Evaluation of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Povetacicept in Patients with Autoimmune Cytopenias: An Open-Label Study

The primary objective of this study is to evaluate the **safety** and tolerability of povetacicept in subjects with autoimmune cytopenias, including warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease (CAD), and immune thrombocytopenia (ITP). This is clinically relevant as it aims to determine the potential adverse effects and overall acceptability of povetacicept, which is crucial for ensuring patient safety and guiding future therapeutic use.

Secondary objectives include:

• Assessing the efficacy of povetacicept in subjects with autoimmune cytopenias, which is important for understanding its therapeutic potential in managing these conditions.
• Evaluating the pharmacokinetics (PK) of povetacicept, providing insights into the drug's absorption, distribution, metabolism, and excretion, which are essential for optimizing dosing regimens.
• Assessing the incidence of anti-drug antibodies (ADA) against povetacicept, which is critical for identifying potential immunogenic responses that could affect treatment efficacy and safety.

The clinical trial involves a total of **92 participants** diagnosed with **autoimmune cytopenias**, including warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease (CAD), and immune thrombocytopenia (ITP). The study population comprises both male and female subjects, with an age range that includes adults and older adults. Participants were selected based on specific criteria related to their medical condition, such as a documented history of the disease and previous treatment responses. The trial includes individuals with a history of failure or relapse to at least two treatment regimens for their respective conditions. The population is characterized by a stable health status concerning protocol-specified standard-of-care medications. The trial also considers vulnerable populations, ensuring comprehensive safety and tolerability assessments of the investigational product, povetacicept, in this diverse group.

The clinical trial is designed to evaluate the **safety** and tolerability of **povetacicept** in subjects with autoimmune cytopenias, including warm autoimmune hemolytic anemia (wAIHA), cold agglutinin disease (CAD), and immune thrombocytopenia (ITP). This is an open-label, Phase 4 study, which will involve the administration of povetacicept as a **solution for injection** via subcutaneous injection. The trial is expected to commence on April 1, 2024, and conclude by July 30, 2026. Participants will be involved in the study for a maximum treatment period of 48 weeks, with a maximum daily dose of 240 mg of povetacicept.

The trial will include several key visits: an initial screening visit to determine eligibility based on specific inclusion criteria, such as documented persistent or chronic primary ITP, wAIHA, or CAD of at least 12 weeks duration, and a history of failure or relapse to at least two treatment regimens. Following the screening, participants will undergo regular follow-up visits to monitor the type, incidence, severity, and seriousness of adverse events (AEs), as well as to assess the efficacy, pharmacokinetics (PK), and anti-drug antibodies (ADA) of povetacicept. The study will conclude with an end-of-study visit to evaluate the overall outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study if they experience significant adverse events or if they do not adhere to the protocol-specified standard-of-care medications. The trial will not include a control group, as it is an open-label study, and all participants will receive the investigational product. The primary endpoint focuses on the safety profile of povetacicept, while secondary endpoints will assess its efficacy and pharmacological properties. The study aims to provide valuable insights into the treatment of autoimmune cytopenias and contribute to the understanding of povetacicept's therapeutic potential in this patient population.

The clinical trial involves the administration of **Povetacicept Injection**, an experimental medication developed by Alpine Immune Sciences Inc. Povetacicept is a protein-based therapeutic agent classified under the pharmaceutical form of a **solution for injection**. The medication is administered via **subcutaneous injection**. The maximum daily dose is 240 mg, with a total maximum dose of 240 mg over the treatment period. The treatment duration is set for a maximum of 48 weeks. Povetacicept is not formulated for pediatric use and is not classified as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the safety and tolerability of Povetacicept in subjects diagnosed with **autoimmune cytopenias**. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. Participants' responses to the treatment are assessed to gather data on the pharmacokinetics and pharmacodynamics of Povetacicept.

The clinical trial titled "Open-Label Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Povetacicept in Subjects with Autoimmune Cytopenias (RUBY-4)" aims to evaluate the efficacy of **povetacicept** in treating autoimmune cytopenias. The primary endpoints for assessing efficacy include the type, incidence, severity, and seriousness of adverse events (AEs). Secondary endpoints involve the assessment of efficacy, pharmacokinetics (PK), and anti-drug antibodies (ADA).

The trial will involve subjects with specific autoimmune cytopenias, including Immune Thrombocytopenia (ITP), Warm Autoimmune Hemolytic Anemia (wAIHA), and Cold Agglutinin Disease (CAD). The efficacy of **povetacicept** will be evaluated through various parameters, including documented histories of platelet counts, hemoglobin levels, and other relevant biomarkers. The trial is designed to ensure that subjects have a documented history of failure or relapse to at least two treatment regimens for their respective conditions.

The study is planned to start recruitment on April 1, 2024, and is estimated to conclude by July 30, 2026. The maximum treatment period for participants is set at 48 weeks. The trial is categorized as a Phase 4 study, focusing on the investigational product's safety and efficacy in the target population. The study will be conducted in an open-label format, allowing for direct observation of the effects of **povetacicept** on the participants.