Efficacy of Luspatercept in Erythropoiesis-Stimulating Agent-Naive Lower-Risk Myelodysplastic Syndromes with Anemia and Transfusion Independence

The primary objective of this study is to evaluate the **erythroid response** (hematologic improvement erythroid, HI-E) rate of **luspatercept** for the treatment of anemia in patients with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) who do not require red blood cell (RBC) transfusions. This is clinically relevant as it aims to assess the efficacy of luspatercept in improving hematologic parameters in a specific subset of MDS patients, potentially reducing the need for transfusions and improving patient outcomes.

Secondary objectives include:

• Evaluating HI-E response duration over 18 months post-response.
• Assessing the time to achieve HI-E.
• Monitoring changes in hemoglobin levels from baseline.
• Evaluating RBC transfusion independence at 8 and 12 weeks.
• Assessing neutrophil and platelet responses (HI-N and HI-P).
• Tracking time course changes in serum erythropoietin (sEPO) levels.
• Assessing the impact of luspatercept on quality of life over 24 weeks.
• Evaluating the safety and toxicity profile of luspatercept, with particular attention to thrombosis and cardiovascular events.

The clinical trial involves participants diagnosed with **myelodysplastic syndromes (MDS)**, specifically those classified as very low, low, or intermediate risk, who present with anemia and are non-transfusion dependent. The study population includes both male and female subjects, with an age range that corresponds to adults and older adults. Participants are required to have symptomatic anemia, characterized by a mean baseline hemoglobin level of less than 10 g/dL. The trial does not include a vulnerable population. The selection criteria ensure that participants have not previously received erythropoiesis-stimulating agent (ESA) treatment. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is a **phase II**, open-label, single-arm study designed to evaluate the efficacy of **luspatercept** in patients with very low, low, or intermediate-risk **myelodysplastic syndromes (MDS)** who present with anemia and are naive to erythropoiesis-stimulating agent (ESA) treatment. The primary objective is to assess the erythroid response, defined as a hematologic improvement in erythroid (HI-E) rate, in subjects who do not require red blood cell (RBC) transfusions. The trial will utilize **Reblozyl**, a powder for solution for injection, administered via subcutaneous injection. The study is expected to last until April 2029, with recruitment having commenced in August 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of MDS according to the WHO classification, a very low to intermediate-risk disease score, non-transfusion dependence, and symptomatic anemia with a mean baseline hemoglobin level of less than 10 g/dL. Following the screening, participants will receive **luspatercept** treatment for a maximum period of 3 months, with the primary efficacy endpoint being determined after 24 weeks of treatment. The primary endpoint is an increase in hemoglobin levels by at least 1.5 g/dL, sustained for at least 8 weeks over the baseline level. Secondary endpoints include evaluating the duration of the HI-E response over an 18-month period post-response.

Participants are expected to be involved in the study for the duration of the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The trial is not categorized as low intervention and is conducted under the sponsorship of Bristol-Myers Squibb Pharma EEIG. The study aims to provide valuable insights into the treatment of anemia in MDS patients who are ESA-naive and do not require RBC transfusions.

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 injection. The maximum daily dose is 1.75 mg/kg, with a total maximum dose of 1.75 mg/kg. The treatment period is limited to a maximum of 3 months. Luspatercept is a recombinant fusion protein consisting of a modified form of the extracellular domain of human activin receptor IIB linked to the human IgG1 Fc domain, also known by the synonym ACE-536. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is authorized for use in the European Union.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the efficacy of luspatercept in erythropoiesis-stimulating agent naive lower-risk myelodysplastic syndromes (MDS) patients who do not require red blood cell (RBC) transfusions. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The trial aims to assess the erythroid response rate, specifically the hematologic improvement erythroid (HI-E) rate, in subjects with anemia due to very low-, low-, or intermediate-risk MDS.

The efficacy of **Luspatercept** in the clinical trial will be assessed primarily through the measurement of erythroid response, specifically hematologic improvement erythroid (HI-E). The primary efficacy endpoint is defined according to the International Working Group (IWG) 2018 criteria. This involves an increase in hemoglobin levels by at least 1.5 g/dL, which must be sustained for a minimum of 8 weeks over the baseline hemoglobin level, calculated as the mean over 16 weeks prior to inclusion. This primary endpoint will be evaluated after 24 weeks of treatment with Luspatercept.

Secondary efficacy assessments will focus on the duration of the HI-E response, with a time horizon of 18 months post-response. The trial is designed to evaluate the efficacy of Luspatercept in patients with anemia due to very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) who do not require red blood cell (RBC) transfusions. The study is open-label and single-arm, targeting erythropoiesis-stimulating agent naive lower-risk MDS patients, with or without ring sideroblasts. The trial will follow a structured schedule for measuring and collecting data on hemoglobin levels to ensure accurate and reliable assessment of the treatment's efficacy.