* Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
* Subject has adequate organ and hematologic function defined as:
1. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 3 x ULN.
2. Serum total bilirubin \< 1.5 x ULN. Higher levels are acceptable if these can be attributed to ineffective erythropoiesis or Gilbert's syndrome.
3. Serum creatinine \< 2 x ULN or creatinine clearance ≥30 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR) estimation.
4. White blood cell count ≥3.0 x109/L and platelet count ≥100 x10\^9/L
* Females of childbearing potential may participate provided they have a negative serum pregnancy test at screening and a negative serum OR urine pregnancy test within 72 hours of starting on treatment. They also must agree to either abstain from sexual intercourse or use two forms of a highly effective method of contraception while on study.
Exclusion Criteria:
* Subjects with primary or secondary MF or pre-fibrotic MF, essential thrombocythemia, or secondary polycythemia
* Subjects with accelerated or blast-phase MPN (≥10% blasts in bone marrow or peripheral blood)
* Any systemic cytoreduction for PV in the medical history prior to study entry except for short courses (i.e., \<6 months) of hydroxyurea
* Any contraindication to ropeg-IFN as defined by the FDA package insert
* Any systemic exposure to a non-pegylated or pegylated interferon-α in the medical history.
* Documented autoimmune disease at screening or in the medical history that requires treatment with systemic immunosuppressive therapy. Treatment with corticosteroids at a prednisone equivalent dose \<20 mg/day at a stable dose for ≥3 months is permitted.
* Clinically relevant pulmonary infiltrates, pneumonia, and pneumonitis at screening.
* Infections with systemic manifestations of active disease, e.g., hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) at screening. Patients with well-controlled disease status based on undetectable HBV, HCV, and HIV viral load are eligible for enrollment.
* Prior thromboembolic events except for DVT/PE more than 6 months prior to enrollment
* History of recurrent or current presence of depression requiring treatment with more than one antidepressant. Patients who are adequately managed on a stable dose of a single antidepressant can be considered for enrollment in discussion with the medical monitor.
* Any risk of suicide at screening based on a score of ≥1 on the Columbia-Suicide Severity Rating Scale (C-SSRS) or previous suicide attempts.
* History of severe or unstable cardiovascular disease (e.g., uncontrolled hypertension, congestive heart failure (≥ NYHA class 2), serious cardiac arrhythmia, significant coronary artery stenosis, unstable angina) or recent (within the last 12 months) stroke or myocardial infarction
* Pregnancy and breast-feeding females of reproductive potential and males not using effective means of contraception. Note: women of childbearing potential not using effective contraceptive methods were not eligible for the study. A woman of childbearing potential was defined as any female having experienced menarche and who is not postmenopausal or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy).
* Evidence of severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmological disorder (due to diabetes mellitus or hypertension).
* Thyroid dysfunction (clinical symptoms of thyroid hyper- or hypofunction) not adequately controlled
* Patients tested positively to thyroglobulin (TgAb) autoantibodies and/or thyroid peroxidase (TPOAb) autoantibodies at screening.
* History of major organ transplantation.
* History of uncontrolled severe seizure disorder
* History of malignant disease, including solid tumors and hematological malignancies (except basal cell and squamous cell carcinomas of the skin and carcinoma in situ of the cervix or other localized, early-stage tumors that have been completely excised and are considered cured) within the last 3 years.
* Unwillingness to be transfused with blood components.
* Other conditions that, in the opinion of the investigator, may compromise the achievement of the objectives of the study
