An Efficacy and Safety Study of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in Japanese Subjects Who Are Not Requiring Red Blood Cell Transfusion

A Phase 2, Multicenter, Single-arm Study to Evaluate the Efficacy, Pharmacokinetics, and Safety of Luspatercept (ACE-536) for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in Japanese Subjects Who Are Not Requiring Red Blood Cell Transfusion

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

This is a Phase 2, multicenter, single-arm study to evaluate the efficacy, safety and Pharmacokinetics (PK) of luspatercept (ACE-536) for the treatment of anemia due to International prognostic scoring system-Revised (IPSS-R) very low, low or intermediate risk Myelodysplastic syndromes (MDS)in Japanese subjects who are not requiring Red blood cell (RBC) transfusion.

The study is divided into the Screening Period, a Treatment Period and a Post-Treatment Follow up Period.

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 efficacy, safety and PK of luspatercept in anemic patients who are categorized as International Prognostic Scoring System-Revised (IPSS-R) very low, low, or intermediate risk Myelodysplastic syndrome (MDS), and not requiring RBC transfusion. Subjects deemed eligible for the study will be enrolled and treated with luspatercept. Best supportive care (BSC) may be used in combination with study treatment when clinically indicated per investigator. Best supportive care includes, but is not limited to, treatment with transfusions, antibiotic, antiviral and/or antifungal therapy, and nutritional support as needed. Best supportive care for this study excludes the use of ESAs. Patients should receive treatment up to a minimum of 24 weeks after which an MDS Disease assessment visit is scheduled to assess the response to treatment. Patients who are determined to be experiencing clinical benefit may continue treatment. Continued clinical benefit will be re-assessed every 24 weeks. 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 ≥ 20 years of age the time of signing the informed consent form (ICF)

2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.

3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.

4. Subject has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of very low, low, or intermediate risk disease, and:

   • < 5% blasts in bone marrow

5. Subject has symptomatic anemia with mean Hgb concentration < 10.0 g/dL from 2 measurements (one performed within 1 day prior to W1D1 and the other performed 7 to 35 days prior to W1D1) that does not require RBC transfusion. If more than one measurement exists in the period of 7 to 35 days prior to W1D1, the most recent value will be used.

6. Subject must be TI, as documented by the following criteria:

   • No RBC transfusion administered within 16 weeks prior to W1D1 (except transfusions due to blood loss or infection that occurred between 16 and 8 weeks prior to W1D1)

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

8. Females of childbearing potential (FCBP), defined as a sexually mature woman who:

1) has achieved menarche at some point, 2) not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy or amenorrhea due to other medical reasons does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months), must:

• Have two negative pregnancy tests as verified by the investigator prior to starting study therapy (unless the screening pregnancy test was done within 72 hours of W1D1). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence1 from heterosexual contact.

• Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, highly effective contraception without interruption, 5 weeks prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks after discontinuation of study therapy.

• If breastfeeding, agree to stop breastfeeding prior to the participation in the study and not to resume breastfeeding after treatment discontinuation.

  9. Male subjects must:

• Practice true abstinence2 (which must be reviewed prior to each IP administration or on a monthly basis [eg, in the event of dose delays]) or agree to use a condom (latex or non-latex, but not made out of natural [animal] membrane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks following investigational product discontinuation, even if he has undergone a successful vasectomy.

Exclusion Criteria:

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

1. Subject with the any of the following prior treatments for underlying disease:

   • Disease modifying agents (eg, immune-modulatory drug [IMiDs such as lenalidomide])

     - Except if the subject received ≤ 1 week of treatment with a disease modifying agent ≥ 8 weeks from W1D1, at the investigator's discretion.

   • Hypomethylating agents

     - Subjects may be enrolled at the investigator's discretion contingent that the subject received no more than 2 injections of HMA. The last dose must be ≥ 8 weeks from the date of W1D1.

