LUSPARA - A basket phase II clinical trial evaluating Luspatercept in patients affected with rare inherited anemias

The primary objective is to evaluate the effect of **luspatercept** on **erythroid response** at 12 weeks in patients with **rare inherited anemias**. This response encompasses reduction of **transfusion burden**, including achievement of **transfusion independence** or significant reduction in transfusion requirements, or increase in **hemoglobin level**. The erythroid response at 12 weeks will be assessed separately in each patient group, specifically **congenital sideroblastic anemia** (CSA), **congenital dyserythropoietic anemia** (CDA), and **non-transfusion-dependent Diamond-Blackfan anemia** (NTD-DBA). This objective addresses a critical clinical need in rare anemia populations where therapeutic options to reduce transfusion dependency and improve hemoglobin levels remain limited.

The secondary objective is to assess the impact of luspatercept treatment on hemoglobin level and, for **transfusion-dependent** (TD) patients, on transfusion burden.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population comprised adult participants aged 18 years and older, including both male and female subjects. Participants were affected with rare **inherited anemias**, specifically **constitutional non-syndromic sideroblastic anemia** (CSA), **congenital dyserythropoietic anemias** (CDA types I and II), or non-transfusion-dependent **Diamond-Blackfan anemia** (NTD-DBA). The trial population was selected based on genetic confirmation of disease diagnosis, requiring the presence of ACMG class 4 or 5 variant(s). Both transfusion-dependent and non-transfusion-dependent patients were eligible for inclusion in the CSA and CDA groups, while DBA patients requiring regular transfusion support were excluded. Transfusion-dependent patients were defined as those requiring 6 to 20 units of packed red cells within the previous 24 weeks with no transfusion-free period exceeding 56 days, whereas non-transfusion-dependent patients were required to have significant anemia with **hemoglobin** levels below 10.5 g/dL. Participants were required to have adequate renal function with **creatinine** less than 1.5 times the upper limit of normal and creatinine clearance of at least 30 mL/min, as well as adequate liver function with **transaminases** and gamma-glutamyl transferase less than 1.5 times the upper limit of normal. An **ECOG performance status** of 0-2 at screening was mandatory. The study included vulnerable populations and required strict contraceptive measures for females of childbearing potential and male participants during the trial period.

This is a phase II basket clinical trial evaluating luspatercept in patients with rare inherited anemias. The study is designed as an open-label, single-arm interventional trial assessing the efficacy and safety of luspatercept administered via subcutaneous injection. The investigational medicinal product consists of Reblozyl (luspatercept) available in two strengths: 25 mg and 75 mg powder for solution for injection. The maximum daily and total dose is 1.25 mg/kg, with a maximum treatment period of 52 weeks. Luspatercept is designated as an orphan drug for this indication.

The trial targets three specific patient populations with rare constitutional anemias: constitutional non-syndromic sideroblastic anemia (CSA) including those with germline mutations in ALAS2, SLC25A38, SLC19A2, GLRX5, HSPA9, and other rare mutations; constitutional dyserythropoietic anemias (CDA) types I and II; and non-transfusion-dependent Diamond-Blackfan anemia (NTD-DBA). For all three disease subtypes, genetic diagnosis must be supported by the presence of ACMG class 4 or 5 variants. The study population includes both transfusion-dependent and non-transfusion-dependent patients, with specific criteria defined for each group.

The primary objective is to evaluate the effect of luspatercept on erythroid response at 12 weeks in each patient group. The primary endpoints include the proportion of patients achieving a reduction in transfusion burden of at least 33% from baseline during 12 weeks plus a reduction of at least 2 red cell units over this interval, and the proportion of patients with a mean hemoglobin concentration increase of 1.0 g/dL or higher from baseline over a continuous 12-week interval in the absence of red blood cell transfusions. Secondary endpoints assess transfusion burden reduction during weeks 13 through 24 and weeks 37 through 48, with both 33% and 50% reduction thresholds evaluated, as well as mean changes from baseline in transfusion burden during these periods.

