Evaluation of the Efficacy, Safety, and Tolerability of Subcutaneous REGN7999 in Adults with Iron Overload Due to Non-Transfusion Dependent Beta-Thalassemia

The primary objective of this study is to evaluate the effect of **REGN7999** on liver iron concentration (LIC) in participants with non-transfusion dependent beta-thalassemia (NTDT) and resultant iron overload (IOL). This is clinically relevant as managing iron overload is crucial in NTDT to prevent organ damage and improve patient outcomes. Additionally, the study aims to evaluate the safety and tolerability of at least two different subcutaneous doses of REGN7999, which is important for determining the optimal dosing regimen for patient safety and efficacy.

Secondary objectives include:

• Evaluating the proportion of participants responding to REGN7999 with improvement in IOL.
• Assessing changes in hemoglobin concentration and red blood cell (RBC) counts in response to REGN7999.
• Evaluating the long-term effect of REGN7999 on LIC and its effect relative to baseline.
• Determining if REGN7999 impacts transfusion requirements.
• Characterizing the pharmacokinetics and assessing the immunogenicity of REGN7999.

The clinical trial involves a total of **85 participants** diagnosed with **non-transfusion dependent beta-thalassemia (NTDT)** and resultant iron overload (IOL). The study population includes both male and female subjects, with an age range of 18 to 64 years. Participants were selected based on specific inclusion criteria, including a clinical diagnosis of NTDT and IOL, defined as liver iron concentration (LIC) of at least 5 mg Fe/g dry weight as measured by R2* MRI at screening, and serum ferritin levels of at least 300 ng/mL. The trial does not involve a vulnerable population. Participants' general health status is characterized by the presence of NTDT and IOL, and no specific lifestyle considerations such as diet or physical activity are highlighted. The selection process ensures that the study population is representative of individuals with the specified medical condition, allowing for the evaluation of the effect of REGN7999 on LIC and the assessment of its safety and tolerability at different subcutaneous doses.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy, safety, and tolerability of subcutaneously administered REGN7999 in participants with **non-transfusion dependent beta-thalassemia** (NTDT) and resultant iron overload (IOL). The trial is structured in two parts and is conducted across multiple centers. The primary objective is to assess the effect of REGN7999 on liver iron concentration (LIC) and to evaluate the safety and tolerability of at least two different subcutaneous doses of REGN7999. The trial is expected to commence recruitment on June 30, 2025, and conclude by January 24, 2028.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a clinical diagnosis of NTDT, LIC ≥ 5 mg Fe/g DW as measured by R2* MRI, and serum ferritin levels ≥ 300 ng/mL. Following successful screening, participants will be randomized to receive either REGN7999 or a matching placebo. The study includes multiple follow-up visits to monitor changes in LIC, hemoglobin levels, and the incidence and severity of treatment-emergent adverse events (TEAEs). The end-of-study visit will assess the overall outcomes and safety of the treatment.

The expected duration of participant involvement in the trial is approximately 2.5 years, from the initial screening to the end-of-study visit. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial will utilize R2* MRI to measure changes in LIC and monitor the concentration of REGN7999 in serum over time, as well as the incidence and titer of anti-drug antibodies (ADA) to REGN7999. The study aims to achieve a ≥20% reduction in LIC and assess changes in hemoglobin and red blood cell transfusion requirements.

The clinical trial involves the administration of **REGN7999**, an experimental medication developed by Regeneron Pharmaceuticals, Inc. **REGN7999** is formulated as a **powder for solution for injection**. The active substance, also named **REGN7999**, is a protein of other origin. The medication is administered via **injection**. The trial aims to evaluate the efficacy, safety, and tolerability of at least two different subcutaneous doses of **REGN7999** in participants with iron overload due to non-transfusion dependent β-thalassemia. The dosing schedule and specific dosage amounts are not detailed in the provided data, but the maximum treatment period is specified as one unit of time, with the unit being unspecified.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is referred to as the "R7999 matching placebo" and is used to maintain the double-blind nature of the trial. The pharmaceutical form, active substance, and route of administration for the placebo are not specified in the data. The placebo serves as a comparator to assess the true efficacy and safety of **REGN7999** by providing a baseline for comparison against the experimental treatment.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change in **Liver Iron Concentration (LIC)** as measured by R2* magnetic resonance imaging (MRI), and the incidence and severity of treatment-emergent adverse events (TEAEs). Secondary endpoints will further evaluate efficacy by measuring the achievement of a ≥20% reduction in LIC by R2* MRI, changes in hemoglobin levels, and the percent change in LIC by R2* MRI. Additional secondary endpoints include the achievement of a ≥1.5 g/dL increase in hemoglobin for two consecutive assessments without red blood cell (RBC) transfusions, the number of RBC transfusions required, and the achievement of transfusion independence. The study will also monitor changes in RBC counts over time, concentrations of REGN7999 in serum, and the incidence and titer of anti-drug antibodies (ADA) to REGN7999 over time.