Inclusion Criteria:
1. Japanese male and female participants aged 18 years or older at the time of signing informed consent.
2. Participant understands the trial procedures, is willing and able to adhere to trial requirements and agrees to participate in the trial by giving written informed consent.
3. Meet revised 2016 WHO criteria for the diagnosis of PV.
4. Phlebotomy requiring defined as ALL of the following:
1. At least 3 phlebotomies due to inadequate hematocrit control in 28 weeks before trial intervention or at least 5 phlebotomies due to inadequate hematocrit control in 1 year before trial intervention, and
2. Last phlebotomy due to inadequate hematocrit control within 3 months before trial intervention, and
3. No phlebotomy within 6 days prior to trial intervention (do not include day of phlebotomy and day of trial intervention in the 6-day count).
Note: Phlebotomies performed within an 8-day period will be counted as a single phlebotomy.
5. Hematology test values at screening:
1. Hematocrit \<45%
2. WBC 4,000/µL to 20,000/µL (inclusive), and
3. Platelets 100,000/µL to 1,000,000/µL (inclusive).
6. ECOG performance status 0, 1 or 2.
7. WOCBP agree to use at least 1 form of highly effective contraception during the trial and for 30 days after the last dose of trial intervention.
8. A female participant must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the trial and for a period of 30 days after receiving the last dose of trial medication.
9. A fertile man agree to use a condom, preferably combined with at least 1 form of acceptable contraception for any WOCBP partner(s) during the trial and for 90 days after the last dose of trial intervention.
10. A male participant must agree not to donate sperm for the purpose of reproduction during the trial and for a minimum of 90 days after receiving the last dose.
11. Participants receiving CRT at trial intervention must be on a stable PV therapy regimen as follows:
1. Hydroxyurea - at least 8 weeks
2. JAK inhibitor - at least 8 weeks
3. Interferon - at least 24 weeks. Note: A "stable dose regimen" of CRT does not mean an unchanged dose regimen. Temporary adjustments in dose regimen or temporary suspension of dosing are allowed. However, the total weekly dose of hydroxyurea and JAK inhibitor or total monthly dose of interferon may not be higher at trial intervention than the dose at the beginning of the pre-trial intervention observation period. The pre-trial intervention observation period is 8 weeks for hydroxyurea and JAK inhibitor and 24 weeks for interferon.
12. Participants treated with phlebotomy alone at trial intervention must have stopped:
1. Hydroxyurea at least 8 weeks before trial intervention
2. JAK inhibitor at least 8 weeks before trial intervention
3. Interferon at least 24 weeks before trial intervention.
Exclusion Criteria:
1. Clinically meaningful laboratory abnormalities at Screening including, but not limited to:
1. eGFR \<15 mL/min/1.73 m\^2 as determined by Japanese Society of Nephrology. Calculated by the correction formula for Japanese\*
\*eGFR=194×(serum creatinine value)-1.094×(age)-0.287×(sex correction factor), Sex correction factor: 0.739 in female (Japanese Society of Nephrology,2023).
2. ALT or AST ≥2.5×ULN
3. Total bilirubin \>1.5×ULN. Note: Screening laboratory tests with abnormal results (if considered by the investigator to be transient and inconsistent with the participant's clinical condition) may be repeated within the screening window to confirm abnormal results. If results return to protocol acceptable limits within the screening period, the participant may enter the trial. Use local labs for all eligibility lab tests.
2. Participants who require phlebotomy at hematocrit levels lower than 45%.
3. Pregnant females will be ineligible to participate in this trial if, despite a negative pregnancy test, the investigator determines that based on interview, clinical assessment, or other relevant information that the individual may be in the very early stages of pregnancy.
4. Is capable of breastfeeding but does not agree to forego breastfeeding from the first dose of trial intervention through 30 days after the last dose of trial intervention.
5. Clinically significant thrombosis (eg, deep vein thrombosis or splenic vein thrombosis) within 2 months prior to trial intervention.
6. Active or chronic bleeding within 2 months prior to trial intervention.
7. Meets the criteria for post-PV myelofibrosis as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).
8. Any infection requiring systemic therapy within 1 month of dosing except controlled: HIV, hepatitis B, and hepatitis C. Prophylactic therapies are allowed.
9. Any serious or unstable medical condition (eg, poorly controlled HIV infection) or uncontrolled psychiatric condition as judged by the investigator that would impair the participant's ability to participate in the trial.
10. Major surgical procedure within 2 months prior to trial intervention unless the participant has fully recovered from surgery or planned major elective surgery during the trial.
11. History of invasive malignancies within the last 5 years, except
1. localized cured cancer (eg, prostate cancer and cervical cancer)
2. localized cured in situ or stage 1 squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or in situ melanoma of the skin.
12. Participants 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 the required dermatology examination at screening unless the cancer is adequately treated (ie, treatment that is expected to be curative, such as Mohs surgery) before trial intervention. Note: Suspicious lesions should be biopsied and results available before trial intervention.
13. Participants with active alcohol or drug addiction that would interfere with their ability to comply with trial requirements.
14. Participants who do not complete at least 4 days of MFSAF v4.0 assessments within 1 week prior to trial intervention.
15. Receipt of an investigational agent within 2 months or 5 half-lives, whichever is longer, prior to trial intervention.
16. Received busulfan within 7 months prior to screening.
17. Participants with hypersensitivity to rusfertide or to any of the excipients.
18. Participants with any lesion or mass detected by physical examination or imaging during screening that is suspicious for malignancy unless evaluated and assessed to be not malignant.
