ADX-324: An Investigational siRNA Therapeutic for Hereditary Angioedema

I. Executive Summary

ADX-324 is an investigational short-interfering RNA (siRNA) therapeutic agent under development by ADARx Pharmaceuticals, Inc., primarily for the prophylactic treatment of Hereditary Angioedema (HAE).[1] The therapeutic strategy of ADX-324 centers on the specific targeting and reduction of plasma prekallikrein (PKK) production, a pivotal protein in the pathophysiological cascade leading to bradykinin generation and subsequent angioedema attacks characteristic of HAE. This is achieved through the RNA interference (RNAi) mechanism, where ADX-324 is designed to silence the KLKB1 messenger RNA (mRNA).[2]

A key feature of ADX-324's development is its utilization of ADARx Pharmaceuticals' proprietary RNA targeting platform. This platform incorporates technologies for liver-directed delivery, primarily through N-acetylgalactosamine (GalNAc) conjugation (referred to as PLR™ - Preeminent Liver RNA, or CTD™ - Cell-Targeted Delivery technology), and advanced oligonucleotide optimization strategies (known as SPE™ - Sequence Specific Platform Enhancement, or MST™ - mRNA Silencing Technology) to enhance potency, stability, and duration of action.[1]

Preclinical investigations, notably studies conducted in non-human primates, have provided encouraging data supporting the potential for ADX-324 to be administered via a long-acting, low-volume subcutaneous dosing regimen, possibly on a bi-annual or even annual basis.[1] Such a dosing schedule would represent a significant advancement in convenience and treatment burden reduction for HAE patients. Pharmacodynamic data from these preclinical efforts were presented at the Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology (ACAAI) in November 2023, signaling progress in understanding the drug's activity profile.[8]

ADX-324 is currently progressing through clinical development. A Phase 1/2a clinical trial (NCT05691361; ADX-324-101) is ongoing, evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) in healthy volunteers and subsequently in patients with HAE.[1] Following this, a pivotal Phase 3 clinical trial (NCT06960213; STOP-HAE) has been designed and is anticipated to begin recruiting participants in mid-2025 to further assess the efficacy and safety of ADX-324 in preventing HAE attacks.[12]

The consistent emphasis in company communications on a "low volume subcutaneous dose regimen" with "bi-annual, and possibly annual" dosing intervals [1] highlights a core strategic objective: to differentiate ADX-324 from existing HAE prophylactic treatments, many of which necessitate more frequent administration. HAE is a chronic condition requiring lifelong prophylaxis, making patient adherence and treatment burden critical considerations. An siRNA therapeutic capable of achieving sustained PKK knockdown with such infrequent dosing could address a significant unmet medical need, influencing the design of the Phase 3 trial which evaluates quarterly and semi-annual dosing.[13]

Furthermore, the development trajectory of ADX-324 serves a dual purpose. Beyond its potential as a specific treatment for HAE, its clinical progression acts as a validation for ADARx's underlying proprietary RNA delivery (PLR™/CTD™) and oligonucleotide modification (SPE™/MST™) technologies. ADARx possesses a diversified pipeline targeting various therapeutic areas.[4] Success with ADX-324, particularly in demonstrating effective liver targeting, durable gene silencing, and a favorable safety profile, would inherently de-risk other programs leveraging these same foundational technologies. The significant collaboration agreement with AbbVie, initiated in May 2025 for other therapeutic areas, further underscores the perceived value and potential of ADARx's RNA platform technologies.[15]

II. Introduction to ADX-324

[A. Developer: ADARx Pharmaceuticals]

ADX-324 is being developed by ADARx Pharmaceuticals, Inc., a clinical-stage biotechnology company based in San Diego, California.[1] The company is dedicated to the discovery and development of next-generation RNA-targeting therapeutics aimed at addressing a wide array of diseases, including genetic disorders, cardiometabolic conditions, complement-mediated diseases, and central nervous system (CNS) ailments.[1] ADARx's strategy involves leveraging its proprietary RNA technologies to create therapies that offer advantages in delivery, precision, and durability, positioning itself as an innovator in the competitive RNA therapeutics landscape.[18] The company's pipeline includes multiple wholly-owned clinical and preclinical candidates targeting the liver, CNS, and adipose tissue, with ADX-324 being its most advanced program, poised for Phase 3 clinical trials for HAE.[15] The company's focus on "next-generation" solutions suggests an ambition to overcome limitations of earlier RNA therapies and establish a leading presence in the field.

[B. Drug Class: Short-interfering RNA (siRNA)]

ADX-324 belongs to the class of drugs known as short-interfering RNAs (siRNAs).[1] siRNAs are double-stranded RNA molecules that harness the cell's natural RNA interference (RNAi) pathway to achieve sequence-specific gene silencing.[5] This mechanism operates post-transcriptionally, where the siRNA molecule is incorporated into a multi-protein complex called the RNA-induced silencing complex (RISC). The siRNA then guides RISC to recognize and cleave the complementary target messenger RNA (mRNA), thereby preventing the mRNA from being translated into its corresponding protein.[5] This targeted approach allows for highly specific downregulation of disease-causing genes. The selection of siRNA as a therapeutic modality allows ADARx to build upon a class of drugs with several precedents of regulatory approval for various conditions, particularly those involving liver-expressed gene targets. This established pathway potentially allows ADARx to concentrate its innovative efforts on enhancing the delivery and oligonucleotide characteristics of its candidates rather than validating an entirely novel therapeutic approach.

