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

A Phase 3, Double-blind, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Placebo for the Treatment of Anemia Due to the IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes in Subjects With Ring Sideroblasts Who Require Red Blood Cell Transfusions.

The study will be conducted in compliance with the International Council on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) versus placebo in participants with anemia due to the Revised International Prognostic Scoring System (IPSS-R) very low, low, or intermediate MDS with ring sideroblasts who require red blood cell (RBC) transfusions.

Anemia is considered to be one of the most prevalent cytopenias in patients who have myelodysplastic syndromes, an umbrella term used to describe disorders relating to the ineffective production of red blood cells, white blood cells, and/or platelets. Ranging in severity from mild (asymptomatic) to severe, anemia can result in patients requiring regular red blood cell (RBC) transfusions, which can lead to further complications from iron overload. The goal of this study is to assess the safety and efficacy of luspatercept versus placebo in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), have ring sideroblasts present, and require constant RBC transfusions. The design of the study will allow a period of initial randomization of patients into either the luspatercept or placebo arm, followed by a double-blind treatment period, and then an MDS disease assessment visit. For those patients that are determined to be experiencing clinical benefit as judged from the study Investigator by this disease assessment visit, they will be permitted to enter the double-blind Extension Phase of the study. Once patients are discontinued from study treatment, they will enter a post treatment follow-up period.

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