⁃ Participants are eligible for the study if all of the following criteria apply:

• Age 18 years or older at the time of signing the informed consent form (ICF).

• For Phase 1b: DIPSS score of 3 to 4 (intermediate 2 risk) or ≥5 (high-risk) primary MF, post PV MF, and/or post ET MF, as confirmed in the most recent local bone marrow biopsy report, according to WHO 2016 criteria.55

• For Phase 2: In addition to the criteria above, DIPSS score of ≥2 (intermediate 1 risk) may also be included.

• Washout of at least 28 days prior to Screening of the following treatments:

∙ Androgens

‣ EPO

‣ Cladribine

‣ Immunomodulators (lenalidomide, thalidomide)

‣ Luspatercept/sotatercept

‣ Systemic corticosteroids are permitted for non-hematological conditions if stable or decreasing dose for ≥28 days prior to Screening and receiving an equivalent to ≤10 mg prednisone for the 28 days immediately prior to Screening.

• Screening can begin before the 28 day washout is completed, but the washout period must be completed prior to collection of Screening blood samples.

• Anemia:

• For Phase 1b: Hgb \<10 g/dL on ≥3 assessments over 84 days prior to Screening, without RBC transfusion, or Hgb \<10 g/dL and receiving RBC transfusions periodically but not meeting criteria for TD participant as defined for the TD Cohort (see Section 6.3). The baseline Hgb value for these participants is the lowest Hgb level during the 84 days prior to Screening, or RBC transfusion dependence, defined as an RBC transfusion frequency of 6 units PRBC over the 84 days immediately prior to Screening There must not be any consecutive 42 day period without an RBC transfusion in the 84 day period, and the last transfusion must be within 28 days prior to Screening.

• For Phase 2:

• TD high transfusion burden cohort: RBC transfusion dependence, defined as an RBC transfusion requirement of 3 to 12 PRBC units over the 84 days immediately prior to Screening TD low transfusion burden cohort: RBC transfusion dependence, defined as an RBC transfusion requirement of 1 to 2 PRBC units over the 84 days immediately prior to Screening nTD cohort: Non-transfusion dependence, baseline Hgb \<10 g/dL as defined on ≥3 assessments over 84 days prior to Screening, without RBC transfusion

• Stable dosing of MF-directed therapy:

∙ Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.

‣ Interferon alpha stable dosing for at least 12 weeks prior to Screening.

‣ JAK inhibitors require 12 weeks of stable dosing prior to Screening. For the TD high, TD low, and nTD cohorts, JAK inhibitors allowed include momelotinib, pacritinib, fedratinib, and ruxolitinib.

‣ If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.

• Eastern Cooperative Oncology Group (ECOG) performance score ≤2.

• Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening.

• TSAT \<75% (local lab acceptable).

• Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review. Required for TD high participants only.

⁃ Serum ferritin ≥50 µg/L at Screening.

⁃ Platelet count ≥25,000/µL and \<1,000,000/µL; neutrophils ≥1,000/µL; and total white blood cell (WBC) count \<50,000/µL at Screening.

⁃ Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 by the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula.

⁃ Aspartate aminotransferase (AST) and ALT \<3x upper limit of normal (ULN) at Screening.

⁃ Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis or Gilbert's syndrome, with approval from Sponsor.

⁃ If male with female sexual partner(s) of childbearing potential, agrees to use 1 of the following highly effective methods of contraception during the study and for at least 8 weeks after the last study drug dose:

• Stable hormonal contraceptive (≥3 months; female partner)

∙ Intrauterine device in place for at least 3 months (female partner)

∙ Surgically sterile by hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)

∙ Confirmed successful vasectomy

⁃ If female, then EITHER postmenopausal (defined as 12 months of spontaneous amenorrhea, 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels \>40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy), surgically sterile, OR agreeable to use 1 of the following highly effective contraception methods (listed below) on Day 1 (or earlier) and for at least 8 weeks after the last dose of study drug:

• Stable hormonal contraceptive (≥3 months)

∙ Intrauterine device in place for at least 3 months

∙ Tubal ligation or single male partner with vasectomy

⁃ Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).

