Efficacy and Safety Evaluation of Luspatercept in Lower-Risk Myelodysplastic Syndrome Requiring Red Blood Cell Transfusions

The primary objective of this study is to evaluate **red blood cell transfusion independence (RBC-TI)** with an associated concurrent mean hemoglobin (Hb) increase of ≥ 1 g/dL after the administration of **luspatercept** at the maximum approved dose. This is specifically for the treatment of anemia in patients with myelodysplastic syndrome (MDS) classified as very low-, low-, or intermediate-risk according to the IPSS-R, who require RBC transfusions. Achieving RBC-TI is clinically significant as it can reduce the burden of transfusions and improve the quality of life for patients with MDS.

Secondary objectives include: - Evaluating the effect of luspatercept on the reduction in RBC transfusions, increase in Hb levels, duration of RBC-TI, and time to achieve RBC-TI in MDS participants. - Assessing the safety and tolerability of luspatercept in MDS participants using a dosing regimen starting at the highest approved dose of 1.75 mg/kg. These objectives are crucial for understanding the broader impact of luspatercept on patient outcomes and ensuring its safe application in clinical practice.

The clinical trial involves a total of **28 participants** diagnosed with **myelodysplastic syndrome**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific criteria, including a documented diagnosis of myelodysplastic syndrome and an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. The trial includes individuals who require regular red blood cell transfusions, with an average transfusion requirement of at least one unit of packed red blood cells over a minimum of eight weeks prior to the initiation of treatment. Participants must have hemoglobin levels of 10.0 g/dL or lower at the time of or within seven days prior to receiving a transfusion to qualify. The trial population encompasses individuals who are either refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatments. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy and safety of **luspatercept** in patients with lower-risk **myelodysplastic syndrome** (MDS) who require red blood cell (RBC) transfusions. This is a Phase 3b, open-label study where participants will receive luspatercept initiated at the maximum approved dose. The trial aims to assess the achievement of RBC transfusion independence (RBC-TI) with a concurrent mean hemoglobin (Hb) increase of ≥ 1 g/dL over a specified period. The study is expected to commence on March 1, 2024, and conclude by May 20, 2027, with a maximum treatment period of 24 weeks for each participant.

The trial will follow a structured sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of MDS, and specific transfusion requirements. Participants must be 18 years or older, have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2, and meet additional criteria related to prior erythropoiesis-stimulating agent (ESA) treatment. The primary endpoint is the achievement of RBC-TI for 8 weeks with a concurrent mean Hb increase from Week 1 to Week 24. Secondary endpoints include changes in total RBC units transfused and the duration of RBC-TI.

Participants will be involved in the study for a period that includes the treatment phase and follow-up visits, with the total duration of involvement potentially extending up to 48 weeks. Follow-up visits will monitor the type, frequency, and severity of adverse events (AEs) related to luspatercept, from screening to 6 weeks post last dose. Conditions that may lead to early termination from the study include the occurrence of severe adverse events or non-compliance with study protocols. The study is not categorized as low intervention, and the trial phase is identified as Phase 5, ensuring rigorous evaluation of the investigational product's safety and efficacy.

The clinical trial involves the administration of **Reblozyl**, a pharmaceutical product containing the active substance **luspatercept**. Reblozyl is available in two formulations: 75 mg and 25 mg powder for solution for injection. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous use. The maximum approved starting dose is 1.75 mg/kg, with a maximum total dose of 60.8 mg. The treatment period is set for a maximum of 24 weeks. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is classified under the ATC code B03XA, indicating its use as an antianemic preparation. The active substance, luspatercept, is a protein of other origin, specifically designed to treat anemia in patients with very low, low, or intermediate-risk myelodysplastic syndromes (MDS) who require red blood cell transfusions.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy and safety of luspatercept initiated at the maximum approved dose. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to assess red blood cell transfusion independence and the associated increase in hemoglobin levels in the target patient population.

The efficacy of the clinical trial will be assessed primarily through the achievement of **red blood cell transfusion independence (RBC-TI)** for an 8-week period, accompanied by a concurrent mean hemoglobin (Hb) increase of at least 1 g/dL from Week 1 to Week 24. This primary endpoint is designed to evaluate the effectiveness of **luspatercept** initiated at the maximum approved dose in patients with low-risk myelodysplastic syndromes (MDS) who require RBC transfusions.

Secondary efficacy endpoints include the mean change in total RBC units transfused over a fixed 16-week period from Week 9 to Week 24 and from Week 33 to Week 48. Additionally, the time from the first dose to the first onset of RBC-TI for periods of 8, 12, and 16 weeks will be measured, as well as the maximum duration of RBC-TI for participants achieving RBC-TI for 8- and 16-week periods. These endpoints will provide further insights into the sustained efficacy of the treatment over time.