   • Luspatercept (ACE-536) or sotatercept (ACE-011)

   • Allogeneic and/or autologous hematopoietic cell transplant

2. Subject with myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) according to WHO 2016 classification (ie, chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), BCR-ABL12, juvenile myelomonocytic leukemia (JMML), MDS/MPN unclassifiable.

3. Subject with 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.

4. Subject with known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration. Subject with drug induced anemia (eg, mycophenolate).

   • Iron deficiency to be determined by serum ferritin < 100 μg/L and additional testing if clinically indicated (eg, calculated transferrin saturation [iron/total iron binding capacity ≤ 20%] or bone marrow aspirate stain for iron).

5. Subject with known history of diagnosis of AML

6. Subject receiving any of the following treatment within 8 weeks prior to W1D1:

   • Anticancer cytotoxic chemotherapeutic agent or treatment
   • ESAs
   • Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor (GM-CSF), unless given for treatment of febrile neutropenia
   • Immunosuppressive therapy for MDS
   • Systemic corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to W1D1 for medical conditions other than MDS
   • Other RBC hematopoietic growth factors (eg, Interleukin-3)
   • Androgens, unless to treat hypogonadism
   • Hydroxyurea, anagrelide
   • Oral retinoids
   • Arsenic trioxide
   • Interferon and interleukins
   • Investigational drug or device, or approved therapy for investigational use (if 5 times the half-life of the previous investigational drug exceeds 8 weeks, then the time of exclusion should be extended up to 5 times the half-life of the investigational drug)

7. Subject with uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment, or with a history of hypertensive crisis or hypertensive encephalopathy.

8. Subject with any of the following laboratory abnormalities:

   • Absolute neutrophil count (ANC) < 500/μL (0.5 x 10^9/L)
   • Platelet count < 30,000/μL (30 x 10^9/L) (Exclude subjects that may be at risk of bleeding regardless of platelet counts. This includes [but is not limited to] subjects currently using aspirin or heparin, immediately after surgery, or easily causes bleeding such as nasal bleeding or subcutaneous bleeding or previous episode of major bleeding where the cause was not effectively treated.)
   • Estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m^2 (via the 4-variable modification of diet in renal disease [MDRD] formula, Appendix G)
   • Serum aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN)
   • Total bilirubin ≥ 2.0 x ULN. - Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or in the presence of known history of Gilbert Syndrome.

9. Subject with prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 5 years. However, subjects with the following history/concurrent conditions are allowed if considered as curatively treated:

   • 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. Subject with major surgery within 8 weeks prior to W1D1. Subjects must have completely recovered from any previous surgery prior to W1D1

11. Subject with history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis within 6 months prior to W1D1 Note: prior superficial thrombophlebitis is not an exclusion criterion.

12. Subject with the following cardiac conditions within 6 months prior to W1D1:

    myocardial infarction, uncontrolled angina, acute decompensated cardiac failure or New York Heart Association (NYHA) Class III-IV heart failure, or uncontrolled cardiac arrhythmia as determined by the investigator. Subjects with a known ejection fraction ˂35%, confirmed by a local echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan performed within 6 months prior to W1D1.

13. Subject with uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment).

14. Subject with known human immunodeficiency virus (HIV), known evidence of active infectious hepatitis B, and/or known evidence of active Hepatitis C. Local laboratory testing confirming HIV, hepatitis B, and hepatitis C status should not have been performed beyond 4 weeks prior to the date of ICF signature.

15. Subject with history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in luspatercept (see current IB).

16. Pregnant or breastfeeding females.

17. Subject has any significant medical condition, laboratory abnormality, psychiatric illness, or is considered vulnerable by local regulations (eg, imprisoned or institutionalized) that would prevent the subject from participating in the study.

18. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.

19. Subject has any condition or receives concomitant medication that confounds the ability to interpret data from the study.

20. Subject has history of active SARS-CoV-2 infection within 4 weeks prior to screening, unless the subject has adequately recovered from COVID-19 symptoms and related complications as per investigator's discretion and following a discussion with the Medical Monitor. Use of a live COVID-19 vaccine is prohibited within 4 weeks prior to W1D1.