Deucrictibant reduces rate of HAE swelling attacks in Phase 2 trial
Therapy is designed to prevent bradykinin from binding to its receptors
“These study results, together with the compelling data from our on-demand program, further strengthens our confidence that deucrictibant can become the preferred option to treat as well as prevent HAE attacks,” Berndt Modig, CEO of Pharvaris, deucrictibant’s developer, said in a company press release.
HAE is a genetic disorder marked by excessive levels of bradykinin, a signaling molecule that triggers swelling by binding to certain receptors on blood vessel cells. Deucrictibant is an oral therapy that’s designed to stop HAE swelling by preventing bradykinin from binding to its receptors.
“Deucrictibant is the first HAE treatment with the potential to combine injectable-like efficacy and a favorable safety profile with the convenience of an oral therapy,” said Peng Lu, MD, PhD, chief medical officer of Pharvaris.
The Phase 2 CHAPTER-1 clinical trial (NCT05047185) enrolled 34 adults with HAE at sites around the world. Participants were given deucrictibant at 20 or 40 mg/day, or a placebo, for about three months. Those who completed the study’s initial part could continue into an open-label extension phase where all are treated with deucrictibant at 40 mg/day.
Effect of high dose of deucrictibant
The study used an immediate-release formulation (known as PHVS416) given twice a day. This is meant to act as a proof-of-concept for a once-daily extended-release tablet formulation of deucrictibant (dubbed PHVS719), according to Pharvaris.
The main goal of CHAPTER-1 was to evaluate the effects of deucrictibant on the rates of swelling attacks.
On average, patients given a placebo had nearly two attacks a month. The average monthly swelling attack rate was 0.4/month with the lower dose and 0.3/month with the higher dose, representing reductions of 79.3% and 84.5%, respectively, compared with a placebo.
Rates of attacks deemed mild to moderate in severity were also reduced by 92.3% with the higher dose. Consistently, patients on the higher dose had 92.6% fewer attacks that required on-demand treatment to manage swelling.
“The study demonstrates, for the first time ever, that antagonism of the bradykinin B2 receptor can provide early and sustained protection from HAE attacks, including substantial reduction of moderate and severe attacks, with clinically meaningful improvement in health-related quality of life,” Lu said.
Among the 10 evaluable patients given the higher dose, all but one saw a reduction in the swelling attack rate of at least 50% compared with the rate seen before treatment. Six of the 10 had a reduction in swelling rates of at least 90%, including four who were attack-free throughout the entire study.
Deucrictibant was generally well tolerated. No serious side effects were reported and none of the participants stopped treatment due to side effects.
“The CHAPTER-1 data represent an important step forward in the evolution of HAE treatment,” said Marc Riedl, MD, a professor at the University of California San Diego and principal investigator of the CHAPTER-1 trial. “The HAE community is seeking highly effective, well tolerated, and less burdensome therapies. Given these encouraging results, deucrictibant has the potential to significantly improve clinical outcomes for people living with HAE.”
Last year, the U.S. Food and Drug Administration (FDA) placed a clinical hold on deucrictibant studies in the U.S., including CHAPTER-1 as well as RAPIDe-2 (NCT05396105), a long-term extension study of its immediate-release formulation as an on-demand treatment.
The FDA hold on studies of prophylactic deucrictibant still applies. Pharvaris said it has completed a rodent toxicology study requested by the FDA. According to the company, the study met its goal and Pharvaris expects to submit the data to the FDA by the end of the year, but noted “neither the nature nor timing of the response from FDA is certain.”