Phase 3 Randomized Double-Blind Placebo-Controlled Trial of ADX-324 for Hereditary Angioedema Attack Prevention

Trial ID: 2025-521352-38-00
Protocol: ADX-324-301
Sponsor: Adarx Pharmaceuticals Inc.

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Diseases & Conditions

Hereditary angioedema

Objectives

The primary objective is to evaluate the efficacy of ADX-324 in the prevention of attacks in patients with hereditary angioedema. 5 Secondary objectives include:

Evaluation of the effects of ADX-324 on the quality and pattern of attacks.

Participants

This clinical trial involves 53 participants diagnosed with hereditary angioedema. The study population consists of both male and female patients, including vulnerable populations. Participants must be at least 18 years of age. Inclusion requires a documented diagnosis of HAE-I or HAE-II based on specific clinical history, C1-esterase inhibitor antigen or functional levels, or SERPING1 gene mutations. Additionally, subjects must have experienced a specified frequency of angioedema attacks during the screening period and maintain access to effective acute therapy. Eligible individuals must be medically appropriate for on-demand treatment as their primary medicinal management.

Plans and Procedures

This Phase 3, randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy of ADX-324, a siRNA targeting prekallikrein, in preventing attacks in individuals with hereditary angioedema. Participants are assigned to receive either ADX-324 via subcutaneous injection or a placebo consisting of sterile normal saline. The protocol begins with a screening period, during which medical history and diagnostic testing for C1-esterase inhibitor levels and complement factor C4 are conducted to confirm the diagnosis. The study assesses the time-normalized number of investigator-confirmed attacks per month from study day 22 through the week 25 visit. The duration of participant involvement extends through the end-of-study visit following the primary assessment period.

Treatment

ADX-324 is an experimental siRNA administered as a solution for injection via subcutaneous injection. This investigational product is being evaluated for the prevention of attacks in participants with hereditary angioedema.

The placebo consists of sterile normal saline (0.9% sodium chloride solution).

Efficacy

The efficacy of ADX-324 in the prevention of hereditary angioedema is evaluated through several endpoints. The primary endpoint is the time-normalized number of attacks confirmed by an investigator per month. This assessment is conducted from Study Day 22 through the Week 25 visit.

Secondary efficacy parameters include:

The time-normalized number of investigator-confirmed attacks requiring acute HAE therapy per month from Study Day 22 to the Week 25 visit.
The time-normalized number of moderate or severe investigator-confirmed attacks per month from Study Day 22 to the Week 25 visit.
The proportion of participants who remain attack-free from Study Day 22 to the Week 25 visit.
The proportion of participants achieving a clinical response, defined as a reduction from the baseline screening rate in the investigator-confirmed attack rate between Study Day 22 and the Week 25 visit.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age ≥18 years.
Have a documented diagnosis of HAE-1or HAE-2 based upon ALL of the following (a, b, AND c): a) Documented clinical history consistent with HAE b) Diagnostic testing (historical documentation or during Screening, with option of one repeat test) that confirms 2 of the following: 1.C1-INH antigen level <50% the lower limit of normal (LLN). 2.C1-INH functional level <50% LLN. 3.C1-INH function ≥50% but ≤60% and a pathogenic mutation in the SERPING1 gene. 4.complement factor C4 level below the LLN. c) Have at least one of the following: 1.Age ≤30 years at reported HAE onset. 2.A family history consistent with HAE-1/HAE-2. 3.Complement component 1q within the normal range.
Must experience ≥1 Investigator-confirmed HAE attacks during the first 4-weeks of Screening or ≥2 Investigator-confirmed HAE attacks in 8 weeks of Screening.
Have access to, and the ability to use, acute HAE therapy to treat HAE attacks (e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) that has been previously shown to be effective for the subject.
Subjects must be deemed medically appropriate for on-demand treatment as the sole medicinal management.

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Exclusion Criteria

Concurrent diagnosis of another form of recurrent angioedema (acquired angioedema, HAE with normal C1-INH, idiopathic angioedema, and recurrent angioedema associated with urticaria).
History of alcohol or drug abuse within the previous year prior to Screening, or current evidence of substance dependence or abuse and/or self-reported alcoholic intake averaging >3 drinks/day.
Any clinically significant medical history including, but not limited to, uncontrolled HTN, uncontrolled DM, or current cardiovascular disease, including recent acute coronary syndrome (within the past 6 months), CHF (NYHA Class III or IV), significant arrhythmias, substance abuse, significant renal disease (CKD Stage 3 eGFR<60 ml/min/1.73 m²) h/o Nephrotic Syndrome), significant hepatic disease, h/o coagulopathies or bleeding diathesis, malignancy within 5 years, active infection (viral, bacterial, fungal, or parasitic) requiring systemic antimicrobial therapy, known HIV infection or positive serology test for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) during screening, Major surgery or significant traumatic injury within 30 days prior to signing the ICF.
Exposure to any of the following LTP for HAE: a. Chronic prophylaxis with C1-INH (CINRYZE, HAEGARDA, RUCONEST) within 2 weeks prior to Screening. b.Chronic prophylaxis with berotralstat (ORLADEYO) within 3 weeks prior to Screening. c. Chronic prophylaxis with lanadelumab (TAKHZYRO) within 8 weeks prior to the Screening. d. Androgen use within 12 weeks prior to Screening.
Exposure to any of the following medications: a. ACE inhibitors within 4 weeks prior to Screening. b. New use of or increase in dose of estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within3 months prior to Screening. Participants on a stable dose of estrogen-containing medications for ≥3 months prior to Screening are eligible.
Received prior treatment with any RNA/DNA-based therapy for HAE (including ADX-324) or is intolerant of any prior RNA/DNA-based therapy for any condition, excluding vaccines.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	01 Oct 2025	2
Belgium	Recruiting	01 Oct 2025	3
Bulgaria	Recruiting	01 Oct 2025	1
Croatia	Recruiting	01 Oct 2025	2
Czechia	Recruiting	01 Oct 2025	3
France	Recruiting	01 Oct 2025	4
Germany	Recruiting	01 Oct 2025	5
Hungary	Recruiting	01 Oct 2025	2
Italy	Recruiting	01 Oct 2025	6
Poland	Recruiting	01 Oct 2025	5