The study is designed to evaluate the safety and efficacy of rusfertide in subjects with polycythemia vera (PV) in maintaining hematocrit control and in improving symptoms of PV.

Phase 3 study in approximately 250 subjects previously diagnosed with polycythemia vera (PV) who require phlebotomy on a routine basis. There is a 32-week period during which rusfertide or placebo will be added-on to each subject's ongoing therapy for polycythemia vera which may include phlebotomy only or phlebotomy plus stable doses of either of hydroxyurea, interferon and/or ruxolitinib. All subjects who successfully complete the double blind 32-week portion of the study will receive rusfertide for 124 weeks. Approximately 6 and 12 months after their last dose of rusfertide, subjects will have a post-study contact (e.g. by phone) for safety.

Main Inclusion Criteria: All subjects must meet ALL of the following inclusion criteria to be enrolled. There are additional inclusion criteria.

• Male and female subjects aged 18 (or the country specific minimum age of consent >18) years or older.

• Meet revised 2016 World Health Organization (WHO) criteria for the diagnosis of polycythemia vera.

• At least 3 phlebotomies due to inadequate hematocrit control in 6 months before randomization or at least 5 phlebotomies due to inadequate hematocrit control in 1 year before randomization.

• CBC values immediately prior to randomization:

  1. Hematocrit <45%,
  2. WBC 4000/μL to 20,000/μL (inclusive), and
  3. Platelets 100,000/μL to 1,000,000/μL (inclusive)

• Subjects receiving cytoreductive therapy at randomization must be on a stable PV therapy regimen.

• Subjects treated with phlebotomy alone at randomization must have stopped cytoreductive therapy 2 to 6 months before screening.

Main Exclusion Criteria: Subjects must meet NONE of the following exclusion criteria to be enrolled. There are additional exclusion criteria.

• Clinically meaningful laboratory abnormalities at Screening.
• Subjects who require phlebotomy at hematocrit levels lower than 45%.
• Clinically significant thrombosis (e.g., deep vein thrombosis or splenic vein thrombosis) within 2 months prior to randomization.
• Active or chronic bleeding within 2 months prior to randomization.
• History of invasive malignancies within the last 5 years, except localized cured prostate cancer and cervical cancer.
• Subjects with in situ or stage 1 squamous cell carcinoma of the skin, in situ or stage 1 basal cell carcinoma of the skin, or in situ melanoma of the skin identified during screen unless the cancer is adequately treated before randomization.
• Received Busulfan, Pipobroman or 32Phosphorus within 7 months prior to screening.