[C. Proprietary Technologies: PLR™, SPE™, CTD™, MST™, and GalNAc Conjugation]

ADARx Pharmaceuticals employs a suite of proprietary technologies to optimize its RNA therapeutic candidates. For ADX-324, company communications have highlighted the use of the PLR™ (Preeminent Liver RNA) delivery platform and SPE™ (Sequence Specific Platform Enhancement) technology.[1]

The company's broader technological capabilities, as detailed on its website, include CTD™ (Cell-Targeted Delivery) and MST™ (mRNA Silencing Technology).[5] The CTD™ platform encompasses strategies for targeted delivery, including the use of proprietary clusters of N-acetylgalactosamine (GalNAc) ligands. These GalNAc clusters facilitate efficient binding to the asialoglycoprotein receptor (ASGPR), which is highly expressed on hepatocytes, thereby enabling effective liver-targeted delivery of RNA drugs.[5] ADX-324 is specifically described as a GalNAc3-conjugated siRNA, indicating its reliance on this liver-targeting mechanism.[6]

The MST™ platform focuses on optimizing the siRNA drug candidates themselves for precise targeting, profound target mRNA reduction, and sustained therapeutic effect. This is achieved by enhancing key aspects of delivery, RISC engagement, and RNA sequence optimization.[5]

It is plausible that PLR™ is the specific branding for ADARx's GalNAc-mediated liver delivery component within the broader CTD™ framework, particularly relevant for hepatically expressed targets like PKK. Similarly, SPE™ likely encapsulates aspects of the MST™ platform related to the chemical modifications and sequence design of the siRNA oligonucleotide to improve its stability, potency, duration of action, and reduce off-target effects. This integrated technology stack—combining targeted delivery with optimized oligonucleotide chemistry—is fundamental to achieving the desired therapeutic profile for ADX-324, including the potential for low-volume, long-acting subcutaneous administration.[1] The distinct branding of these platform components may also reflect a nuanced communication strategy, emphasizing specific technological advantages relevant to particular drug candidates or audiences.

III. Mechanism of Action and Therapeutic Rationale

[A. Target: Prekallikrein (PKK) and its Role in Hereditary Angioedema (HAE)]

ADX-324 is designed to target plasma prekallikrein (PKK), also known by its gene name KLKB1.[2] PKK is a zymogen that, upon activation to plasma kallikrein (PKa), plays a crucial role in the plasma kallikrein-kinin system.[21] This system is central to the pathophysiology of Hereditary Angioedema (HAE), particularly HAE Types I and II. These types are most commonly caused by mutations in the SERPING1 gene, leading to a deficiency or dysfunction of the C1 esterase inhibitor (C1-INH) protein.[6]

C1-INH normally regulates the activity of several proteases, including those in the contact system like factor XIIa and plasma kallikrein. In the absence of sufficient functional C1-INH, the contact system becomes overactive, leading to uncontrolled generation of plasma kallikrein.[21] Plasma kallikrein then cleaves high-molecular-weight kininogen (HMWK) to release bradykinin.[6] Bradykinin is a potent vasoactive peptide that binds to bradykinin B2 receptors on endothelial cells, increasing vascular permeability. This results in the leakage of fluid into the interstitial space, causing the recurrent, localized, and potentially life-threatening swelling attacks (angioedema) characteristic of HAE.[21] The liver is the primary organ responsible for the synthesis of prekallikrein.[6] The selection of PKK as a therapeutic target is supported by a strong biological rationale and clinical validation from other therapies aimed at the kallikrein-kinin pathway for HAE management. This established understanding reduces the inherent risk associated with novel target discovery and allows development efforts to focus on optimizing drug delivery, dosing frequency, and long-term safety.

[B. Pharmacological Action: Inhibition of PKK Expression via RNA Interference]

ADX-324 functions as an siRNA therapeutic that specifically targets the mRNA encoding PKK.[1] Through the RNAi pathway, ADX-324 guides the RISC to bind and cleave PKK mRNA molecules. This degradation of PKK mRNA occurs primarily within hepatocytes, the main liver cells, due to the GalNAc-mediated liver-targeting delivery mechanism of ADX-324.[5] By preventing the translation of PKK mRNA into protein, ADX-324 effectively reduces the synthesis and subsequent secretion of PKK from the liver into the bloodstream.[6] This upstream intervention, by inhibiting the production of new PKK protein, offers the potential for a more durable and sustained reduction in plasma PKK levels compared to therapies that directly inhibit the activity of already circulating PKK or kallikrein. This sustained effect is a cornerstone of the strategy to achieve a long-acting prophylactic treatment.

[C. Intended Therapeutic Effect: Prevention of HAE Attacks]

The ultimate therapeutic goal of ADX-324 is the prophylactic prevention of HAE attacks.[1] By substantially lowering plasma PKK levels, ADX-324 aims to reduce the capacity for excessive bradykinin generation. This, in turn, is expected to decrease the frequency, severity, and predictability of angioedema episodes in patients with HAE Types I and II.[4] The mechanism of action, focused on reducing the synthesis of PKK, inherently positions ADX-324 as a preventative therapy rather than an acute treatment for ongoing attacks. This prophylactic approach aligns with the chronic nature of HAE and the objective of providing patients with long-term control over their condition, as reflected in the design of its clinical trials which focus on attack prevention.[13]

IV. Therapeutic Indication: Hereditary Angioedema (HAE)

[A. Brief Overview of HAE (Types I & II)]

