The main purpose of this study is to evaluate the efficacy of sapablursen in reducing the frequency of phlebotomy and in improving quality of life assessments in participants with polycythemia vera.

This is a Phase 2a, multi-center, randomized, open-label study of sapablursen in up to 40 participants with PD-PV. The study consists of 4 periods: 1) Screening Period: up to 7 weeks; 2) Treatment Period: 37 weeks 3) Treatment Extension Period: 36 weeks; 4) Post-treatment Period: 13 weeks.

In the Treatment Period, study drug is given by subcutaneous (under the skin) injection(s). There will be a total of 9 doses given over about 8 months.

In the Treatment Extension Period, there will be a total of 9 doses given over about 8 months.

Participants will be assigned to receive one of 2 Dosing Levels - a higher or a lower level, with an equal chance of being assigned to either Dosing Level. All participants will receive study drug; there is no placebo.

This study was extended to allow participants to receive sapablursen for an additional 36 weeks following the initial 37-week treatment period.

Inclusion Criteria

1. Meet modified World Health Organization (WHO) 2016 diagnostic criteria for polycythemia vera (PV) at the time of clinical diagnosis
2. Participant must be phlebotomy dependent.
3. Participants do not need to be on cytoreductive therapy and do not need to have been previously treated with cytoreductive therapy. If the patient was previously on cytoreductive therapy it must have been discontinued at least 3 months prior to Screening, with all associated AEs resolved. If the patient is currently on cytoreductive therapy they must be on a stable dose of hydroxyurea, recombinant or PEGylated interferon, or ruxolitinib for at least 3 months prior to Screening.

Exclusion Criteria

1. Meets criteria for post-polycythemia vera myelofibrosis (PPV-MF) as defined by the International Working Group- Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
2. Moderate to severe splenic pain or spleen-related organ obstruction
3. Active or chronic bleeding within 1 month of Screening, significant concurrent/recent coagulopathy, history of immune thrombocytopenic purpura (ITP)
4. Known primary or secondary immunodeficiency
5. Active infection with human immunodeficiency virus (HIV), hepatitis C, or hepatitis B.
6. Active infection requiring systemic antiviral or antimicrobial therapy or active novel coronavirus disease (Covid-19) infection
7. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or non-metastatic prostate cancer that has been successfully treated
8. Surgery requiring general anesthesia within 1 month prior to Screening

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.