Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia

RALLY-MF: A Phase 1b/2 Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of DISC-0974 in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia

This phase 1b/2a open-label study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of DISC-0974 as well as categorize the effects on hematologic response in participants with myelofibrosis or myelodysplastic syndrome and anemia.

Inclusion Criteria for Participants with MF and Anemia:

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

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

2. For Phase 1b: Dynamic International Prognostic Scoring System (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 World Health Organization (WHO) 2016 criteria.

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

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

   1. Androgens
   2. EPO
   3. Cladribine
   4. Immunomodulators (lenalidomide, thalidomide)
   5. Luspatercept/sotatercept
   6. 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.

4. 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. 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

5. Stable dosing of MF-directed therapy:

   1. Hydroxyurea, or, if taking any other treatment for MF, stable for at least 28 days prior to Screening.
   2. Interferon alpha stable dosing for at least 12 weeks prior to Screening.
   3. 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.
   4. If the participant discontinues JAK inhibitor (including momelotinib/pacritinib/ruxolitinib/fedratinib) and/or hydroxyurea prior to Screening, a 60-day washout period is required.

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

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

8. TSAT <75% (local lab acceptable) at or within 2 weeks of Screening.

9. 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.

10. Serum ferritin ≥50 µg/L at Screening.

11. 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.

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

13. Aspartate aminotransferase (AST) and ALT <3.0x upper limit of normal (ULN) at Screening.

14. 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.

15. 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:

    1. Stable hormonal contraceptive (≥3 months; female partner)
    2. Intrauterine device in place for at least 3 months (female partner)
    3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
    4. Confirmed successful vasectomy

16. 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:

    1. Stable hormonal contraceptive (≥3 months)
    2. Intrauterine device in place for at least 3 months
    3. Tubal ligation or single male partner with vasectomy

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

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

19. Able to comply with all study procedures.

Inclusion Criteria for Exploratory Cohort of Participants with MDS and Anemia:

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

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

2. 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.

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

   1. Androgens
   2. EPO-stimulating agents
   3. Luspatercept
   4. Sotatercept (ACE-011)
   5. Imetelstat
   6. Granulocyte colony-stimulating factor (G CSF) OR granulocyte-macrophage CSF (GM CSF).
   7. 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.

4. Anemia:

   1. 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
   2. Medical history of ≤24 units of PRBC for MDS and anemia

5. ECOG performance score ≤2

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

7. TSAT <75% (local lab acceptable) at or within 2 weeks of Screening

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

9. Serum ferritin ≥50 μg/L at Screening

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

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

12. AST and ALT <3x ULN at Screening

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

14. 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:

    1. Stable hormonal contraceptive (≥3 months; female partner)
    2. Intrauterine device in place for at least 3 months (female partner)
    3. Surgically sterile hysterectomy, bilateral oophorectomy, or bilateral tubal ligation (female partner)
    4. Confirmed successful vasectomy

15. 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:

    1. Stable hormonal contraceptive (≥3 months)
    2. Intrauterine device in place for at least 3 months
    3. Tubal ligation or single male partner with vasectomy

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

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

18. Able to comply with all study procedures.

Exclusion Criteria for Participants with MF and Anemia:

Participants are excluded from the study if any of the following criteria apply:

Medical History, Participants with MF and Anemia

1. Hereditary hemochromatosis

2. Hemoglobinopathy or intrinsic RBC defect associated with anemia

3. Total splenectomy

4. Hematopoietic cell transplant within the past 2 years, or graft vs host disease requiring immunosuppression

5. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding

6. Active immune-mediated hemolytic anemia

7. Symptomatic bleeding, unrelated to surgery, in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥2 g/dL or leading to transfusion of ≥2 units of RBCs in the 6 months prior to Screening

8. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery

9. Malignancy within the past 3 years, other than primary MF, post ET, or post PV MF. The following history or concurrent conditions are allowed:

   1. basal or squamous cell carcinoma of the skin
   2. carcinoma in situ of the cervix or the breast
   3. histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) A history of completed treatment (medical or surgical) of stage 1-2 cancers may be permitted with prior Sponsor agreement

10. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 3 months prior to Screening

11. Known allergic reaction to any study drug excipient

12. A history of anti-drug antibody formation

13. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction <35%

14. Hepatitis B or C, or human immunodeficiency virus (HIV) with detectable viral load

15. Uncontrolled fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection, without improvement despite appropriate treatment)

    Treatment History, Participants with MF and Anemia

16. Iron chelation therapy in the 28 days prior to Screening

17. Change in anticoagulant therapy regimen within 8 weeks prior to Screening

    Laboratory Exclusions, Participants with MF and Anemia

18. Peripheral blood myeloblasts ≥10% of WBC differential at most recent evaluation prior to Screening

19. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening

    Miscellaneous, Participants with MF and Anemia

20. Pregnant or lactating

21. Condition or concomitant medication that would confound the ability to interpret study data

22. Other medical or psychiatric condition or laboratory finding not specifically noted above that, in the judgment of the Investigator or Sponsor, would put the participant at unacceptable risk or otherwise preclude the participant from participating in the study

23. Participation in any other clinical protocol or investigational study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening

Exclusion Criteria for Exploratory Cohort of Participants with MDS and Anemia:

Participants are excluded from the MDS exploratory cohort if any of the following criteria apply:

Medical History, Participants with MDS and Anemia

1. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation from other diseases

2. Peripheral blasts ≥5%

3. Current treatment with hypomethylating agent or other acute myeloid leukemia (AML)-like combination chemotherapy or planned use within 6 months after Screening

4. Prior treatment with >3 anemia-directed therapies (unless otherwise approved by Sponsor) including:

   1. Luspatercept
   2. Sotatercept (ACE-011)
   3. EPO-stimulating agent
   4. Imetelstat

5. Hereditary hemochromatosis

6. Hemoglobinopathy or intrinsic RBC defect associated with anemia

7. Total splenectomy

8. Hematopoietic cell transplant within the past 10 years

9. Current anemia from iron deficiency, vitamin B12 or folate deficiency, infection, or bleeding

10. Active immune-mediated hemolytic anemia

11. Symptomatic bleeding, unrelated to surgery, in a critical area or organ and/or bleeding causing a decrease in Hgb of ≥2 g/dL or leading to transfusion of ≥2 units of RBCs in the 6 months prior to Screening

12. Major surgery within 8 weeks prior to Screening or incomplete recovery from any previous surgery

13. Malignancy within the past 3 years, other than MDS or MDS/MPN without excess blasts. The following history or concurrent conditions are allowed:

    1. Basal or squamous cell carcinoma of the skin
    2. Carcinoma in situ of the cervix or the breast
    3. Histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system) A history of completed treatment (medical or surgical) of stage 1-2 cancers may be permitted with prior Sponsor agreement

14. Stroke, deep vein thrombosis, or pulmonary or arterial embolism within 6 months prior to Screening

15. Known allergic reaction to any study drug excipient

16. A history of antidrug antibody formation

17. Inadequately controlled heart disease (New York Heart Association Classification 3 or 4) and/or known to have left ventricular ejection fraction <35%

18. Active hepatitis B or C, or HIV with detectable viral load

19. Uncontrolled fungal, bacterial, or viral infection (ongoing signs/symptoms related to the infection, without improvement despite appropriate treatment)

    Treatment History, Participants with MDS and Anemia

20. Iron chelation therapy in the 28 days prior to Screening

21. Change in anticoagulant therapy regimen within 8 weeks prior to Screening

    Laboratory Exclusions, Participants with MDS and Anemia

22. Positive direct antiglobulin test in conjunction with a reactive RBC eluate at Screening

    Miscellaneous, Participants with MDS and Anemia

23. Pregnant or lactating

24. Condition or concomitant medication that would confound the ability to interpret study data

25. Other medical or psychiatric condition or laboratory finding not specifically noted above that, in the judgment of the Investigator or Sponsor, would put the participant at unacceptable risk or otherwise preclude the participant from participating in the study

26. Participation in any other clinical protocol or investigational study that involves administration of experimental therapy and/or therapeutic devices within 30 days prior to Screening