Hereditary Angioedema is a rare, autosomal dominant genetic disorder characterized by recurrent, unpredictable, and often debilitating episodes of angioedema.[1] These swelling attacks can affect various parts of the body, including the skin (extremities, face, genitals), the gastrointestinal tract (causing severe abdominal pain, nausea, and vomiting), and the upper airways (larynx), where swelling can be life-threatening due to asphyxiation.[21]

HAE is primarily classified into types based on C1-inhibitor (C1-INH) levels and function:

• HAE Type I: Accounts for approximately 85% of cases and is characterized by low quantitative levels of C1-INH protein.[21]
• HAE Type II: Accounts for about 15% of cases and is characterized by normal or elevated levels of C1-INH protein, but the protein is dysfunctional.[21]

Both HAE Type I and Type II result from mutations in the SERPING1 gene, which encodes C1-INH.[21] The deficiency or dysfunction of C1-INH leads to dysregulation of several plasma cascade systems, most notably the contact system (kallikrein-kinin system), resulting in the overproduction of bradykinin, the principal mediator of swelling in HAE.[6] The clinical development program for ADX-324 specifically targets patients with HAE Type I or Type II, as this population shares the common underlying pathophysiology of C1-INH deficiency leading to bradykinin-mediated angioedema, making PKK inhibition a rational therapeutic strategy.[13]

[B. Unmet Medical Needs in HAE Treatment]

While the therapeutic landscape for HAE has evolved significantly with the availability of on-demand treatments for acute attacks and several prophylactic options, unmet medical needs persist.[23] A major challenge for patients requiring long-term prophylaxis is the treatment burden associated with many current therapies. Some prophylactic treatments involve frequent intravenous or subcutaneous injections (e.g., C1-INH replacement therapies administered twice weekly, or other pathway inhibitors requiring administration every one to four weeks).[25] This can significantly impact a patient's quality of life, adherence to treatment, and overall well-being.

ADX-324 aims to directly address this unmet need by offering a potentially highly effective prophylactic treatment with a significantly reduced dosing frequency. Preclinical data suggest the possibility of bi-annual or even annual subcutaneous administration.[1] Such an extended dosing interval, if validated in clinical trials, would represent a substantial improvement in convenience and could transform the management of HAE, allowing patients greater freedom and a reduced focus on their chronic condition. This focus on convenience, alongside efficacy and safety, is a key differentiating factor for ADX-324.

V. Preclinical Development and Findings

[A. Summary of Key Preclinical Studies]

The preclinical development of ADX-324 has involved a series of studies to establish its mechanism of action, pharmacokinetics, pharmacodynamics, and safety prior to human testing. Notably, these included evaluations in non-human primate (NHP) models, which are often used to assess the activity and duration of effect of RNAi therapeutics due to their physiological similarity to humans.[1] These NHP studies were pivotal in supporting the potential for a long-acting dosing regimen for ADX-324. While company press releases have alluded to these "promising preclinical studies" [1], detailed peer-reviewed publications comprehensively outlining the full preclinical data package for ADX-324 specifically in HAE-relevant animal models were not available within the scope of the provided information. This is a common occurrence in the early stages of drug development, where key findings are often first disseminated through company announcements and conference presentations before formal publication in scientific journals.

[B. Evidence of PKK Knockdown and Potential for Long-Acting Dosing]

A central finding from the preclinical program, as highlighted by ADARx Pharmaceuticals, is the confirmation in NHP studies of robust and sustained reduction (knockdown) of PKK levels following administration of ADX-324.[1] This sustained knockdown is the basis for the anticipated long-acting dosing interval, with the company suggesting the likelihood of a bi-annual or possibly even annual low-volume subcutaneous dose regimen for ADX-324.[1] Early clinical observations from the Phase 1 trial in healthy volunteers appear to corroborate these preclinical findings, with reports indicating "very deep knockdown" of prekallikrein proteins.[6] This suggests that the targeted engagement and mechanism of action observed in preclinical models are translating to early human studies, providing a strong rationale for investigating less frequent dosing schedules in later-stage clinical trials.

[C. Pharmacodynamics Data Presented (e.g., ACAAI 2023)]

ADARx Pharmaceuticals presented pharmacodynamics data from a preclinical trial of ADX-324 for HAE at the Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology (ACAAI) in November 2023.[8] Scientific conferences such as ACAAI serve as important venues for disseminating emerging data to the clinical and scientific communities, often well in advance of peer-reviewed publication. However, the specific details of the pharmacodynamic data presented at this meeting, such as the precise levels of PKK reduction achieved, the duration of this effect in the preclinical models used, or other specific endpoints, were not available in the provided research materials. The available information confirms the event of the presentation but does not include the abstract content or poster details.

VI. Clinical Development Program

The clinical development of ADX-324 is advancing through a structured program designed to evaluate its safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and ultimately its efficacy in preventing HAE attacks.

