Efficacy and Safety of Luspatercept for the Treatment of Anemia Due to MDS With del5q, Refractory/Resistant/Intolerant to Prior Treatments, RBC-TD

Inclusion Criteria:

1. Subject must understand and voluntarily sign an ICF prior to any study-relatedassessments/procedures being conducted.

2. Documented diagnosis of MDS with del5q according to 2018 WHO classification

3. IPSS-R classification (Greenberg, 2012) of very low, low, or intermediate riskdisease, and:

• < 5% blasts in bone marrow

• Peripheral blood WBC count <13,000/μL

4. Refractory or intolerant to, or ineligible for, prior ESA treatment

5. If previously treated with ESAs or granulocyte colony-stimulating factor (G-CSF),both agents must have been discontinued ≥ 4 weeks prior to date of screening.

6. Refractory or intolerant to, or ineligible for, prior lenalidomide treatment, asdefined by any one of the following:

• Refractory to prior lenalidomide treatment for at least 4 cycles; -documentation of non-response or response that is no longer maintained (HI-E)

• Intolerant to prior lenalidomide treatment - documentation of discontinuationof lenalidomide at any time after introduction due to intolerance or an adverseevent

• lenalidomide ineligible -platelet counts below 50000/mmc or absolute neutrophilcount below 500/mmc at the start of treatment

• lenalidomide must have been discontinued ≥ 4 weeks prior to date of screening. Requires RBC transfusions, as documented by the following criteria:

• average transfusion requirement of ≥ 2 units/8 weeks of pRBCs confirmed for aminimum of 16 weeks immediately preceding enrolment.

• Hb levels at the time of or within 7 days prior to administration of a RBCtransfusion must have been ≤ 10.0 g/dL in order for the transfusion to becounted towards meeting eligibility criteria. RBC transfusions administeredwhen Hb levels were > 10.0 g/dL and/or RBC transfusions administered forelective surgery will not qualify as a required transfusion for the purpose ofmeeting eligibility criteria.

• no consecutive 56-day period that was RBC transfusion-free during the 16 weeksimmediately preceding screening

7. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

8. Females of childbearing potential, defined as a sexually mature woman who: 1) hasnot undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturallypostmenopausal (amenorrhea following cancer therapy does not rule out childbearingpotential) for at least 24 consecutive months (ie, has had menses at any time in thepreceding 24 consecutive months), must:

• Have two negative pregnancy tests as verified by the Investigator prior tostarting study therapy (unless the screening pregnancy test was done within 72hours of C1D1). Refer to Section 6.1 for additional details. She must agree toongoing pregnancy testing during the course of the study, and after the end ofstudy treatment.

• If sexually active, agree to use, and be able to comply with, highly effectivecontraception without interruption, 5 weeks prior to starting investigationalproduct, during the study therapy (including dose interruptions), and for 12weeks after discontinuation of study therapy.

9. Male subjects must:

• Agree to use a condom, defined as a male latex condom or non latex condom notmade out of natural (animal) membrane (for example, polyurethane), duringsexual contact with a pregnant female or a female of childbearing potentialwhile participating in the study, during dose interruptions and for at least 12weeks following investigational product discontinuation, even if he hasundergone a successful vasectomy.

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

Exclusion Criteria:

1. P53 mutation at screening

2. Prior therapy with disease modifying agents for underlying MDS disease (hypomethylating agents)

• subjects who previously received HMA may be enrolled at the investigator'sdiscretion contingent that the subject received no more than 1 dose of HMA).The last dose must be ≥ 5 weeks from the date of screening.

3. Previously treated with either luspatercept (ACE-536) or sotatercept (ACE-011)

4. Secondary MDS, ie, MDS that is known to have arisen as the result of chemical injuryor treatment with chemotherapy and/or radiation for other diseases. 5 Knownclinically significant anemia due to iron, vitamin B12, or folate deficiencies, orautoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

5. Prior allogeneic or autologous stem cell transplant 7. Known history of diagnosis ofAML 8. Use of any of the following within 5 weeks prior to study entry:

• anticancer cytotoxic chemotherapeutic agent or treatment

• corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 weekprior to study entry for medical conditions other than MDS

• iron-chelating agents, except for subjects on a stable or decreasing dose for atleast 8 weeks prior to screening

• other RBC hematopoietic growth factors

• investigational drug or device, or approved therapy for investigational use. If thehalf- life of the previous investigational product is known, use within 5 times thehalf- life prior to screening or within 5 weeks, whichever is longer is excluded. 9.Uncontrolled hypertension, defined as repeated elevations of diastolic bloodpressure (DBP) ≥ 100 mmHg despite adequate treatment. 10. Estimated glomerularfiltration rate (eGFR) or creatinine clearance < 40 mL/min.

11. Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase oralanine aminotransferase/serum glutamic pyruvic transaminase ≥ 3.0 x upperlimit of normal (ULN) 12. Total bilirubin ≥ 2.0 x ULN.

• higher levels are acceptable if these can be attributed to active red blood cellprecursor destruction within the bone marrow (ie, ineffective erythropoiesis) or inthe presence of known history of Gilbert Syndrome.

• subjects are excluded if there is evidence of autoimmune hemolytic anemia 13. Priorhistory of malignancies, other than MDS, unless the subject has been free of thedisease (including completion of any active or adjuvant treatment for priormalignancy) for ≥ 5 years. However, subjects with the following history/concurrentconditions are allowed:

• Basal or squamous cell carcinoma of the skin

• Carcinoma in situ of the cervix

• Carcinoma in situ of the breast

• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes,metastasis [TNM] clinical staging system)