Evaluation of Long-Term Safety of Oral Deucrictibant (PHA-022121) for Acute Hereditary Angioedema Attacks in C1-Inhibitor Deficient Patients

The primary objective of this study is to evaluate the **safety** of long-term on-demand treatment with deucrictibant for acute hereditary angioedema (HAE) attacks, including laryngeal attacks without breathing difficulties. This is clinically relevant as it addresses the need for a safe therapeutic option for managing acute episodes in patients with HAE, a condition characterized by unpredictable and potentially life-threatening swelling episodes.

Secondary objectives include:

• Evaluating the efficacy of deucrictibant in achieving symptom relief in participants with acute HAE attacks, including laryngeal attacks without breathing difficulties.
• Assessing the maintenance of deucrictibant efficacy in achieving symptom relief for any subsequent acute HAE attacks, including laryngeal attacks without breathing difficulties.
• Determining the proportion of deucrictibant-treated attacks requiring a second dose of deucrictibant or rescue medication to achieve symptom relief.

The clinical trial involves a total of **87 participants** diagnosed with **hereditary angioedema attacks** caused by Type 1 and 2 C1-Inhibitor deficiency. The study population includes both male and female subjects, with an age range encompassing adolescents to adults. Participants were selected based on their previous involvement in related studies, specifically Study C201 and Study C306, and their ability to comply with the protocol as assessed by the investigator. The trial includes a vulnerable population, indicating that special considerations are in place for their participation. Lifestyle factors such as diet and physical activity are not specified, but female participants of childbearing potential are required to adhere to specific pregnancy testing and contraception guidelines. The trial aims to evaluate the safety of long-term on-demand treatment with deucrictibant for acute hereditary angioedema attacks, including laryngeal attacks without breathing difficulties.

The clinical trial is designed to evaluate the safety and efficacy of **deucrictibant** for the acute treatment of **hereditary angioedema** attacks in patients with C1-Inhibitor deficiency, specifically Type I or Type II. This is a Phase II/III, randomized, double-blind, controlled study. The trial will extend over a period of approximately 48 months, with an estimated end date in June 2027. Participants will be involved in the study for the duration of the trial unless early termination criteria are met, such as the occurrence of treatment-emergent adverse events (TEAEs) leading to discontinuation.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. The screening visit will determine eligibility based on inclusion criteria, such as previous participation in related studies and compliance with protocol requirements. Follow-up visits will monitor the safety and efficacy of the treatment, assessing primary endpoints like TEAEs and secondary endpoints such as time to symptom relief. The end-of-study visit will conclude the participant's involvement, ensuring all safety assessments are completed.

Participants will be randomly assigned to receive either the investigational product, **PHA-022121**, or a comparator, with the administration route being oral for the investigational product and subcutaneous for the comparator. The maximum daily dose for the investigational product is 60 mg, with a total treatment period not exceeding 48 months. Conditions for early termination include non-compliance with the study protocol or the emergence of serious adverse events. The trial aims to provide comprehensive data on the long-term safety and efficacy of deucrictibant in managing acute hereditary angioedema attacks.

The clinical trial involves the administration of **PHA-022121**, a soft capsule containing the active substance **(S)-N-(1-DEUTERO-1-(3-CHLORO-5-FLUORO-2-((2-METHYL-4-(1-METHYL-1H-1,2,4-TRIAZOL-5-YL)QUINOLIN-8-YLOXY)METHYL)PHENYL)ETHYL)-2-(DIFLUOROMETHOXY)ACETAMIDE**. This experimental medication is administered orally with a maximum daily dose of 60 mg, and the treatment period extends up to 48 weeks. The pharmaceutical form is a soft capsule, and the medication is produced by Pharvaris Netherlands B.V. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen.

Another experimental treatment in the study is **Deucrictibant (PHA-022121)**, also provided in a soft capsule form for oral administration. The active substance is **DEUCRICTIBANT**, and the maximum daily dose is set at 40 mg, with a treatment duration of up to 48 weeks. This medication is also manufactured by Pharvaris Netherlands B.V. Participant compliance is closely monitored to maintain the integrity of the dosing schedule.

The study includes a comparator treatment with **ICATIBANT**, which is administered subcutaneously. The maximum daily dose for ICATIBANT is 60 mg, and the treatment period is up to 48 weeks. This non-experimental treatment serves as a standard-of-care therapy for comparison with the experimental medications. The administration route and dosing are consistent with established guidelines for the management of hereditary angioedema.

Additionally, a placebo, referred to as **Test IMP (PHA-022121) without active substance**, is included in the trial. This placebo is used to assess the efficacy and safety of the experimental treatments by providing a control for comparison. The placebo does not contain any active substance and is administered in a manner consistent with the experimental treatments to maintain blinding and study integrity.

The efficacy of the clinical trial will be assessed using several secondary endpoints focused on the treatment of acute attacks in patients with **Hereditary Angioedema** (HAE) due to C1-Inhibitor Deficiency. The primary efficacy parameters include the time to onset of symptom relief and the time to substantial symptom relief. These will be measured using the Patient Global Impression of Change (PGI-C) and the Patient Global Impression of Severity (PGI-S) scales. Specifically, the time to onset of symptom relief is defined as achieving a PGI-C rating of at least "a little better" for two consecutive timepoints within 12 hours post-treatment. Substantial symptom relief is defined as achieving a PGI-C rating of at least "better" for two consecutive timepoints within the same timeframe.

Additional efficacy assessments will involve the Visual Analog Scale (VAS) and the Angioedema Multidimensional Rating Assessment (AMRA). The time to onset of symptom relief by VAS is defined as a reduction of at least 30% from pretreatment in the VAS composite score, sustained for two consecutive timepoints. Similarly, the time to symptom relief by VAS is based on achieving a 50% reduction from pretreatment in the VAS composite score, sustained for two consecutive timepoints. For AMRA, the time to onset of symptom relief is defined as a reduction of at least 30% from pretreatment in the AMRA composite score, sustained for two consecutive timepoints, while the time to symptom relief is based on achieving a 50% reduction from pretreatment in the AMRA composite score, sustained for two consecutive timepoints.