[A. Phase 1/2a Clinical Trial (NCT05691361 / ADX-324-101)]

The foundational human study for ADX-324 is a Phase 1/2a trial registered under NCT05691361 and also identified as ADX-324-101.[9]

• 1. Study Design and Objectives: This first-in-human study is designed in two parts. Part A is a randomized, double-blind, placebo-controlled, single ascending dose (SAD) evaluation in healthy adult volunteers.1 Up to six dose cohorts are planned for this SAD portion, employing a sentinel dosing strategy where a small number of participants in each cohort receive the drug or placebo before escalating to the full cohort, allowing for safety review at each dose level.9 Part B of the study is an open-label expansion cohort in patients with HAE, who will receive a dose selected based on the findings from Part A.9 The primary objectives across both parts are to evaluate the safety and tolerability of ADX-324 when administered by subcutaneous injection.1 This involves monitoring the incidence, relationship, and severity of adverse events (AEs), serious adverse events (SAEs), and changes in vital signs and electrocardiogram (ECG) parameters.9
• 2. Participant Population: For Part A (Healthy Volunteers - HV), the trial enrolls male and female adults aged 18 to 55 years with a Body Mass Index (BMI) between 18 and 30 kg/m².9 For Part B (HAE Patients), participants are male and female adults aged 18 years or older with a confirmed diagnosis of HAE Type I or II and a history of at least one HAE attack per month on average.9 Participants must have access to, and be able to use, acute medication for HAE attacks.9 Key exclusion criteria for all participants generally include any significant medical history, active malignancy, history of liver disease, clinically significant renal impairment (defined as estimated creatinine clearance <60 mL/min or serum creatinine >1.5 times the upper limit of normal), active infection, major surgery within the preceding three months, known hypersensitivity to study drug components, and pregnancy or lactation.9 For HAE patients specifically, exclusion criteria include a concurrent diagnosis of any other type of chronic angioedema, a history of clinically significant arterial or venous thrombosis, or the use of C1-INH products, androgens, antifibrinolytics, or other small molecule medications for routine HAE prophylaxis within four half-lives prior to screening.9
• 3. Interventions and Dosage: ADX-324 is administered as a subcutaneous injection.1 In the SAD portion for healthy volunteers, participants receive either ADX-324 at one of up to six ascending dose levels or a placebo (saline).9 The HAE patient cohort in Part B receives open-label ADX-324 at a dose level selected based on the safety and pharmacodynamic data from Part A.9
• 4. Primary and Secondary Outcome Measures: The primary outcome measures focus on safety and tolerability, assessed by the incidence, relationship, and severity of AEs and SAEs, as well as changes in ECG parameters (PR, QRS, QT, and QTcF intervals) throughout a 365-day follow-up period.9 Secondary outcome measures include characterization of the PK profile of ADX-324 in both healthy volunteers and HAE patients. This involves measuring parameters such as maximum observed concentration (Cmax​), time to maximum concentration (Tmax​), area under the concentration-time curve (AUC), apparent volume of distribution (Vz​/F), terminal elimination rate constant (λz​), total apparent body clearance (CL/F), and apparent terminal half-life (t1/2​).9 These PK parameters are assessed at various time points, up to 8 days for some parameters and up to 365 days for others. Pharmacodynamic (PD) effects are also key secondary outcomes, evaluated by measuring the change from baseline in plasma concentrations of prekallikrein (PKK) and kallikrein (KK) over a 365-day period in both healthy volunteers and HAE patients.9
• 5. Current Status, Timelines, and Preliminary Observations: The NCT05691361 trial is currently recruiting participants.2 ADARx Pharmaceuticals announced the dosing of the first cohort in this study on January 20, 2023.1 The trial is being conducted in Australia, with CMAX Clinical Research in Adelaide, South Australia, identified as a study site.1 Timelines for the study include a start date of December 14, 2022. The estimated primary completion date varies slightly across different registry sources, cited as January 2, 2025 9 or July 21, 2025.2 The estimated study completion date is December 26, 2025.9 Preliminary observations, reported in October 2023, indicated that early data from healthy volunteers showed "very deep knockdown" of prekallikrein proteins.6 It was anticipated that Part B of the trial, enrolling HAE patients, would commence before the end of 2023.6 The study design, which incorporates an open-label HAE patient cohort within the Phase 1/2a structure, allows ADARx to gather initial signals of PKK reduction and safety data in the target patient population relatively early. This approach can expedite the decision-making process for advancing to Phase 3 development. The choice of Australia for conducting this first-in-human study is a common strategic decision for biotechnology companies, often driven by favorable regulatory timelines and research infrastructure.

Table 1: Summary of NCT05691361 (ADX-324-101) Trial Design

Feature	Details
Trial ID	NCT05691361 / ADX-324-101
Title	Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients
Phase	Phase 1/2a
Status	Recruiting (as of latest updates)
Sponsor	ADARx Pharmaceuticals, Inc.
Indication	Hereditary Angioedema (HAE) Types I & II
Study Design	Part A: Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose in Healthy Volunteers. Part B: Open-Label in HAE Patients.
Number of Participants	Up to 6 dose cohorts in Part A; expansion cohort in Part B (specific total N not detailed in snippets)
Key Interventions	ADX-324 (subcutaneous injection, ascending doses), Placebo (saline)
Primary Outcomes	Safety and Tolerability (AEs, SAEs, ECG changes) over 365 days
Key Secondary Outcomes	Pharmacokinetics of ADX-324; Pharmacodynamics (change in plasma PKK and Kallikrein levels) over 365 days
Key Timelines	Start: Dec 2022; Est. Primary Completion: Jan 2025/Jul 2025; Est. Study Completion: Dec 2025
Location	Australia (e.g., CMAX Clinical Research, Adelaide)

Sources: [1]

[B. Phase 3 Clinical Trial (NCT06960213 - STOP-HAE / ADX-324-301)]

Following the Phase 1/2a study, ADX-324 is planned to advance into a pivotal Phase 3 trial, named STOP-HAE (Study of siRNA Targeting of Prekallikrein with ADX-324 in Participants with Hereditary Angioedema), registered under NCT06960213 and also identified as ADX-324-301.[6]

