Anemia, Myelodysplastic Syndromes, Myelofibrosis, Myelofibrosis; Anemia, Myelofibrosis Due to and Following Polycythemia Vera, Post-essential Thrombocythemia Myelofibrosis, Primary Myelofibrosis
Conditions
Keywords
Myeloproliferative Neoplasm, Myeloproliferative Disorders
Brief summary
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.
Interventions
DRUGDISC-0974
DISC-0974 is administered subcutaneously.
Sponsors
Disc Medicine, Inc
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of DISC-0974 (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | Assessed by treatment-emergent adverse events |
| Safety and Tolerability of DISC-0974 assessed through blood testing (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies |
| Safety and Tolerability of DISC-0974 assessed through urine testing (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | The urine testing will include a urinalysis |
| Transfusion-dependent (TD) high cohort: transfusion independence (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | Defined as the absence of packed red blood cell (PRBC) transfusions over any rolling 12-week interval during the treatment period with a minimum hemoglobin (Hgb) of 7 g/dL. Participants meeting this criterion will be considered to have a major response to treatment. |
| TD low cohort: transfusion independence (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | Defined as the absence of PRBC transfusions over any rolling 16-week interval during the treatment period with a minimum Hgb of 7 g/dL. Participants meeting this criterion will be considered to have a major response to treatment. |
| Non-transfusion-dependent (nTD) cohort: anemia response (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | Defined as the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline. Participants meeting this criterion will be considered to have a major response to treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anemia response defined per IWG-MRT 2006 criteria (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | Response in nTD participants is defined as ≥2.0 g/dL increase from baseline in Hgb levels. Response in TD participants requires absence of PRBC transfusions during any rolling 12-week period during the treatment period, capped by an Hgb level of ≥8.5 g/dL. |
| TD high and TD low participants will be evaluated for absence of PRBC transfusions for any rolling 12-week interval during the treatment period (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| TD high participants will be evaluated for absence of PRBC transfusions with minimum Hgb of 7 g/dL during any rolling 12-week interval during the treatment period (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| TD low participants will be evaluated for absence of PRBC transfusions with minimum Hgb of 7 g/dL during any rolling 16-week interval during the treatment period (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| nTD participants will be evaluated for ≥1.5 g/dL increase from baseline Hgb levels during the treatment period (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| nTD participants will be evaluated for the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| Incidence of TEAEs following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts (collectively referred to as MDS) and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | Proportion of participants with treatment-emergent adverse events |
| Incidence of clinically abnormal vital signs following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| Incidence of clinically abnormal physical exam following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| Incidence of clinically abnormal electrocardiograms (ECGs) following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| Incidence of abnormal laboratory test results following repeated DISC-0974 SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | — |
| Pharmacokinetic data of DISC-0974 following repeated SC doses in participants with myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) without excess blasts and anemia (Phase 1b only) | From Day 1 to the end of treatment on Day 169 | Pharmacokinetic parameters include DISC-0974 pre-dose concentrations at different visits |
| Proportion of participants achieving a mean Hgb increase ≥1 g/dL or ≥2 g/dL from baseline over any rolling 12-week period in absence of PRBC transfusions in each cohort (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | Participants who are nTD and achieve a mean Hgb increase ≥1 g/dL from baseline over any rolling 12-week period in the absence of transfusion will be considered to have a minor response to treatment. |
| PD markers of mechanism engagement, including exploratory cohorts assessed through serum iron levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| PD markers of mechanism engagement, including exploratory cohorts assessed through TSAT levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| PD markers of mechanism engagement, including exploratory cohorts assessed through Ferritin levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| PD markers of mechanism engagement, including exploratory cohorts assessed through Transferrin levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| PD markers of mechanism engagement, including exploratory cohorts assessed through Serum-hepcidin-25 levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Hematologic Parameters assessed through Reticulocyte count (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Hematologic Parameters assessed through Hemoglobin levels (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Hematologic Parameters assessed through Reticulocyte Hemoglobin (CHr) (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Hematologic Parameters assessed through Red Blood Cell Count (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Rate of RBC transfusions per participant month during the treatment period for each cohort (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| The number of units of RBC transfusions per participant month during the treatment period for each cohort (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Transfusion-dependent cohorts will be evaluated for proportion of participants who reduce their transfusion requirement by ≥50%, as compared to baseline, over any rolling 12-week period during treatment. (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | Participants who are TD and achieve a reduction in transfusion requirement ≥50% as compared to baseline over any rolling 12-week period during treatment will be considered to have a minor response to treatment. |
| nTD participants will be evaluated for longest duration of mean Hgb increase of ≥1.5 g/dL from baseline during the treatment period (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Mean change in Hgb over 12-week treatment periods will be evaluated for all cohorts (nTD, TD low, and TD high) (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Maximum duration of RBC-transfusion-independent response for TD participants (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Proportion of participants that require dose escalation in each cohort (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Proportion of participants that improve Functional Assessment of Cancer Therapy-Anemia (FACT-An) subscale by at least 3 points in each cohort during the treatment period (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Mean hemoglobin increase of ≥1.5 g/dL over any rolling 12-week interval and an increase in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue of 3 points by the end of study (EOS) for nTD participants (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| TD high cohort will be evaluated for absence of packed red blood cell (PRBC) transfusions a terminal 12-week interval during the treatment period with a minimum hemoglobin (Hgb) of 7 g/dL (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| TD low cohort: will be evaluated for the absence of PRBC transfusions a terminal 16-week interval during the treatment period with a minimum Hgb of 7 g/dL (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | — |
| Non-transfusion-dependent (nTD) cohort will be evaluated for anemia response (Phase 1b and 2) | From Day 1 to the end of treatment on Day 169 | Defined as the composite of the absence of transfusions over any rolling 12-week period and a concomitant mean Hgb increase of ≥1.5 g/dL over baseline |
| Safety and Tolerability of DISC-0974 (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | Assessed by treatment-emergent adverse events |
| Safety and Tolerability of DISC-0974 assessed through blood testing (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies |
| Safety and Tolerability of DISC-0974 assessed through urine testing (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | The urine testing will include a urinalysis |
| Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | Assessed by treatment-emergent adverse events |
| Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy assessed through blood testing (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | The blood testing will include a hematology panel, blood chemistry panel, serology/virology panel, biomarker assessments, PK assessments, and Anti-Drug Antibodies |
| Safety and tolerability of DISC-0974 following repeated SC doses in participants with MF receiving concomitant momelotinib or pacritinib therapy assessed through urine testing (Phase 2 only) | From Day 1 to the end of treatment on Day 169 | The urine testing will include a urinalysis |
Countries
Australia, United States
Contacts
CONTACTDisc Medicine Clinical Trials
STUDY_DIRECTORWill Savage, MD PhD
Disc Medicine
Outcome results
None listed