New treatment cuts swelling attacks in early hereditary angioedema trial
Early data back Phase 3 study of long-acting therapy onvuzosiran
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Treatment with onvuzosiran (ADX-324), Adarx Pharmaceuticals’ experimental treatment for hereditary angioedema (HAE), was well tolerated and lowered kallikrein levels and the frequency of swelling attacks, according to interim data from a Phase 1/2 trial.
The data were presented at the American Academy of Allergy, Asthma & Immunology annual scientific meeting, held in Philadelphia, Pennsylvania. Kallikrein is a protein that helps trigger swelling attacks in people with HAE.
Phase 3 study design highlights next step in development
The presentation also highlighted the design of the ongoing Phase 3 STOP-HAE study (NCT06960213), which is still recruiting participants at sites in the U.S., Canada, and Europe.
“[Blood] kallikrein is a clinically validated target in HAE, and onvuzosiran has demonstrated deep, sustained inhibition, a favorable safety profile, and the potential for less frequent dosing,” Donald Fong, MD, chief medical officer of ADARx, said in a company press release.
“By leveraging our highly differentiated siRNA platform, we believe onvuzosiran could meaningfully advance the long-term prophylactic treatment landscape, with the goal of delivering a best-in-class profile with semi-annual dosing,” Fong added.
HAE is caused by genetic mutations that impair the production or function of the C1-inhibitor (C1-INH) protein. Without C1-INH, kallikrein becomes overactive, triggering the release of bradykinin. High levels of bradykinin make blood vessels more permeable, allowing fluid to leak into tissues and causing swelling.
“While progress has been made in prophylactic HAE therapy, there remains significant need to further reduce attack frequency and ease the treatment burden that both impact quality of life for patients,” Fong said.
How onvuzosiran works to prevent swelling attacks
Onvuzosiran is a small interfering RNA (siRNA) therapy designed to lower the production of prekallikrein (PKK) — a precursor protein to kallikrein — thus reducing kallikrein levels. As such, the therapy is expected to reduce excessive bradykinin release and help control swelling attacks. It is designed as a long-acting treatment that aims to reduce the frequency of swelling attacks while requiring fewer injections.
The Phase 1/2 clinical trial (NCT05691361) consists of two parts: the first tested onvuzosiran in healthy volunteers. Based on those results, the second part tested a selected treatment dose in people with HAE.
In the Phase 1 part of the study, in which healthy volunteers received a single onvuzosiran dose (0.4 to 6 mg/kg) or a placebo, the treatment was well-tolerated, with no serious adverse events or treatment discontinuations reported. It also led to significant, sustained reductions in PKK levels. Specifically, a 300 mg dose showed a 93% reduction in kallikrein at its lowest point, with about an 80% reduction maintained for nearly six months.
In the Phase 2a part of the trial, which is testing the treatment in HAE patients given once every six months, there were similar reductions in kallikrein levels. Patients who achieved about 80% reductions in kallikrein experienced no swelling attacks.
Early results support launch of larger Phase 3 study
These results supported the initiation of the STOP-HAE trial, which is assessing the safety and effectiveness of onvuzosiran compared with a placebo in up to 90 adults with HAE type 1 or 2. Participants receive treatment according to one of two dosing regimens: 300 mg every six months or 240 mg every three months.
The trial’s main goal is to evaluate the treatment’s ability to prevent swelling attacks. Secondary outcome measures include its effects on patients’ patterns of HAE attacks and quality of life.
After completing the study, patients may enroll in a long-term, open-label extension to continue receiving the therapy for up to three years.
Onvuzosiran has received orphan drug designation from the U.S. Food and Drug Administration (FDA) for the treatment of HAE. This designation aims to support the development of therapies for rare diseases, offering benefits such as tax credits, fee waivers, and market exclusivity if approved.