• 1. Study Design and Objectives: The STOP-HAE trial is designed as a randomized, double-blind, placebo-controlled, parallel-group, multicenter study.6 Randomization will be stratified based on the participants' baseline HAE attack rate to ensure balance across treatment arms.13 The primary objective of this registrational study is to evaluate the efficacy of two different dose levels and regimens of ADX-324 compared to placebo in preventing HAE attacks in individuals with HAE Type I or Type II.13 Secondary objectives include assessments of safety, pharmacokinetics (PK), pharmacodynamics (PD), and health-related quality of life (HRQoL) measures.13
• 2. Target Participant Population: The trial aims to enroll approximately 90 participants.13 Eligible participants will be adults (≥18 years) with a documented diagnosis of HAE Type I or Type II.13 A key inclusion criterion is a history of HAE attacks, specifically experiencing at least one investigator-confirmed HAE attack in the first four weeks of the screening period or at least two investigator-confirmed HAE attacks in the eight weeks of screening.13 Participants must have access to, and the ability to use, at least one acute HAE therapy for breakthrough attacks and must be deemed medically appropriate for on-demand treatment as their sole medicinal management for HAE during the study period, as per the investigator's assessment.13 Significant exclusion criteria include a concurrent diagnosis of another form of recurrent angioedema (e.g., acquired angioedema, HAE with normal C1-INH), uncontrolled hypertension or diabetes mellitus, current cardiovascular disease, clinically significant renal disease (e.g., eGFR < 60 mL/min/1.73 m²) or hepatic disease (e.g., active hepatitis, cirrhosis), prior treatment with any RNA/DNA-based therapy for HAE (including ADX-324) or intolerance to such therapies, use of ACE inhibitors within four weeks prior to screening, or new use or increased dose of estrogen-containing medications within three months prior to screening.13
• 3. Interventions and Dosage Regimens: Participants will be randomized in a 1:1:1 ratio to one of three treatment groups 13:
• Group 1: ADX-324 240mg administered subcutaneously on Day 1 and Week 13. This regimen evaluates dosing every three months (Q3M).
• Group 2: ADX-324 300mg administered subcutaneously on Day 1, with a placebo (saline) injection at Week 13. This arm is designed to assess a dosing regimen of every six months (Q6M), with the Week 13 placebo maintaining the blind for the Q3M assessment period.
• Group 3: Placebo (saline) administered subcutaneously on Day 1 and Week 13.
• 4. Primary and Secondary Outcome Measures: The primary outcome measure will assess the efficacy of ADX-324 in preventing HAE attacks. While the specific metric (e.g., mean monthly attack rate reduction) is not detailed in the provided summaries, this is typical for HAE prophylactic trials.13 Secondary outcomes will include comprehensive evaluations of safety and tolerability, PK parameters of ADX-324, PD markers (likely PKK levels), and HRQoL assessments.13 The inclusion of HRQoL measures highlights the importance of patient-reported outcomes in evaluating the overall benefit of a new HAE therapy.
• 5. Current Status and Timelines: As of May 14, 2025, the STOP-HAE Phase 3 trial was reported as "Not yet recruiting".6 Estimated timelines suggest a study start date around May 2025, with an estimated primary completion in May 2026 and final study completion in December 2026.13 The rapid progression from the initiation of Phase 1/2a studies in early 2023 to the planning of a Phase 3 trial indicates a potentially accelerated development pathway, likely driven by promising early data and the significant unmet need for more convenient and effective HAE prophylactic treatments. The design of this pivotal trial, directly testing long-acting dosing regimens, underscores the company's confidence in ADX-324's potential to significantly alter the HAE treatment paradigm.

Table 2: Summary of NCT06960213 (STOP-HAE / ADX-324-301) Trial Design

Feature	Details
Trial ID	NCT06960213 / ADX-324-301
Acronym	STOP-HAE
Title	Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE
Phase	Phase 3
Status	Not yet recruiting (as of May 2025)
Sponsor	ADARx Pharmaceuticals, Inc.
Indication	Hereditary Angioedema (HAE) Types I & II
Study Design	Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter
Number of Participants	Approximately 90
Key Interventions	ADX-324 240mg SC Q3M; ADX-324 300mg SC Q6M (initial dose, then placebo at Wk13); Placebo SC Q3M
Primary Outcome	Efficacy in preventing HAE attacks (e.g., reduction in attack rate)
Key Secondary Outcomes	Safety and Tolerability, Pharmacokinetics, Pharmacodynamics (PKK levels), Health-Related Quality of Life (HRQoL)
Key Timelines	Est. Start: May 2025; Est. Primary Completion: May 2026; Est. Study Completion: Dec 2026

Sources: [6]

VII. Regulatory Status

[A. Orphan Drug Designation Status (FDA, EMA)]

According to information from AdisInsight, ADX-324 does not currently hold Orphan Drug Designation from regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[8] This is noteworthy given that HAE is a recognized rare disease, and other therapies in development for HAE, such as garadacimab, sebetralstat, and deucrictibant, have received such designations.[27]

Orphan Drug Designation is typically sought for drugs intended to treat rare diseases (e.g., prevalence <5 in 10,000 in the EU, or affecting <200,000 people in the U.S.) and provides various incentives to developers, including market exclusivity periods, fee reductions, and protocol assistance.[31] The absence of a reported orphan drug designation for ADX-324 could be due to several factors: ADARx Pharmaceuticals may not have yet applied for this status, the application process might be ongoing, or the available databases may not be fully up-to-date on this specific aspect for ADX-324. Alternatively, the company might have a different regulatory strategy. Nevertheless, the fact that competitor HAE drugs have secured orphan status underscores the recognized unmet medical need and the regulatory support available for developing treatments for this condition.

