Over 90% reduction in HAE attacks seen with 3 years of deucrictibant in testing
New data show oral therapy stops swelling fast, prevents future flares
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On-demand treatment with deucrictibant, an experimental oral small molecule in the pipeline at Pharvaris, provides rapid relief from sudden swelling due to hereditary angioedema (HAE) and, when taken daily for up to three years, can reduce the frequency of attacks over the long term.
That’s according to new data from two clinical studies: the now-completed global Phase 3 RAPIDe-3 study (NCT06343779), and the open-label extension part of a Phase 2 clinical study called CHAPTER-1 (NCT05047185). The findings were presented at this year’s American Academy of Allergy, Asthma & Immunology (AAAAI) meeting, held from late February to early March in Philadelphia.
Specifically, the RAPIDe-3 data show that symptom relief with deucrictibant took slightly more than one hour, with complete resolution of signs of HAE in slightly less than 12 hours. CHAPTER-1 findings, meanwhile, show a reduction in HAE attacks of more than 90% with the therapy over nearly three years, according to Pharvaris.
“We are pleased to present these pivotal data at AAAAI and look forward to future exchanges with the HAE community about deucrictibant’s potential to become standard of care in the treatment of HAE attacks,” Peng Lu, MD, PhD, chief medical officer of Pharvaris, said in a company press release.
Per Pharvaris, the RAPIDe-3 study testing deucrictibant “met the primary and all 11 secondary efficacy endpoints with high statistical significance.”
Angioedema occurs when fluid collects under the skin or mucous membranes, causing repeated swelling that can occur anywhere in the body. In HAE, genetic mutations cause the body to produce too much bradykinin. Excess bradykinin widens blood vessels and causes fluid to leak into surrounding tissues.
Deucrictibant tested as on-demand therapy in RAPIDe-3 study
Deucrictibant is designed to block the bradykinin B2 receptor, preventing bradykinin from causing blood vessels to leak and leading to swelling. It is being developed in two forms: an immediate-release capsule that reaches therapeutic levels in less than 30 minutes, aiming to stop attacks as they happen, and an extended-release tablet that dispenses deucrictibant slowly over 24 hours to prevent attacks and reduce their frequency.
The RAPIDe-3 clinical study tested the immediate-release capsule as an on-demand treatment in 134 adults and adolescents, who had a mean age of 39. The participants had been diagnosed with HAE type 1 or 2 for an average of 17.7 years. All received either 20 mg of deucrictibant or a placebo at the start of two attacks, in random order.
Data from the study, on deucrictibant’s use as an on-demand therapy, were presented at AAAAI in a poster titled “Oral Deucrictibant Immediate-Release Capsule in Treatment of Hereditary Angioedema Attacks: Results of the Phase 3 RAPIDe-3 Study.”
Overall, that data showed deucrictibant was well tolerated, with no serious treatment-related side effects.
[There was] significantly faster onset of symptom relief with deucrictibant compared with [the] placebo. … The proportion of attacks achieving onset of symptom relief at [four] hours was 83.1% for deucrictibant and 27.6% for [the] placebo.
The main goal was to see how quickly symptoms improved, measured by a Patient Global Impression of Change (PGI-C) rating of at least “a little better” within 12 hours of treatment. Secondary goals were relief within four hours, the need for rescue medication, and complete resolution within a day. According to researchers, the study met that primary goal, as well as all of the secondary endpoints tied to effectiveness.
There was “significantly faster onset of symptom relief with deucrictibant compared with [the] placebo,” the researchers wrote in the poster, noting that “the proportion of attacks achieving onset of symptom relief at [four] hours was 83.1% for deucrictibant and 27.6% for [the] placebo.”
Altogether, the data show the median time to onset of symptom relief was 1.28 hours, compared with more than 12 hours for the placebo. The proportion of attacks rated at least “a little better” by 12 hours was significantly higher with deucrictibant (90.4% vs. 48.3%). Deucrictibant also shortened the duration of attacks, with a median time to the end of attack progression of 17.47 minutes versus nearly four hours.
Symptoms were completely resolved after a median of 12 hours with deucrictibant, compared with more than 48 hours, or two days, with the placebo, the data showed.
“The RAPIDe-3 data confirm the robust and consistent clinical effects of deucrictibant … confirming its potentially differentiated profile for the treatment of all types of HAE attacks,” Lu said. “Due to its mechanism of action, deucrictibant is expected to outcompete bradykinin at the B2 receptor, resulting in direct modulation of bradykinin signaling, as demonstrated by the rapid and sustained symptom relief.”
Attacks drop from more than 2 to less than 1 per month with therapy
The new RAPIDe-3 data add to the benefits seen with deucrictibant in the CHAPTER-1 clinical study, which enrolled 34 adults diagnosed with HAE type 1 or 2.
CHAPTER-1 was designed to test the therapy’s long-term effectiveness when used for prophylaxis, or preventive treatment. Participants were randomly assigned to receive 20 or 40 mg of immediate-release capsules of deucrictibant daily or a placebo for three months.
A total of 30 patients completed this first part and joined the open-label extension part of the study, where all received 40 mg of deucrictibant daily for up to nearly three years.
Final data from the open-label extension part, presented in the study “Long-Term Safety and Efficacy of Oral Deucrictibant for Prophylaxis in Hereditary Angioedema: Final Results of the Phase 2 CHAPTER-1 Open-Label Extension Study,” showed that deucrictibant may have long-term benefits.
On average, there was a 92.4% reduction in attacks, with the 2.18 attacks per month at the start of the study down to 0.12 attacks per month after nearly three years. Almost half of the patients (48%) remained free of any attacks of HAE during the open-label extension, the data showed.
Blood pressure remained stable throughout the extension, and no new side effects were reported. In addition, no side effects led to treatment discontinuation, per the researchers.
The developer noted that 21 participants from the CHAPTER-1 study are now taking part in a Phase 3 open-label extension study, dubbed CHAPTER-4 (NCT06679881), which is testing deucrictibant as an extended-release tablet. That study is being conducted at 24 sites worldwide.
