DE MONITOR schreef op 11 april 2023 21:20:
PHVS416 shows promise in treating HAE swelling attacks: Trial data
Long-term extension study now underway to evaluate safety, efficacy
Pharvaris’ PHVS416, a soft-gel capsule of PHA121, now also known as deucrictibant, continues to show promising safety and effectiveness for treating swelling attacks in people with hereditary angioedema (HAE).
That’s according to data from RAPIDe-1 (NCT04618211), a Phase 2 clinical trial that’s comparing on-demand treatment with PHVS416 versus a placebo in people with HAE, and has now has completed its last patient’s final visit.
Meanwhile, RAPIDe-2 (NCT05396105), a long-term extension study evaluating the safety and efficacy of on-demand treatment with PHVS416 for acute HAE attacks, is underway outside the U.S. RAPIDe-2 is enrolling HAE patients who participated and received at least one dose of PHVS416 in RAPIDe-1.
“The positive outcome of the RAPIDe-1 clinical study, announced in December 2022, demonstrates the potential of PHVS416 to offer meaningful improvement over the standard of care for people living with HAE in their on-demand treatment of attacks,” Berndt Modig, CEO of Pharvaris, said in a company press release.
Company prepares to move forward with Phase 3 clinical trial of PHVS416
With the data in hand, the company is now preparing the steps needed to move PHVS416 into RAPIDe-3, a Phase 3 clinical trial that will further evaluate its safety and efficacy as an on-demand treatment for swelling attacks in people with HAE.
Top-line data from CHAPTER-1 (NCT05047185), another Phase 2 clinical trial that’s testing how well PHVS416 may prevent swelling attacks when used as a prophylactic treatment, are expected in the second half of the year. CHAPTER-1 is currently on hold in the U.S. based on a review of nonclinical data, but continues to recruit participants at all other locations, including Canada, Israel, and six European countries.
To address the concerns of the U.S. Food and Drug Administration (FDA), the company has launched a 26-week toxicology study in rodents that should provide additional nonclinical data by the end of the year.
“With the non-clinical study underway, we believe we have a path forward to address the remaining clinical holds in the U.S.,” Modig said. “We anticipate important milestones this year.”
HAE is a type of angioedema where parts of the body suddenly become swollen due to mutations that result in an overproduction of bradykinin. Too much bradykinin makes blood vessels widen and become leaky, resulting in swelling.
“Currently approved on-demand therapies for HAE attacks are administered intravenously or subcutaneously and can be associated with treatment burden,” Marc A. Riedl, MD, clinical director of the U.S. Hereditary Angioedema Association Angioedema Center at the University of California San Diego, said in another company press release.
“An unmet need exists for on-demand oral therapies that are effective and well-tolerated, and that may reduce the treatment burden,” said Riedl, who is also a professor of medicine and clinical service chief for allergy and immunology at the university.
PHA121, now given the global nonproprietary name of deucrictibant, is an oral small molecule that blocks the B2 receptor for bradykinin. Blocking the B2 receptor prevents bradykinin from binding to it and triggering the cascade of events that would lead to swelling attacks.
“The consistent results across all endpoints in the RAPIDe-1 trial provide evidence supporting the efficacy and well-tolerated profile of PHVS416 in treating HAE attacks and provide a foundation for its further development as a potential on-demand therapy,” Riedl said.
Riedl presented the data at the 2023 HAEi Regional Conference APAC, held March 17-19, in Bangkok. The presentation was titled, “Efficacy and safety of Bradykinin B2 Receptor Antagonism with Oral PHVS416 in Treating Hereditary Angioedema Attacks: Results of RAPIDe-1 Phase 2 Trial.”
The study included people ages 18-75 with a diagnosis of HAE type 1 or 2. To be eligible to enter the study, patients had to have experienced three or more attacks in the last four months or two or more attacks in the last two months prior to screening.
Of a total of 74 patients, there were 62 (20 men and 42 women) who experienced a total of 147 swelling attacks that qualified for the study’s efficacy analysis. These were treated either with PHVS416 in different doses (10, 20, or 30 mg) or a placebo.
Studying how well PHVS416 relieved symptoms within four hours
Researchers looked at how well PHVS416 worked to relieve symptoms within four hours by looking at changes in a visual analogue scale (VAS-3) of skin pain, skin swelling, and abdominal pain.
They found that patients treated with PHVS416 in any of the three doses scored around 15-17 points less in VAS-3 compared with those given placebo, indicating they had significantly less severe symptoms.
They also found that PHVS416 reduced by almost six times the median time to halve the VAS-3 score compared with placebo (3.9 vs. 22.8 hours).
Moreover, fewer patients treated with PHVS416 required rescue medication, that is, additional treatment to manage HAE symptoms, compared with placebo (6.5% to 18.9% vs. 60.8%).
PHVS416 was generally well tolerated, with up to 4.3% of patients reporting treatment-related side effects. The most common were nausea and headache.
Similar data were shared in a poster, “Efficacy and Safety of Bradykinin B2 Receptor Inhibition with Oral PHVS416 in Treating Hereditary Angioedema Attacks: Results of RAPIDe-1 Phase 2 Trial,” which had been presented about one month earlier at the American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting in San Antonio.
Final data from RAPIDe-1 include the two remaining U.S. patients who rejoined the study to complete their on-demand treatment after the FDA agreed to partially lift the clinical hold.