[B. Other Relevant Regulatory Interactions or Designations]

No information regarding other specific regulatory designations for ADX-324, such as Fast Track or Breakthrough Therapy, was found in the provided research materials. The initial Phase 1/2a clinical trial (NCT05691361) is being conducted in Australia [1], a common strategy for early-phase clinical development by international biotechnology companies due to factors such as efficient regulatory pathways and established clinical trial infrastructure. This does not preclude subsequent regulatory filings and development in other major jurisdictions like the U.S. and Europe.

VIII. Corporate and Financial Context

[A. Key Funding Rounds Supporting ADX-324 Development]

ADARx Pharmaceuticals has successfully secured significant funding to support the development of its pipeline, including ADX-324. In August 2023, the company announced an oversubscribed $200 million Series C financing round. This round saw participation from a syndicate of prominent investors, including Blackrock, T. Rowe Price Associates, and Venrock, among others.[2] These funds were earmarked, in part, to advance ADX-324 through its clinical trials. Prior to this, in January 2023, coinciding with the initiation of the Phase 1 trial for ADX-324, ADARx announced the closure of a $46 million Series B-1 financing round.[2] The substantial capital raised in these financing rounds, particularly the $200 million Series C, signals robust investor confidence in ADARx's RNA technology platform and the potential of its lead candidates, including ADX-324. This financial backing is critical for supporting the resource-intensive later stages of clinical development, such as the planned global Phase 3 trial for ADX-324.

[B. Strategic Collaborations (e.g., AbbVie Partnership)]

In May 2025, ADARx Pharmaceuticals entered into a significant strategic collaboration and license option agreement with AbbVie.[15] Under the terms of this agreement, AbbVie made an upfront payment of $335 million to ADARx, with ADARx being eligible for substantial additional option-related fees, milestone payments, and tiered royalties that could amount to "several billion dollars".[15] This collaboration is focused on the development of next-generation siRNA therapeutics across multiple disease areas, specifically neuroscience, immunology, and oncology.[15] It leverages ADARx's proprietary siRNA technology and RNA discovery expertise alongside AbbVie's extensive experience in biotherapeutic drug development, antibody-drug conjugates (ADCs), and tissue delivery approaches.[15]

Importantly, the ADX-324 program for HAE remains wholly owned by ADARx Pharmaceuticals and is not part of this specific collaboration with AbbVie, which targets different therapeutic areas.[6] Nevertheless, this major partnership serves as a strong external validation of ADARx's core RNA technology platform (PLR™, SPE™, CTD™, MST™). Such a significant investment and commitment from a major pharmaceutical company like AbbVie indicates a high degree of confidence in the potential of ADARx's platform to generate viable and innovative drug candidates. This development indirectly supports the prospects of ADX-324, as it originates from the same foundational technologies. ADARx's strategy appears to involve advancing its lead, wholly-owned assets in areas like rare diseases (e.g., ADX-324 for HAE) while simultaneously leveraging its platform's broader applicability through strategic partnerships to generate non-dilutive funding and access expanded development and commercialization capabilities.

IX. Future Outlook and Considerations

[A. Potential Clinical Impact of ADX-324 in HAE Management]

Should ADX-324 successfully navigate its clinical development program and gain regulatory approval, its potential for a bi-annual or possibly annual subcutaneous administration regimen could significantly alter the HAE prophylactic treatment landscape.[1] Such a reduction in dosing frequency would substantially lessen the treatment burden currently experienced by many HAE patients who rely on more frequently administered therapies. This improvement in convenience could lead to better long-term adherence and an enhanced quality of life for individuals living with this chronic condition. The inclusion of health-related quality of life (HRQoL) as an outcome measure in the Phase 3 STOP-HAE trial underscores the importance of this aspect.[13] Effective and sustained PKK knockdown leading to a clinically meaningful reduction in HAE attack frequency and severity would be the primary driver of its clinical impact.

[B. Comparison with Existing and Emerging HAE Therapies]

The HAE therapeutic field includes several established and emerging prophylactic options. Current treatments include C1-inhibitor replacement therapies (plasma-derived and recombinant), other plasma kallikrein inhibitors (such as the monoclonal antibody lanadelumab and the investigational antibody garadacimab [30]), and bradykinin B2 receptor antagonists (for acute treatment).[6] The pipeline also features other innovative approaches targeting PKK, including antisense oligonucleotides (ASOs) like donidalorsen, which also aims for infrequent subcutaneous dosing, and gene therapies like NTLA-2002, which seeks a one-time curative approach by knocking out the KLKB1 gene.[6]

ADX-324's key differentiating attributes within this competitive environment will likely be its siRNA mechanism of action, which offers reversible gene silencing, and its potential for a very infrequent, low-volume subcutaneous dosing schedule. While the HAE market is becoming more crowded, a therapy that combines strong efficacy with a highly convenient administration profile could capture a significant share. The reversible nature of siRNA-mediated gene silencing might also be perceived by some patients and clinicians as a favorable characteristic compared to permanent genetic modifications offered by gene therapies, particularly concerning long-term safety considerations.

[C. Key Milestones and Challenges Ahead]

The successful advancement of ADX-324 hinges on several critical milestones and the navigation of inherent challenges in late-stage drug development. The foremost of these is the successful completion of the ongoing Phase 1/2a trial (NCT05691361) and, crucially, the demonstration of robust efficacy and a favorable safety profile in the pivotal Phase 3 STOP-HAE trial (NCT06960213). Establishing long-term safety will be paramount, especially given the novel nature of RNAi therapeutics and the chronic prophylactic use intended for ADX-324.

