Pharvaris: Data for prophylactic and on-demand treatment of hereditary angioedema

Pharvaris (Nasdaq: PHVS), a late-stage biopharmaceutical company developing novel, oral bradykinin B2 receptor antagonists to prevent and treat hereditary angioedema (HAE) attacks, highlighted the differentiated profile of deucrictibant as a prophylactic and on-demand treatment of HAE attacks at the Bradykinin Symposium 2024.

“Based on a snapshot analysis, treatment with deucrictibant led to a 93% reduction in attack rate compared to study baseline, a median attack rate of zero for every month, and a mean proportion of attack-free days of 99% after more than a year of mean duration of treatment in a prophylactic extension study. Together with the improvements in disease control and health-related quality of life observed in the randomized, placebo-controlled part of the CHAPTER-1 study, these data underscore the potential of deucrictibant to be an effective and well-tolerated prophylactic agent in the treatment of HAE,” said Peng Lu, M.D., Ph.D., Chief Medical Officer of Pharvaris. “Long-term extension data of deucrictibant in the on-demand setting similarly confirm its potential to become a preferred option for the treatment of HAE attacks with a median onset of symptom relief of 1.1 hours, as measured by Patient Global Impression of Change (PGI-C) and median complete resolution of 11.5 hours, as measured by Patient Global Impression of Severity (PGI-S). The rapid onset of symptom relief reported in RAPIDe-2 and the results of a propensity score-matched analysis favoring deucrictibant over standard of care provide confidence in our ability to differentiate deucrictibant in the on demand HAE space. Lastly, the safety and tolerability profile of deucrictibant has been reaffirmed in multiple nonclinical and clinical studies.”

Marc A. Riedl, M.D., M.S., Professor of Medicine, Clinical Director of the U.S. Hereditary Angioedema Association (HAEA) Angioedema Center at the University of California San Diego (UCSD), Clinical Service Chief for Allergy/Immunology at UCSD, added, “The goal of HAE management is for affected individuals to live a normal life, ensuring they can engage in all work, school, family, and leisure activities as desired without limitation from angioedema symptoms. Therapies that offer improved efficacy, tolerability, and convenience have the potential to normalize the lives of people living with HAE. These long-term extension and health-related quality of life data, together with the Phase 2 clinical trial data, provide evidence of the benefits of deucrictibant as a potential treatment for HAE, and highlight the importance of additional data from late-stage clinical development of deucrictibant in both treatment settings.”

Prophylactic Program
CHAPTER-1 (NCT05047185) is a two-part Phase 2 study evaluating the efficacy and safety of deucrictibant for long-term prophylaxis of HAE attacks. Positive top-line data from the double-blind, randomized, placebo-controlled portion (part 1) of the CHAPTER 1 study were announced in December 2023. Further exploration of disease control, health-related quality of life (HRQoL), and treatment satisfaction data were presented by Dr. Markus Magerl in an oral presentation and showed that 90% of participants receiving deucrictibant (N=20) reported well-controlled HAE at week 12 compared to 37.5% of participants receiving placebo (N=8) as measured by the Angioedema Control Test (AECT). Deucrictibant-treated participants reported greater satisfaction than those treated with placebo with regards to effectiveness and the domain of global satisfaction, and a comparable satisfaction for side effects.

All eligible participants completing part 1 of CHAPTER-1 (N=30) enrolled into the ongoing open-label extension (part 2) during which they have received deucrictibant 40 mg/day with a mean treatment duration in the extension of 12.83 months. The analysis (cutoff date: June 10, 2024) was presented by Dr. Riedl in a poster presentation and showed that deucrictibant was well-tolerated, with no safety signals observed. Efficacy analyses showed:

• Deucrictibant reduced the attack rate in the open-label extension by 93.0% compared to the part 1 study baseline
• The occurrence of “moderate and severe” attacks and of attacks treated with on-demand medication remained low in the open-label extension

On-Demand Program
Dr. Emel Aygören-Pürsün presented a poster on RAPIDe-2 (NCT05396105), an ongoing two-part Phase 2/3 extension study, evaluating long-term safety and efficacy of orally administered deucrictibant immediate-release capsule for the on-demand treatment of HAE attacks. The safety analysis (cutoff date: June 10, 2024) included a total of 337 attacks and shows that deucrictibant was well-tolerated for all studied doses with no new safety signals observed. The efficacy analysis (cutoff date: March 1, 2024) included a total of 265 attacks and showed:

• Median time to onset of symptom relief was 1.1 (PGI-C) hours with 98.5% of attacks achieving onset of symptom relief by 12 hours
• Median time to reduction in attack severity was 2.6 hours (PGI-S) with 97.7% of attacks achieving reduction in attack severity by 12 hours
• Median time to complete attack resolution was 11.5 hours with 85.8% of attacks achieving complete attack resolution within 24 hours (PGI-S) and 90.2% of these attacks requiring a single dose of deucrictibant

RAPIDe-2 data were used to conduct a comparison of deucrictibant immediate-release capsule to standard of care on-demand therapy in a propensity-score matched analysis. The analysis presented by Dr. Riedl in a poster presentation, indicated that PGI-C- and PGI-S-based outcomes were more favorable for the attacks treated with deucrictibant in RAPIDe-2 study than for the attacks treated with standard of care in an observational study.

Safety
Dr. Nieves Crespo predented a poster on an assessment of the cardiovascular safety of deucrictibant after repeated dosing which showed no evidence of impact on cardiovascular parameters in nonclinical studies in non-human primates, including a 3 month and chronic study, nor in clinical studies to date, following prophylactic treatment up to 12 weeks of administration in the randomized, placebo-controlled part 1 of CHAPTER-1 clinical study and up to one year of mean duration of treatment in its ongoing open-label extension.

About Deucrictibant
Deucrictibant is a novel, potent, oral small-molecule bradykinin B2 receptor antagonist. By inhibiting bradykinin signaling through the bradykinin B2 receptor, deucrictibant has the potential to prevent the occurrence of HAE attacks and to treat the manifestations of an attack if they occur. Based on its chemical properties, Pharvaris is developing two formulations of deucrictibant for oral administration: an extended-release tablet to enable sustained absorption and efficacy for prophylactic treatment, and an immediate-release capsule to enable rapid onset of activity for on-demand treatment.