A Phase 1b/2 Single and Multiple Dose Study to Assess the Safety, Tolerability, Clinical Activity, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of STAR-0215 in Participants with Hereditary Angioedema (The ALPHA-STAR Trial)

The primary objective of this study is to evaluate the **safety** and **tolerability** of subcutaneous administration of single and multiple doses of STAR-0215 in participants with Type I or Type II **hereditary angioedema** (HAE). This is clinically relevant as it aims to ensure that the treatment is safe for patients, minimizing adverse effects while providing therapeutic benefits.

Secondary objectives include:

• Assessing the efficacy of STAR-0215 in managing symptoms of HAE.
• Characterizing the **pharmacokinetics** (PK) of STAR-0215 to understand how the drug is absorbed, distributed, metabolized, and excreted in the body.
• Characterizing the **pharmacodynamics** (PD) to determine the drug's biological effects and mechanism of action.
• Evaluating the **immunogenicity** of STAR-0215 to assess the potential for immune response development against the drug.

The clinical trial involves a total of **37 participants** diagnosed with **Hereditary Angioedema (HAE)**, specifically Type I or Type II. The study population includes both male and female subjects, aged 18 years and older, who have a documented diagnosis of HAE. Participants were selected based on their ability to provide informed consent and a clinical history consistent with HAE, including experiencing at least two HAE attacks during the Run-In period. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The population includes individuals who are considered vulnerable, although specific details regarding this aspect are not provided. The selection criteria ensure that participants have a history of nonpruritic swelling episodes without accompanying urticaria, with the onset of symptoms at 30 years of age or younger, or a family history consistent with HAE Type I or II.

The clinical trial is designed to evaluate the **safety** and tolerability of the investigational drug STAR-0215, administered subcutaneously, in participants diagnosed with Type I or Type II **hereditary angioedema** (HAE). This study is structured as a Phase 1b/2 trial, incorporating both single and multiple dose regimens. The trial employs a randomized, double-blind, and controlled methodology to ensure the reliability and validity of the results. The estimated duration of the trial spans from September 29, 2023, to October 20, 2024, encompassing the recruitment, treatment, and follow-up phases.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, documented diagnosis of HAE, and a history of HAE attacks. Following successful screening, participants will be randomized to receive either the investigational drug or a control. Subsequent visits will be scheduled to monitor the incidence of adverse events, changes in vital signs, and other clinical parameters. These follow-up visits are crucial for assessing the primary endpoints, which include the incidence of adverse events and changes in clinical evaluations.

The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate the long-term safety and efficacy of STAR-0215. The expected length of participant involvement is contingent upon the dosing schedule 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 non-compliance with study protocols. Secondary endpoints will also be evaluated, such as changes in the monthly HAE attack rate, severity, and duration of attacks, as well as pharmacokinetic and pharmacodynamic parameters.

The clinical trial involves the administration of **STAR-0215**, an experimental medication developed by Astria Therapeutics, Inc. STAR-0215 is formulated as a **sterile solution** and is intended for **subcutaneous use**. The active substance in STAR-0215 is a protein of other origin, specifically designed for the treatment of **hereditary angioedema** (HAE). The trial aims to evaluate the safety and tolerability of both single and multiple doses of STAR-0215 in participants diagnosed with Type I or Type II HAE. The dosing schedule and frequency of administration are determined by the study protocol, with careful monitoring of participant compliance to ensure adherence to the treatment regimen.

In this study, STAR-0215 is the primary investigational product, and no additional non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified. The trial does not include a pediatric formulation of the medication, and STAR-0215 is not classified as an orphan drug. The study protocol outlines the procedures for monitoring participant compliance, which may include regular follow-up visits, electronic diaries, or other methods as deemed appropriate by the investigators. The trial is conducted in accordance with regulatory guidelines to ensure the safety and well-being of all participants.

The efficacy of STAR-0215 in the treatment of **Hereditary Angioedema (HAE)** will be assessed through a series of primary and secondary endpoints. Primary endpoints include the incidence of adverse events and changes in vital signs, ECG findings, physical examination findings, and clinical laboratory evaluations. Secondary endpoints focus on the change from baseline in the monthly HAE attack rate, the incidence and severity of HAE attacks categorized as mild, moderate, or severe, and the duration of HAE attacks, which will be classified into timeframes such as shorter than 12 hours, 12 to 24 hours, 24 to 48 hours, and longer than 48 hours. Additionally, the number of HAE attacks requiring on-demand therapy and the time to the first HAE attack after the first and last dosing will be evaluated.

Pharmacokinetic (PK) parameters will be derived from the concentration of STAR-0215, and changes in plasma kallikrein activity will be measured. The formation of anti-drug antibodies against STAR-0215 will also be monitored. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the clinical activity and immunogenicity of STAR-0215 in participants with Type I or Type II HAE. The trial is designed to provide comprehensive data on the safety, tolerability, and clinical efficacy of STAR-0215 administered subcutaneously in single and multiple doses.