Beyond clinical success, ADARx will need to navigate the complex regulatory approval processes with global health authorities, including the FDA and EMA. Ensuring consistent and scalable manufacturing of a complex biologic like an siRNA therapeutic to meet potential commercial demand is another significant undertaking. Finally, achieving favorable market access and reimbursement in an increasingly competitive HAE landscape, where multiple effective therapies exist or are emerging, will be essential for ADX-324 to reach patients who could benefit from it. The "not yet recruiting" status of the Phase 3 trial as of May 2025 indicates that pivotal data confirming its efficacy and safety are still some time away.[12]

X. Conclusion

ADX-324 represents a promising investigational siRNA-based therapeutic for the prophylactic treatment of Hereditary Angioedema, a rare and debilitating genetic disorder. Developed by ADARx Pharmaceuticals, ADX-324 leverages the company's proprietary RNA delivery (PLR™/CTD™) and oligonucleotide optimization (SPE™/MST™) technologies to achieve targeted knockdown of plasma prekallikrein, a key mediator in HAE pathophysiology.

The primary appeal of ADX-324 lies in its potential to offer a highly differentiated treatment profile characterized by a long-acting, low-volume subcutaneous dosing regimen, possibly bi-annually or annually. This could significantly reduce the treatment burden for HAE patients, improving their quality of life and adherence to prophylactic therapy. Preclinical studies in non-human primates and early pharmacodynamic data from healthy volunteers in the ongoing Phase 1/2a clinical trial (NCT05691361) have supported this potential by demonstrating deep and sustained PKK knockdown.

The planned Phase 3 trial (NCT06960213, STOP-HAE) will be critical in definitively establishing the efficacy and safety of ADX-324 with infrequent dosing regimens. While regulatory designations such as Orphan Drug status were not confirmed for ADX-324 in the reviewed materials, the strong investor backing and strategic collaborations, such as the recent agreement with AbbVie (though for different indications), highlight the perceived value of ADARx's underlying RNA technology platform.

Successful development of ADX-324 would not only provide a valuable new therapeutic option for individuals with HAE but also serve as a significant validation of ADARx Pharmaceuticals' innovative approach to RNA-based medicines. The journey of ADX-324 exemplifies the broader advancements in applying sophisticated RNA technologies to address unmet medical needs in rare diseases, with a clear focus on enhancing both clinical outcomes and patient convenience. The progression of its late-stage clinical trials will be closely monitored by the medical and scientific communities.

XI. References

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324 - ADARx Pharmaceuticals.

2 Ozmosi | ADX-324 Drug Profile.

8 ADX 324 - AdisInsight.

12 ADX-324 - MedPath.

3 ADX-324 Drug Profile - Ozmosi.2

2 ADX-324 Drug Profile - Ozmosi.2

4 Pipeline - ADARx Pharmaceuticals.

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.

13 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - Veeva CTV.

9 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema (HAE) - Clinrol.

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

18 ADARx Pharmaceuticals - CRISPR Medicine News.

21 HAE Fact Sheet - Ionis Pharmaceuticals.

22 Plasma Prekallikrein and Hereditary Angioedema - Frontiers in Medicine.

8 ADX 324 - AdisInsight.8

6 ADX-324 - Synapse Patsnap.

14 STOP-HAE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of siRNA Targeting of Prekallikrein With ADX-324 in Participants With Hereditary Angioedema - AdisInsight.

8 ADX 324 - AdisInsight.8

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

7 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324 - Business Wire.

10 Australian New Zealand Clinical Trials Registry - Search Results (Page 560, showing NCT05691361).

11 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - CenterWatch.

24 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - ClinConnect.

9 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema (HAE) - Clinrol.9

32 Aldeyra Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for ADX-2191 to Treat Retinitis Pigmentosa - Aldeyra Therapeutics.

31 Orphan designation overview - European Medicines Agency.

25 Hereditary Angioedema: Novel Molecules for Treatment of Acute Attacks and Long-Term Prophylaxis - MDPI.

8 ADX 324 - AdisInsight.8

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

27 Angioedema Clinical Trial Pipeline Analysis Demonstrates 15+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight - GlobeNewswire.

28 Major Advances in Angioedema Pipeline: Intellia's Gene Therapy Enters Phase 3 as Multiple Companies Race for Novel Treatments - Trial MedPath News.

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

35 AbbVie Dives Further Into siRNA With $335M Upfront in ADARx Deal - BioSpace.

14 STOP-HAE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of siRNA Targeting of Prekallikrein With ADX-324 in Participants With Hereditary Angioedema - AdisInsight.14

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

7 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324 - Business Wire.7

27 Angioedema Clinical Trial Pipeline Analysis Demonstrates 15+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight - GlobeNewswire.27

28 Major Advances in Angioedema Pipeline: Intellia's Gene Therapy Enters Phase 3 as Multiple Companies Race for Novel Treatments - Trial MedPath News.28

16 AbbVie and ADARx Pharmaceuticals Announce Collaboration and License Option Agreement to Develop Next-Generation siRNA Therapies Across Multiple Therapeutic Areas - PR Newswire.

