ADARx Pharmaceuticals has achieved a significant milestone in hereditary angioedema (HAE) treatment development by dosing the first patient in its Phase 3 STOP-HAE clinical trial evaluating ADX-324. The company simultaneously announced that the U.S. Food and Drug Administration has granted Orphan Drug Designation to ADX-324 for HAE treatment, underscoring the therapeutic's potential to address persistent unmet medical needs in this rare genetic disorder.
Addressing Current Treatment Limitations
Despite advances in prophylactic therapy, most HAE patients remain at risk of breakthrough attacks and do not achieve sustained, long-term attack-free control. Current approved prophylaxis treatments require monthly or more frequent injections, creating a significant treatment burden for patients. Zhen Li, President and Chief Executive Officer of ADARx, emphasized that the FDA's Orphan Drug Designation "underscores the continued need for additional treatment options and highlights the potential of ADX-324 to provide extended attack-free periods with substantially reduced dosing frequency."
Phase 3 Trial Design and Objectives
The Phase 3 STOP-HAE clinical trial represents a randomized, double-blind, placebo-controlled study designed to evaluate ADX-324's efficacy in preventing HAE attacks in adults with Type I and Type II HAE. The trial will assess multiple parameters including safety, pharmacokinetics, pharmacodynamics, and patient-reported health-related quality of life. Approximately 90 patients will be enrolled and randomized to receive either ADX-324 300 mg every 6 months, ADX-324 240 mg every 3 months, or placebo during the study period. Patients completing the trial will be eligible to enroll in a long-term open-label extension study.
Mechanism of Action and Therapeutic Rationale
HAE is characterized by recurrent, unpredictable attacks of swelling that can be painful, disabling, and life-threatening. These attacks result from dysregulation of the kallikrein-kinin system, which regulates blood pressure, inflammation, coagulation, and pain. Prekallikrein (PKK) serves as a critical protein in the plasma kallikrein pathway that activates kallikrein, which produces bradykinin, a potent vasodilator. A dysfunctional kallikrein-kinin system leads to excessive bradykinin release, causing the characteristic swelling attacks in HAE.
ADX-324 is an investigational siRNA therapy designed to inhibit PKK generation at the mRNA level and reduce plasma PKK production, thereby averting bradykinin generation and potentially preventing HAE attacks. Compared to currently approved prophylactic treatments, ADX-324 is expected to decrease PKK to a greater degree, offering the potential for greater and more durable control of kallikrein activity. This mechanism is expected to result in a higher proportion of patients remaining attack-free with a less frequent dosing regimen.
Clinical Development Progress
The Phase 3 program enrollment follows positive Phase 1/2 data demonstrating that ADX-324 achieved significant and durable suppression of prekallikrein protein levels with a favorable safety profile. This clinical progression represents a critical advancement for ADARx's RNA therapeutic platform and the HAE patient community.
Li noted that "dosing the first patient in our ADX-324 Phase 3 clinical trial is a significant milestone for ADARx and we look forward to advancing this program for the HAE community." The company's approach represents a potential paradigm shift toward less frequent dosing regimens while maintaining or improving therapeutic efficacy in HAE prevention.