Principal inclusion criteria require patients to be at least 18 years of age at first screening with adequate renal function (creatinine less than 1.5 times upper limit of normal, creatinine clearance ≥30 mL/min) and adequate liver function (transaminases and gamma-glutamyl transferase less than 1.5 times upper limit of normal). Patients must have an ECOG performance status of 0-2 at screening. For CSA and CDA, transfusion-dependent patients must have received 6 to 20 units of packed red cells within the previous 24 weeks with no transfusion-free period exceeding 56 days, while non-transfusion-dependent patients must have significant anemia with hemoglobin below 10.5 g/dL. Females of childbearing potential must have two negative pregnancy tests prior to starting the investigational product and agree to ongoing monthly pregnancy testing, as well as use highly effective contraception for 5 weeks prior to starting treatment, during treatment, and for 12 weeks after discontinuation. Male subjects must agree to use condoms during sexual contact with pregnant females or females of childbearing potential throughout the study and for at least 12 weeks following discontinuation.

The estimated recruitment start date is September 2025, with an estimated study end date of September 2029. The expected duration of participant involvement is up to 52 weeks of treatment. Patients must be willing and able to provide written informed consent and comply with all study procedures for the duration of the study. Early termination from the study may occur based on conditions specified in the protocol, though specific termination criteria are determined by the investigator in accordance with the study design and safety monitoring procedures.

The experimental medication utilized in this clinical trial is **Reblozyl**, which contains the active substance **luspatercept**, a protein-based therapeutic agent. Luspatercept is supplied as a **powder for solution for injection** that is reconstituted to form a **solution for injection** prior to administration. The investigational medicinal product is available in two strengths: **25 mg** and **75 mg**. The pharmaceutical formulation is administered via **subcutaneous injection**. The dosing regimen consists of a maximum daily dose of **1.25 mg/kg** body weight, with a maximum total dose of **1.25 mg/kg**. The treatment period extends up to **52 weeks**. Reblozyl holds **orphan drug designation** under the designation number EU/3/14/1331 and is authorized under the marketing authorization number EU/1/20/1452 by Bristol-Myers Squibb Pharma EEIG. The sponsor product code for this investigational medicinal product is CA056-1115.

The trial evaluates luspatercept in patients affected with rare inherited anemias, specifically targeting congenital sideroblastic anemia, congenital dyserythropoietic anemia, and non-transfusion-dependent Diamond-Blackfan anemia. The primary objective is to assess the effect of luspatercept on erythroid response at 12 weeks, which includes reduction of transfusion burden through either transfusion independence, significant reduction in transfusion requirements, or increase in hemoglobin levels. Participant compliance monitoring and adherence to the dosing schedule are essential components of the study protocol to ensure accurate evaluation of the therapeutic efficacy and safety profile of the investigational medicinal product throughout the treatment period.

Efficacy will be assessed through the evaluation of **erythroid response** in patients with rare inherited anemias. The primary efficacy endpoints include the proportion of patients who achieve a reduction in transfusion burden of at least 33% from baseline during a 12-week period, with a reduction of at least 2 red cell units over this interval. Additionally, the proportion of patients with a mean **hemoglobin concentration** increase of 1.0 g/dL or higher from baseline over a continuous 12-week interval in the absence of red blood cell transfusions will be assessed. Baseline is defined as the 12-week period before the first dose of **luspatercept**.

Secondary efficacy endpoints include the proportion of patients achieving a reduction in transfusion burden of at least 33% or at least 50% from baseline during weeks 13 through 24, with a reduction of at least 2 red cell units over this 12-week interval. Similar assessments will be conducted during weeks 37 through 48, evaluating both 33% and 50% reductions in transfusion burden with a reduction of at least 2 red cell units. The mean change from baseline in transfusion burden during weeks 13 through 24 and during weeks 37 through 48 will also be analyzed. Efficacy will be evaluated separately for each patient group, including **congenital sideroblastic anemia**, **congenital dyserythropoietic anemia**, and non-transfusion-dependent **Diamond-Blackfan anemia**.