Evaluation of REGN7257, an Anti-IL2RG Monoclonal Antibody, in Adults with Severe Aplastic Anemia Refractory or Relapsed to Immunosuppressive Therapy

The primary objective of this study is to assess the **safety** and **tolerability** of REGN7257, an anti-Interleukin 2 Receptor Subunit Gamma (IL2RG) monoclonal antibody, in patients with severe aplastic anemia (SAA) that is refractory to or has relapsed on immunosuppressive therapy (IST). This evaluation is crucial for determining the potential risks and adverse effects associated with REGN7257, thereby informing its clinical use in this patient population. An additional primary objective, specific to Part B of the study, is to evaluate the clinical efficacy of REGN7257 in patients with IST-relapsed SAA as a proof of concept, which is essential for understanding the therapeutic potential of the treatment.

The secondary objectives include: - Clinical response over time, which will provide insights into the duration and sustainability of the treatment effects. - Maintenance of response, assessing the long-term effectiveness of the therapy. - Impact on transfusion requirements, which is significant for evaluating the treatment's ability to reduce dependency on blood transfusions. - Effect on blood counts and cell populations, offering data on hematological improvements. - Pharmacokinetics (PK), to understand the drug's absorption, distribution, metabolism, and excretion. - Immunogenicity, to evaluate the potential for immune response against the treatment.

The clinical trial involves a total of **19 participants** diagnosed with **severe aplastic anemia (SAA)**, specifically those who are refractory or have relapsed following immunosuppressive therapy (IST). The study population includes both male and female subjects, with an age range that spans from adolescents to adults. Participants were selected based on specific criteria, including the unavailability or unsuitability of hematopoietic stem cell transplantation (HSCT) as a treatment option, or refusal of HSCT by the patient. All participants are required to have adequate hepatic and renal function. The trial does not include a vulnerable population, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The study aims to assess the safety, tolerability, and clinical efficacy of REGN7257 in this patient population.

The clinical trial is designed to evaluate the **safety** and **tolerability** of REGN7257, an anti-interleukin 2 receptor subunit gamma monoclonal antibody, in patients with severe aplastic anemia (SAA) that is refractory to or has relapsed on immunosuppressive therapy. This study is structured as a Phase 1/2 trial, categorized as a category 2 clinical trial according to EMA guidance. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The estimated duration of the trial spans from October 1, 2020, to July 14, 2026, encompassing both the recruitment and follow-up phases.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as the unavailability or unsuitability of hematopoietic stem cell transplantation and adequate hepatic and renal function. Following successful screening, participants will be randomized to receive the investigational product via intravenous administration. Subsequent follow-up visits will be scheduled to monitor the incidence of adverse events, serious adverse events, and treatment-emergent adverse events, as well as to evaluate the overall response rate and other secondary endpoints such as changes in blood cell counts and drug concentrations in serum over time.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to gather comprehensive data on the primary and secondary endpoints. The expected length of participant involvement will vary depending on individual response and the occurrence of any adverse events. Conditions that may lead to early termination from the study include the development of severe adverse reactions or withdrawal of consent by the participant. The trial aims to provide valuable insights into the clinical efficacy of REGN7257 as a potential treatment for patients with severe aplastic anemia who have limited therapeutic options.

The clinical trial involves the administration of **REGN7257**, an experimental medication developed by Regeneron Pharmaceuticals, Inc. **REGN7257** is a lyophilisate for solution for injection, specifically designed for intravenous use. The active substance in this medication is a monoclonal antibody targeting the interleukin 2 receptor subunit gamma (IL2RG). The pharmaceutical form of the medication is a lyophilized powder that requires reconstitution before administration. The dosing schedule and frequency of administration are determined by the study protocol, which aims to assess the safety, tolerability, and clinical efficacy of **REGN7257** in patients with severe aplastic anemia (SAA) that is refractory to or has relapsed on immunosuppressive therapy (IST).

In addition to the experimental treatment, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, as specified in the study protocol. These treatments are used to provide a baseline for evaluating the effects of **REGN7257**. Participant compliance with the dosing schedule is monitored throughout the study to ensure accurate assessment of the medication's effects. The trial is conducted in accordance with regulatory guidelines to ensure the safety and well-being of participants.

The clinical trial aims to evaluate the efficacy of **REGN7257**, an anti-Interleukin 2 Receptor Subunit Gamma (IL2RG) monoclonal antibody, in patients with severe aplastic anemia (SAA) that is refractory to or has relapsed on immunosuppressive therapy (IST). Efficacy will be assessed through several primary and secondary endpoints. For Part B of the trial, the primary efficacy endpoint is the overall response rate (ORR), which will be measured alongside the incidence of serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs).

Secondary endpoints for both Parts A and B include the ORR, complete response (CR), partial response (PR), and time to best and first response. Additional parameters include the frequency of platelet and red blood cell transfusions per month, changes in various blood cell counts (lymphocyte, neutrophil, hemoglobin, reticulocyte, and platelet), and changes in whole blood immune cell subsets (T cells, B cells, and natural killer cells). Drug concentrations in serum and the incidence of treatment-emergent anti-drug antibodies (ADA) over time will also be evaluated. These endpoints will be measured using validated laboratory tests and clinical assessments at specified timepoints throughout the trial duration.