Long‑Term Safety of Repeated Subcutaneous ADX‑324, a Prekallikrein‑Targeting siRNA, in Adults With Hereditary Angioedema: Phase 3 Extension Study

The primary objective is to assess the Hereditary Angioedema long‑term safety profile of repeated subcutaneous administration of ADX‑324. Secondary objectives include:

• Evaluation of the efficacy of ADX‑324 in preventing HAE attacks.
• Assessment of the impact of ADX‑324 on the quality and pattern of HAE attacks.

Fifty‑three participants with a diagnosis of Hereditary Angioedema were enrolled. The cohort included both male and female adults, spanning the age categories indicated by codes 3 and 4, representing a broad adult age range. All subjects had previously received two doses of the study drug or placebo in Study ADX‑324‑301 and completed that study. Inclusion required written informed consent, ability to comply with study requirements, and access to an acute HAE therapy such as plasma‑derived or recombinant C1‑INH concentrate or a bradykinin‑2 receptor antagonist. Women of childbearing potential and fertile men with partners of childbearing potential were required to use acceptable contraception from enrollment through the end of the study and for a defined period thereafter. Participants were generally in stable health apart from HAE and were classified as a vulnerable population due to the disease characteristics.

The study is a Phase 3 extension trial evaluating the long‑term safety of repeat subcutaneous administration of ADX‑324 in participants with hereditary angioedema who completed the antecedent study and received two prior doses of study drug or placebo; the design incorporates continued dosing with either ADX‑324 or sterile normal saline as a placebo, with participants remaining blinded to allocation. Recruitment is scheduled to begin on 1 August 2026 and continue until 30 April 2030, with each enrolled participant followed for the entire extension period, encompassing a screening (inclusion) visit, a baseline visit on Day 1 for drug administration, subsequent follow‑up visits at regular intervals (e.g., every 12 weeks) to assess safety, record treatment‑emergent adverse events, and capture HAE attack frequency, and a final end‑of‑study visit after the last dose. The primary endpoint is the incidence and severity of treatment‑emergent adverse events, while secondary endpoints include time‑normalized rates of investigator‑confirmed HAE attacks, attacks requiring acute therapy, moderate or severe attacks, and the proportion of attack‑free participants. Early termination may occur for reasons such as serious adverse events, pregnancy, non‑compliance with study procedures, or participant withdrawal of consent.

The investigational product, ADX-324, is supplied as a sterile solution for injection and is administered by subcutaneous injection at a dose of 00 mg per administration; dosing frequency and schedule are defined in the study protocol for participants with hereditary angioedema.

The comparator used in the trial is sterile normal saline (0.9 % sodium chloride solution), which serves as the placebo and is provided in a standard formulation; it is administered using the same route as the investigational product according to the protocol‑specified schedule.

All study drug administrations are recorded in the case report form, and participant compliance is monitored through scheduled study visits and documented dosing logs to ensure adherence to the defined dosing regimen.

Efficacy will be evaluated using several secondary endpoints that quantify the frequency and severity of Hereditary Angioedema attacks. The primary efficacy parameters include the time‑normalized number of investigator‑confirmed HAE attacks per month, the time‑normalized number of attacks requiring acute HAE therapy per month, the time‑normalized number of moderate or severe investigator‑confirmed attacks per month, and the proportion of participants who remain attack‑free during the observation period.

All attack counts will be recorded by the investigator at each study visit and expressed as rates normalized to the duration of exposure (per month). The proportion of participants without any investigator‑confirmed attack will be calculated as a binary outcome. Data will be aggregated across the extension phase and analyzed using descriptive statistics and appropriate comparative methods to assess the long‑term efficacy of repeat dosing with ADX‑324.