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

10 Australian New Zealand Clinical Trials Registry - Search Results (Page 560, showing NCT05691361).

34 HAE Therapy ADX-324 Enters Phase 1 Clinical Testing - Angioedema News.

24 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - ClinConnect.24

9 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema (HAE) - Clinrol.9

8 ADX 324 - AdisInsight.8

5 ADARx Technology - ADARx Pharmaceuticals.

19 Science Overview - ADARx Pharmaceuticals.

26 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - ADARx Pharmaceuticals (Link to NCT05691361).

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

13 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - Veeva CTV.13

8 ADX 324 - AdisInsight.8

29 Angioedema Clinical Trials and Pipeline 2025: EMA, PDMA, FDA Approvals, Therapies, MOA, ROA, Companies, and Future Outlook - OpenPR.

6 ADX-324 - Synapse Patsnap.6

17 AbbVie and ADARx Pharmaceuticals Announce Collaboration and License Option Agreement to Develop Next-Generation siRNA Therapies Across Multiple Therapeutic Areas - AbbVie News Center.

14 STOP-HAE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of siRNA Targeting of Prekallikrein With ADX-324 in Participants With Hereditary Angioedema - AdisInsight.14

4 Pipeline - ADARx Pharmaceuticals.4

13 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - Veeva CTV.13

36 Orphan medicinal products in the European Union: an analysis of the first two decades - PMC.

31 Orphan designation overview - European Medicines Agency.31

4 Pipeline - ADARx Pharmaceuticals.4

26 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - ADARx Pharmaceuticals.26

23 Hereditary Angioedema: Novel Molecules for Treatment of Acute Attacks and Long-Term Prophylaxis - ResearchGate PDF.

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

27 Angioedema Clinical Trial Pipeline Analysis Demonstrates 15+ Key Companies at the Horizon Expected to Transform the Treatment Paradigm, Assesses DelveInsight - GlobeNewswire.27

9 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema (HAE) - Clinrol.9

11 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - CenterWatch.11

24 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - ClinConnect.24

6 ADX-324 - Synapse Patsnap.6

5 ADARx Technology - ADARx Pharmaceuticals.5

20 ADARx Pharmaceuticals Homepage (Specific to PLR/SPE publication context).

37 STAR-0215 Phase 1a Data - SEC Filing (Astria Therapeutics, not ADARx, context for NHP PKK knockdown).

38 STAR-0215 Phase 1a Update - SEC Filing (Astria Therapeutics, not ADARx, context for NHP PKK knockdown).

30 FDA Decisions Expected by June 2025 - Prime Therapeutics (Context for orphan drugs).

4 Pipeline - ADARx Pharmaceuticals.4

26 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - ADARx Pharmaceuticals.26

8 ADX 324 - AdisInsight.8

9 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema (HAE) - Clinrol.9

24 Efficacy, Safety, PK, PD and HRQoL of 2 Dose Levels and Regimens of ADX-324 in Preventing HAE Attacks Compared With Placebo in Participants With Type 1 and Type II HAE - ClinConnect.24

39 Company Overview - ADARx Pharmaceuticals (Context for PLR/SPE white paper/investor presentation).

5 ADARx Technology - ADARx Pharmaceuticals.5

14 STOP-HAE: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of siRNA Targeting of Prekallikrein With ADX-324 in Participants With Hereditary Angioedema - AdisInsight.14

6 Fresh off massive fundraising, ADARx preps 3rd clinical program and mulls IPO - Fierce Biotech (via Synapse Patsnap for ADX-324).

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

26 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - ADARx Pharmaceuticals.26

7 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324 - Business Wire.7

6 ADX-324 - Synapse Patsnap.6

40 Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs: A Primer for Clinical Pharmacologists - PubMed.

41 Pharmacokinetic and pharmacodynamic profile of GalNAc 3-conjugated PS-2′MOE ASO in humans - ResearchGate Figure.

35 AbbVie Dives Further Into siRNA With $335M Upfront in ADARx Deal - BioSpace.35

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

30 FDA Decisions Expected by June 2025 - Prime Therapeutics.30

33 Tempest Receives Orphan Drug Designation from the U.S. Food and Drug Administration for Amezalpat to Treat Patients with Hepatocellular Carcinoma (HCC) - Tempest Therapeutics.

1 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324.1

26 Safety, Tolerability, PK, PD of ADX-324 in Healthy Volunteers and Hereditary Angioedema Patients - ADARx Pharmaceuticals.26

7 ADARx Pharmaceuticals Announces Dosing of First Cohort in Phase 1 Clinical Study of ADX-324 - Business Wire.7

6 ADX-324 - Synapse Patsnap.6

35 AbbVie Dives Further Into siRNA With $335M Upfront in ADARx Deal - BioSpace.35

15 AbbVie eyes siRNA moves with $335M options deal for RNA biotech ADARx - Fierce Biotech.15

30 FDA Decisions Expected by June 2025 - Prime Therapeutics.30

33 Tempest Receives Orphan Drug Designation from the U.S. Food and Drug Administration for Amezalpat to Treat Patients with Hepatocellular Carcinoma (HCC) - Tempest Therapeutics.33

4 Pipeline - ADARx Pharmaceuticals.4

5 ADARx Technology - ADARx Pharmaceuticals.5

5 ADARx Technology - ADARx Pharmaceuticals.5

5 ADARx Technology - ADARx Pharmaceuticals.5

42 Our Investors - ADARx Pharmaceuticals (Context for investor presentations).

42 Our Investors - ADARx Pharmaceuticals.42

Note: Many snippets are duplicates or provide overlapping information. I will synthesize and cite the most comprehensive or primary source where possible.

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