The purpose of this study is to evaluate the efficacy and safety of sapablursen when added on to current standard of care (SOC) for Polycythemia Vera (PV) therapy. The study will be conducted in three sequential parts (Part 1a blinded treatment, Part 1b open-label treatment, & Part 2 long-term extension). Participants may receive treatment for up to 156 weeks.

Inclusion Criteria:

1. Meet revised 2022 World Health Organization (WHO) and 2022 International Consensus Classification criteria for the diagnosis of PV.
2. Participants must be phlebotomy-dependent.
3. Hct less than (<) 45% at study start.
4. Participants receiving Cytoreduction therapy (CRT) must be on a stable regimen at study start.
5. Adequate organ function and electrolytes.

Exclusion Criteria:

1. Prior treatment of PV with Transmembrane serine protease 6 (TMPRSS6) inhibitors, including sapablursen, or hepcidin mimetics.
2. Clinically significant thrombosis (eg, myocardial infarction, stroke, deep vein thrombosis or splenic vein thrombosis) within 1 month prior to randomization.
3. Participants who require phlebotomy at Hct levels <45%.
4. Meet the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment.
5. Any serious or unstable medical condition or uncontrolled psychiatric condition that would interfere with their ability to comply with study requirements.