A Study of Etavopivat for the Treatment of Anemia in Patients With Myelodysplastic Syndromes (MDS)

INCLUSION CRITERIA:

1. Patient has provided documented informed consent; the informed consent form (ICF)must be reviewed and signed by each patient prior to any study-relatedassessments/procedures being conducted.

2. Age ≥ 18 years at time of first dose.

3. Patients, if female and of childbearing potential, must agree to use acceptablemethods of contraception and agree not to donate ova from study start to 90 daysafter the last dose of study drug, and who if male are willing to use acceptablemethods of contraception and agree not to donate sperm, from study start to 90 daysafter the last dose of study drug.

4. Documented diagnosis of idiopathic/de novo MDS according to World HealthOrganization (WHO) classification that meets the IPSS-R classification of very low,low, or intermediate risk disease, and:

• < 5% blasts in bone marrow based on local pathology review

• < Intermediate risk cytogenetic abnormalities per IPSS-R

5. Anemia defined as:

• Non-transfusion dependent (NTD): Subjects with mean Hb concentration < 10.0g/dL of 2 measurements (1 performed within 3 days prior to Day 1 and the otherperformed 7 to 28 days prior to Day 1, not influenced by RBC transfusion within 7 days of measurement) and < 3 RBC transfusions for anemia in the prior 16weeks before Day 1 of etavopivat dosing OR

• Transfusion dependent (TD): Subjects having received ≥ 3 units of RBCs for thetreatment of anemia within 16 weeks prior to Day 1

6. Serum erythropoietin level > 200 U/L, OR, if ≤ 200 U/L, subject is non-responsive,refractory, or intolerant to erythropoiesis-stimulating agents, orerythropoiesis-stimulating agents are contraindicated or unavailable.

7. ECOG performance status of ≤ 2

8. Subject is non-responsive, refractory, or intolerant to luspatercept, orluspatercept is contraindicated or not indicated.

9. No alternative treatment options are available and/or appropriate for the subject,at the discretion of the investigator.

10. Patient is willing and able to adhere to the study visit schedule and other protocolrequirements

EXCLUSION CRITERIA:

[MDS History]

1. MDS associated with del 5q cytogenetic abnormality and known TP53 abnormality

2. Therapy-associated MDS (eg. t-MDS) that is known to have arisen as the result ofchemical injury or treatment with chemotherapy and/or radiation for other diseases

3. Known history of acute myeloid leukemia (AML)

[Medical Conditions]

4. Female who is breast feeding or pregnant

5. Known clinically significant anemia due to iron, vitamin B12, or folatedeficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinalbleeding

6. Absolute neutrophil count < 500/µL (0.5 x 10^9/L)

7. Platelet count < 50,000/µL (50 x 10^9/L) without transfusion support within 2 weeks

8. Hepatic dysfunction characterized by:

• Alanine aminotransferase (ALT) > 5.0 × upper limit of normal (ULN)

• Total bilirubin > 3.0 × ULN

• History of cirrhosis

9. Severe renal dysfunction (estimated glomerular filtration rate at the Screeningvisit; calculated by the local laboratory < 30 mL/min/1.73 m^2 ) or on chronicdialysis.

10. Patients with clinically significant and active bacterial, fungal, parasitic, orviral infection.

• Patients with acute bacterial, fungal, parasitic, or viral infection requiringsystemic therapy should delay Screening/ enrollment until active therapy hasbeen completed.

• Patients with acute viral infections without available therapies (eg,coronavirus disease 2019 [COVID-19]) should delay Screening/ enrollment untilthe acute infection has resolved. Note: Infection prophylaxis is allowed.

11. Known human immunodeficiency virus (HIV) positivity

12. Active infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] andhepatitis B core antibody [HepBcAb] positive)

13. Active hepatitis C infection

14. History of malignancy, other than MDS, within the past 2 years prior to treatmentDay 1 requiring systemic chemotherapy and/or radiation.

• Patients with malignancy considered surgically cured are eligible (eg,non-melanoma skin cancer, carcinoma in situ of the cervix, or carcinoma in situof the breast)

• Patients with incidental histologic findings of prostate cancer (T1a or T1b)are eligible

15. History of unstable or deteriorating cardiac or pulmonary disease within 6 monthsprior to consent including but not limited to the following:

• Unstable angina pectoris or myocardial infarction or elective coronaryintervention

• Heart disease, heart failure as classified by the New York Heart Associationclassification 3 or higher, or significant arrhythmia requiring treatment,

• Pulmonary fibrosis or pulmonary hypertension which are clinically significantie, ≥ Grade 3 National Cancer Institute (NCI) Common Terminology Criteria forAdverse Events (CTCAE) version 4.0 (or higher)

16. Uncontrolled hypertension, defined as repeated elevation of diastolic blood pressure ≥ 100 mmHg despite adequate treatment

17. Any condition affecting drug absorption, such as major surgery involving the stomachor small intestine (prior cholecystectomy is acceptable).

[Prior/Concomitant Therapy]

18. Prior treatment with azacitidine (injectable or oral) or decitabine

19. Use of erythropoietin, other hematopoietic growth factor treatment or lenalidomidewithin 30 days of starting study treatment or anticipated need for such agentsduring the study.

20. Prior use of luspatercept:

• NTD patients must not have received luspatercept within 30 days prior to Day 1treatment

• TD patients must not have received luspatercept within 16 weeks prior to Day 1treatment

21. Receiving or use of concomitant medications that are strong inducers of cytochromeP450 (CYP)3A4/5 (see Appendix F) within 2 weeks of starting study treatment oranticipated need for such agents during the study.

22. Prior allogeneic or autologous stem cell transplant

23. Initiation of a new chelation therapy within 3 months before the first dose of studytreatment.

[Prior/Concurrent Clinical Study Experience]

24. Participated in another clinical trial of an investigational agent (or medicaldevice) within 30 days or 5 half-lives of date of informed consent, whichever islonger, or is currently participating in another trial of an investigational agent (or medical device).

[Other Exclusions]

25. Medical, psychological, or behavioral conditions, which, in the opinion of theInvestigator, may preclude safe participation, confound study interpretation,interfere with compliance, or preclude informed consent.