A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

   1. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).

   2. Documented diagnosis of MDS according to World Health Organization (WHO)/French
   American British (FAB) classification that meets IPSS R classification of very low,
   low, or intermediate risk disease, and:

Ring sideroblast ≥ 15% of erythroid precursors in bone marrow or ≥ 5% (but < 15%) if SF3B1
mutation is present.

   - < 5% blasts in bone marrow

   - Peripheral blood white blood cell (WBC) count < 13,000/µL 3. Requires red blood cell
   RBC transfusions 4. Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 5.
   Subjects who are refractory/intolerant/ineligible to prior erythropoietin-stimulating
   agents (ESA) treatment, defined as:

   - Refractory to prior - erythropoietin stimulating agents treatment: documentation of
   non-response or response that is no longer maintained to prior ESA-containing regimen,
   either as single agent or combination (eg, with granulocyte colony stimulating factor
   (G-CSF); ESA regimen must have been either recombinant human erythropoietin (rHu EPO)
   ≥ 40,000 IU/wk for at least 8 doses or equivalent OR darbepoetin alpha ≥ 500 μg Q3W
   for at least 4 doses or equivalent

   - Intolerant to prior ESA treatment: documentation of discontinuation of prior
   ESA-containing regimen, either as single agent or combination (eg, with G-CSF), at any
   time after introduction due to intolerance or an adverse event

   - ESA ineligible: low chance of response to ESA base on endogenous serum erythropoietin
   level > 200 U/L for subjects not previously treated with ESAs

Exclusion Criteria:

The presence of any of the following will exclude a subject from enrollment:

   1. Prior therapy with disease modifying agents for underlying MDS disease.

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

   3. MDS associated with del 5q cytogenetic abnormality

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

   5. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies,
   or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding

   - iron deficiency to be determined by serum ferritin less than or equal to 15 ug/L and
   additional testing if clinically indicated (eg, calculated transferrin saturation
   [iron/total iron binding capacity less than or equal to 20%] or bone marrow aspirate
   stain for iron).

   6. Prior allogeneic or autologous stem cell transplant

   7. Known history of diagnosis of acute myeloid leukemia (AML)

   8. Use of any of the following within 5 weeks prior to randomization:

      - anticancer cytotoxic chemotherapeutic agent or treatment

      - corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week
      prior to randomization for medical conditions other than MDS

      - iron-chelating agents, except for subjects on a stable or decreasing dose for at
      least 8 weeks prior to randomization

      - other RBC hematopoietic growth factors (eg, Interleukin-3)

      - investigational drug or device, or approved therapy for investigational use. If
      the half-life of the previous investigational product is known, use within 5
      times the half-life prior to randomization or within 5 weeks, whichever is longer
      is excluded.

   9. Prior history of malignancies, other than MDS, unless the subject has been free of the
   disease (including completion of any active or adjuvant treatment for prior
   malignancy) for ≥ 5 years. However, subjects with the following history/concurrent
   conditions 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)

10. Major surgery within 8 weeks prior to randomization. Subjects must have completely
   recovered from any previous surgery prior to randomization