Open-Label Study on Long-Term Safety of Berotralstat in Hereditary Angioedema Patients from Previous Clinical Trials

The primary objective of this study is to monitor the long-term **safety** of berotralstat in subjects with **Hereditary Angioedema** (HAE) who were previously enrolled in berotralstat studies. This is clinically relevant as it ensures the ongoing assessment of the drug's safety profile, which is crucial for the management of HAE, a condition characterized by recurrent episodes of severe swelling.

Secondary objectives include:

• To provide continued access to berotralstat for subjects who have participated in Studies BCX7353-302 and BCX7353-204, are expected to continue benefiting from treatment with berotralstat, and do not have other means of access to the medication.

The clinical trial involves a total of **79 participants** diagnosed with **Hereditary Angioedema**. The study population includes both male and female subjects, with an age range of 12 to 17 years. Participants were selected based on their current or previous enrollment in BioCryst-sponsored Study 302 or 204, provided they did not discontinue due to an adverse event or noncompliance. The trial includes individuals who, in the opinion of the investigator, would benefit from continued berotralstat treatment. Female participants are required to meet specific criteria regarding childbearing potential and contraceptive use. The study population is characterized by its inclusion of a vulnerable group, necessitating careful consideration of ethical standards and informed consent processes. Participants are expected to comply with all study procedures as assessed by the investigator.

The clinical trial is designed to monitor the long-term safety of **berotralstat** in subjects with **hereditary angioedema** who were previously enrolled in related studies. This is an open-label, phase IIIb trial, which will provide continued access to the medication. The trial is expected to run until July 2026, with recruitment having started in July 2021. Participants will be involved in the study for a maximum treatment period of 240 days, receiving a daily oral dose of 150 mg of berotralstat. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to conclude participation. The primary endpoints focus on the number and proportion of subjects experiencing treatment-related adverse events, including serious adverse events and treatment-emergent chemistry abnormalities. Secondary endpoints will assess the availability of alternative mechanisms for drug provision or the discontinuation of berotralstat's global commercialization. Participants may be terminated early from the study if they experience significant adverse events, if alternative drug access becomes available, or if they fail to comply with study procedures. The trial is not categorized as low intervention, and it adheres to the revised transparency rules without requesting deferral. The study is open to males and non-pregnant, non-lactating females who meet specific inclusion criteria, including the ability to provide informed consent and the potential benefit from continued treatment as assessed by the investigator.

The clinical trial involves the administration of **BEROTRALSTAT**, an experimental medication designed for the treatment of hereditary angioedema. **BEROTRALSTAT** is provided in the form of a hard capsule, with each capsule containing the active substance of chemical origin, **berotralstat**. The medication is administered orally, with a maximum daily dose of 150 mg. Participants are instructed to take the medication once daily, and the treatment period extends up to 240 days. The capsules are distinctively marked with a black band and are packaged in bottles containing 30 capsules each. Both the trial-specific capsules and those authorized for general use are utilized in this study.

In this open-label study, no placebo or comparator treatment is employed. The primary objective is to monitor the long-term safety of **BEROTRALSTAT** in subjects with type I and II hereditary angioedema who have previously participated in **BEROTRALSTAT** studies. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the prescribed treatment schedule. The study does not include any additional non-experimental treatments or standard-of-care therapies.

Efficacy in this clinical trial will be assessed primarily through the monitoring of treatment-related adverse events. The primary endpoints include the number and proportion of subjects experiencing a treatment-related treatment-emergent adverse event (TEAE), serious adverse events (SAEs), and treatment-related Grade 3 or 4 TEAEs. Additionally, the trial will evaluate the number and proportion of subjects who experience a treatment-related Grade 3 or 4 treatment-emergent chemistry abnormality and those who discontinue due to a TEAE. These parameters will provide insights into the safety profile of **berotralstat** in subjects with type I and II hereditary angioedema.