Deucrictibant benefits maintained as treatment for HAE: Trial data
Therapy continued to control, stop swelling attacks in 2 trials
Oral deucrictibant continued to control swelling attacks as a preventative therapy and rapidly stop swelling attacks as an on-demand treatment for hereditary angioedema (HAE), according to new data from the open-label extension portions of two clinical trials.
All open-label extension participants said that preventive deucrictibant controlled their HAE attacks, leading to a high level of treatment satisfaction and improved quality of life. As an on-demand treatment, deucrictibant’s ability to rapidly stop swelling attacks affecting the upper airways and larynx (voice box) was similar to attacks occurring in other locations on the body.
“Additional analyses of deucrictibant data demonstrate consistency in the clinical profile shown in both the prophylactic and on-demand treatment settings,” Berndt Modig, CEO of Pharvaris, the therapy’s developer, said in a company press release. “Pharvaris continues to diligently execute on the deucrictibant clinical program and is planning for two pivotal data readouts in the next 18 months.”
New data were presented at the 14th C1-Inhibitor Deficiency and Angioedema Workshop, held May 29-June 1 in Budapest, Hungary.
Bradykinin-mediated angioedema refers to conditions marked by swelling attacks caused by elevated levels of bradykinin, a signaling molecule that causes blood vessels to widen and become permeable.
Treatment for HAE has preventive, on-demand potential, company says
In HAE, genetic mutations lead to a deficiency in C1-inhibitor (C1-INH), a protein that regulates bradykinin production. Without sufficient C1-INH, bradykinin levels rise, triggering angioedema attacks.
Deucrictibant is an orally available small molecule that blocks the bradykinin receptor called B2, intending to prevent bradykinin from boosting blood vessel leakage and thus control swelling. It’s being developed in two oral formulations: an extended-release tablet as a preventive (prophylactic) therapy and an immediate-release capsule for on-demand treatment.
“Deucrictibant remains the only drug in development for bradykinin-mediated angioedema that has the potential to both prevent attacks and treat them when they occur,” said Peng Lu, MD, PhD, Pharvaris’ chief medical officer.
Deucrictibant is being evaluated as a therapy to prevent HAE attacks in the Phase 2 CHAPTER-1 trial (NCT05047185) and its long-term extension (OLE) study. CHAPTER-1 data have demonstrated that prophylactic treatment significantly reduced swelling attacks compared with a placebo. After a year in the extension study, attack rates dropped by 93% relative to the start of CHAPTER-1.
In an oral presentation titled, “Long-Term Safety and Efficacy of Oral Deucrictibant for Prophylaxis in Hereditary Angioedema: Data Snapshot Results of the CHAPTER-1 Open-Label Extension Study,” Emel Aygören-Pürsün, MD, of University Hospital Frankfurt, provided an update on CHAPTER-1 extension study results.
Data showed attack rates that were reduced after one week in CHAPTER-1 remained low for more than a year and a half in the OLE. That included attacks deemed moderate or severe. Overall, the significant drop in attack rates seen at one year was maintained in the OLE, with most participants (79.3%) experiencing a 90% reduction in attacks. In a separate analysis, the response for on-demand treatment of breakthrough attacks appeared to be maintained when used for breakthrough attacks during preventive treatment.
“The data from the ongoing study further bolsters the potential value proposition of deucrictibant as it provides initial evidence that a bradykinin B2 receptor antagonist can effectively manage a breakthrough attack during treatment with a B2 receptor antagonist, if it were to occur,” Lu said.
In a poster titled, “Long-Term Prophylactic Treatment with Oral Deucrictibant Improves Health-Related Quality of Life and Disease Control in Participants with Hereditary Angioedema: CHAPTER-1 Open-Label Extension Study,” Markus Magerl, MD, a professor at Charité – Universitätsmedizin Berlin, described deucrictibant’s impact on patient-reported disease control, treatment satisfaction, and health-related quality of life (HRQoL) during the OLE.
After one year in the OLE, all patients reported improved quality of life and well-controlled HAE with deucrictibant. Benefits from CHAPTER-1 were maintained, including quality of life, symptom control, and treatment satisfaction, based on multiple patient-reported measures.
Benefits as on-demand treatment for HAE shown
Meanwhile, the Phase 2 RAPIDe-1 (NCT04618211) trial and its long-term extension RAPIDe-2 (NCT05396105) are assessing deucrictibant as an on-demand treatment for HAE. RAPIDe-1 data showed that on-demand deucrictibant outperformed a placebo in easing swelling and pain in the skin and abdomen, with faster time to symptom relief. Early results from the extension study showed that the severity of nearly all attacks was reduced by 12 hours.
In an oral presentation titled “Long-Term Safety and Efficacy of Oral Deucrictibant for Treatment of Hereditary Angioedema Attacks: Results of the RAPIDe-2 Extension Study,” Marc A. Riedl, MD, an allergist/immunologist at the University of California San Diego, provided an update on RAPIDe-2 data.
New efficacy analyses focused on 465 attacks from 19 participants. Data showed that the median time to symptom relief was 1.1 hours, and nearly all (97.8%) attacks achieved symptom relief in 12 hours. Complete attack resolution occurred at a median of 10.6 hours, with most (86.9%) attacks reaching complete resolution at 24 hours. Even with a single dose of deucrictibant, most patients (89%) achieved symptom resolution after one day.
In a poster titled, “Safety and Efficacy of Oral Deucrictibant for Treatment of Upper Airway and Laryngeal Hereditary Angioedema Attacks: Results from the RAPIDe-2 Extension Study,” Ramón Lleonart, MD, head of service at the Bellvitge University Hospital, in Spain, described deucrictibant’s impact on swelling attacks that affect the upper airways and the larynx (voice box).
The median time to symptom relief for upper airway attacks was 1.4 hours, compared with 1.1 hours for non-upper airway attacks. Overall symptom trajectories were similar across both types of attacks, and nearly all (92.9%) of upper airway attacks were treated with a single dose of deucrictibant.
“Deucrictibant’s early-onset and durable treatment response in the on-demand setting, the maintenance of attack reduction for over a year and a half in the prophylactic setting, and the potential for deucrictibant to be used together in both the prophylactic and on-demand settings, if needed, provide additional evidence of deucrictibant’s potential in the treatment of bradykinin-mediated angioedema,” Modig said.
The company has been testing deucrictibant in Phase 3 trials: CHAPTER-3 (NCT06669754) to test the therapy as a preventive treatment for swelling attacks and RAPIDe-3 (NCT06343779) to evaluate it as an on-demand treatment. A third long-term extension Phase 3 trial, CHAPTER-4 (NCT06679881), will enroll those who participated in CHAPTER-1 or may have rolled over from CHAPTER-3.
“We believe further confirming these post-hoc open-label findings in our ongoing CHAPTER-3 study would provide additional evidence on the potential of deucrictibant to help address unmet needs of people living with bradykinin-mediated angioedema,” Lu said.
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