A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE 536) vs Epoetin Alfa for the Treatment of Anemia Due to Revised International Prognostic Scoring System (IPSS-R) Very Low, Low, or Intermediate Risk Myelodysplastic Syndrome (MDS) in Erythropoiesis-stimulating Agent (ESA)-naive Participants who are Non-transfusion Dependent (NTD): The “ELEMENT-MDS” Trial

The primary objective of this study is to compare the proportion of participants with lower-risk non-transfusion dependent (**NTD**) Myelodysplastic Syndrome (**MDS**) who convert to transfusion dependence (defined as requiring ≥ 3 units over 16 weeks) between those treated with **luspatercept** versus **epoetin alfa**. This objective is clinically relevant as it aims to evaluate the effectiveness of luspatercept in delaying or preventing the need for blood transfusions, which is a significant concern in the management of MDS, impacting patient quality of life and healthcare resources.

Secondary objectives include comparing the erythroid response of luspatercept versus epoetin alfa in participants with lower-risk NTD MDS based on the International Working Group (IWG) 2018 criteria. This comparison is important for understanding the relative efficacy of these treatments in stimulating erythropoiesis, which is crucial for managing anemia in MDS patients.

The clinical trial involves a total of **204 participants** diagnosed with **Myelodysplastic Syndrome (MDS)**, specifically targeting those with lower-risk non-transfusion-dependent (NTD) MDS. The study population includes both male and female subjects, aged 18 years and older, who are transfusion independent and have a documented diagnosis of MDS according to the World Health Organization (WHO) 2016 criteria. Participants are required to have a baseline endogenous serum erythropoietin level of ≤ 500 U/L and a baseline hemoglobin concentration of ≤ 9.5 g/dL. The trial population was selected based on specific inclusion criteria, ensuring that participants have symptoms of anemia and an Eastern Cooperative Oncology Group score of 0, 1, or 2. The study does not exclude based on lifestyle factors such as diet or physical activity, but participants must be erythropoiesis-stimulating agent naive or have limited prior exposure to such agents. The trial includes a vulnerable population, ensuring comprehensive representation of the affected demographic.

The clinical trial is designed as a **randomized**, open-label, controlled study to evaluate the efficacy and safety of **luspatercept** compared to **epoetin alfa** in treating anemia in patients with Myelodysplastic Syndrome (MDS). The trial targets participants who are erythropoiesis-stimulating agent (ESA)-naive and non-transfusion dependent. The study is structured to include a treatment period of up to 96 weeks, with the primary endpoint being the conversion to transfusion dependence (TD) as defined by the International Working Group (IWG) 2018 criteria. Secondary endpoints include achieving an increase in mean hemoglobin (Hb) values from baseline in the absence of transfusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented diagnosis of MDS, and baseline Hb concentration. Following randomization, participants will receive either luspatercept or epoetin alfa administered via subcutaneous injection. The trial includes regular follow-up visits to monitor safety, efficacy, and any adverse events. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.

The expected duration of participant involvement is up to 96 weeks, depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or failure to adhere to the study protocol. The trial aims to provide comprehensive data on the comparative effectiveness of luspatercept and epoetin alfa in managing anemia in MDS patients, contributing valuable insights into treatment strategies for this condition.

The clinical trial involves the administration of **Luspatercept**, marketed under the name Reblozyl, which is provided as a powder for solution for injection. The pharmaceutical form is a **solution for injection**, and it is administered via the **subcutaneous** route. The dosage is calculated based on body weight, with a maximum daily dose of 1.25 mg/kg and a total maximum dose of 14 mg/kg. The treatment period for Luspatercept is up to 48 weeks. The product is manufactured by Bristol-Myers Squibb Pharma EEIG and is designated as an orphan drug. The administration involves secondary packaging and labeling specific for clinical supply.

The comparator treatment in the study is **Epoetin Alfa**, marketed as Binocrit, which is available in various dosages: 40,000 IU/1 mL, 4,000 IU/0.4 mL, 6,000 IU/0.6 mL, 2,000 IU/1 mL, 20,000 IU/0.5 mL, and 30,000 IU/0.75 mL. All forms are solutions for injection in pre-filled syringes and are administered subcutaneously. The maximum daily dose for Epoetin Alfa is 1050 IU/kg, with a total maximum dose of 100,800 IU/kg. The treatment period for Epoetin Alfa extends up to 96 weeks. The product is manufactured by Sandoz GmbH and is not designated as an orphan drug. Participant compliance with the dosing schedule is monitored throughout the trial.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the conversion to transfusion dependence (TD), defined by the International Working Group (IWG) 2018 criteria as the requirement of ≥ 3 units of red blood cells (RBCs) within any continuous 16-week interval during the 96-week treatment period. This will be measured to determine the proportion of participants with lower-risk non-transfusion dependent (NTD) myelodysplastic syndrome (MDS) who convert to TD when treated with **luspatercept** compared to **epoetin alfa**.

The secondary endpoint involves the achievement of an increase in mean hemoglobin (Hb) values from baseline of ≥ 1.5 g/dL in any continuous 16-week interval within the 48-week treatment period, in the absence of transfusion. This will be assessed to evaluate the improvement in anemia symptoms in participants. The Hb levels will be calculated using the mean of the two lowest available Hb measurements within 16 weeks prior to randomization, ensuring at least one central lab Hb reading is included within the screening period.