⁃ Able to understand the study aims, procedures, and requirements, and provide written informed consent.

⁃ Able to comply with all study procedures.

⁃ Participants are eligible for the MDS exploratory cohort if all of the following criteria apply:

• Age 18 years or older at the time of signing the ICF.

• Molecular International Prognostic Scoring System (IPSS-M) classification of very low, low, or intermediate (ie, lower risk) MDS-ringed sideroblasts (RS) negative, MDS/MPN with ringed sideroblasts and thrombocytosis (RS-T), Chronic Myelomonocytic Leukemia (CMML), Atypical Chronic Myeloid Leukemia (aCML), or Myelodysplastic/Myeloproliferative Neoplasms, Unclassifiable (MDS/MPN-U) as confirmed in the most recent local bone marrow biopsy report according to WHO criteria.

• Washout of at least 28 days is required for prior anemia/neutropenia-directed therapies, including:

∙ Androgens

‣ EPO-stimulating agents

‣ Luspatercept

‣ Sotatercept (ACE-011)

‣ Imetelstat

‣ Granulocyte colony-stimulating factor (G-CSF) OR granulocyte-macrophage CSF (GM-CSF)

‣ Systemic corticosteroids (except for participants on a stable or decreasing dose for ≥28 days prior to randomization for non-hematological conditions and receiving an equivalent to ≤10 mg prednisone for the 28 days immediately prior to Screening) Screening can begin before the 28-day washout is completed, but the washout period must be completed prior to collection of Screening blood samples.

• Anemia:

∙ Baseline Hgb of \<10 g/dL on ≥3 assessments over 84 days prior to Screening, without RBC transfusion, or Hgb \<10 g/dL and receiving RBC transfusions periodically during the 84 days prior to Screening

‣ Medical history of ≤24 units of PRBC for MDS and anemia

• ECOG performance score ≤2

• Infusion of hematopoietic stem cell transplant not anticipated within 8 months after Screening

• TSAT \<75% (local lab acceptable)

• Liver iron concentration by MRI \<7 mg/g dry weight within 3 months of eligibility confirmation by central review

• Serum ferritin ≥50 μg/L at Screening

⁃ Platelet count ≥25,000/μL and \<1,000,000/μL, and total WBC count \<50,000/μL at Screening or otherwise approved by Sponsor

⁃ eGFR ≥30 mL/min/1.73 m2 by the CKD-EPI formula

⁃ AST and ALT \<3x ULN at Screening

⁃ Direct bilirubin \<2x ULN at Screening. Higher levels are acceptable if these can be attributed by the Investigator to ineffective erythropoiesis.

⁃ If male with female sexual partner(s) of childbearing potential, agrees to use 1 of the following highly effective methods of contraception during the study and for at least 8 weeks after the last study drug dose:

• Stable hormonal contraceptive (≥3 months; female partner)

∙ Intrauterine device in place for at least 3 months (female partner)

∙ Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)

∙ Confirmed successful vasectomy

⁃ If female, then EITHER postmenopausal (defined as 12 months of spontaneous amenorrhea, 6 months of spontaneous amenorrhea with serum FSH levels \>40 mIU/ml, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy), surgically sterile, OR agreeable to use 1 of the following highly effective contraception methods (listed below) on Day 1 (or earlier) and for at least 8 weeks after the last dose of study drug:

• Stable hormonal contraceptive (≥3 months)

∙ Intrauterine device in place for at least 3 months

∙ Tubal ligation or single male partner with vasectomy

⁃ Negative urine pregnancy test (females of childbearing potential) at Screening (Days 28 to 2).

⁃ Able to understand the study aims, procedures, and requirements, and provide written informed consent.

⁃ Able to comply with all study procedures.