Pharvaris: Data supports clinical development for bradykinin-mediated angioedema drug

Pharvaris (Nasdaq: PHVS), a late-stage biopharmaceutical company developing novel, oral bradykinin B2 receptor antagonists to help address unmet needs of those living with bradykinin-mediated diseases such as hereditary angioedema (HAE) and acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH), today announced a summary of data that were presented at the 14th C1-Inhibitor Deficiency and Angioedema Workshop.

“Additional analyses of deucrictibant data demonstrate consistency in the clinical profile shown in both the prophylactic and on-demand treatment settings,” said Berndt Modig, Chief Executive Officer of Pharvaris. “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. Pharvaris continues to diligently execute on the deucrictibant clinical program and is planning for two pivotal data readouts in the next 18 months.”

See all below mentioned posters here.

Prophylaxis

• Long-Term Safety and Efficacy of Oral Deucrictibant for Prophylaxis in Hereditary Angioedema:
  Data Snapshot Results of the CHAPTER-1 Open-Label Extension Study, an oral presentation by Emel Aygören-Pürsün, M.D. The ongoing Phase 2 CHAPTER-1 open-label extension (OLE) study provides further evidence on the long-term safety and efficacy of oral deucrictibant for prevention of HAE attacks. The attack rate has remained low, irrespective of baseline attack rate, for over a year and a half in OLE participants. When evaluating mechanism-on-mechanism responses, the response to icatibant for on-demand treatment of breakthrough attacks appeared to be maintained when used for breakthrough attacks during prophylactic treatment with deucrictibant.

  Peng Lu, M.D., Ph.D., Chief Medical Officer of Pharvaris, stated, “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. 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. 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.”

• 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, a poster presentation by Markus Magerl, M.D. The impact of deucrictibant treatment on health-related quality of life (HRQoL), disease control, and treatment satisfaction during the ongoing CHAPTER-1 OLE was evaluated. All of the participants who received deucrictibant reported clinically meaningful improvements in HRQoL at the end of the randomized portion of the trial, which was maintained at week 62 of the OLE. All of the participants in the OLE reported well controlled HAE and a high level of satisfaction with treatment.
• Sustained Therapeutic Exposure with Once-Daily Oral Deucrictibant XR Tablet for Prophylaxis of Hereditary Angioedema Attacks: Results of a Pharmacokinetics Study in Healthy Volunteers, a poster presentation by Zhi-Yi Zhang, Ph.D. To confirm its potential for once-daily prophylactic treatment, a Phase 1 pharmacokinetic study was conducted to compare the profile of the XR formulation (40 mg) to the immediate-release (IR) formulation (2 x 20 mg in a single administration), which was shown to be efficacious and well tolerated in the proof-of-concept CHAPTER-1 prophylaxis study. Deucrictibant extended-release (XR) tablet was well tolerated with no adverse events. Deucrictibant XR’s pharmacokinetic profile demonstrated sustained exposure for over 24 hours, supporting once-daily dosing, and showed, on average, approximately a four-fold higher mean plasma concentration than therapeutic threshold (EC85) at 24 hours, supporting its further investigation as a potential oral once-daily prophylactic therapy for bradykinin-mediated angioedema.
• CHAPTER-3 Phase 3 Trial Design: Efficacy and Safety of the Oral Bradykinin B2 Receptor Antagonist Deucrictibant Extended-Release Tablet for Prophylaxis of Hereditary Angioedema Attacks, a poster presentation by Andrea Zanichelli, M.D., Ph.D. CHAPTER-3 is an ongoing, global, Phase 3 study designed to evaluate the efficacy and safety of once-daily, oral deucrictibant (40 mg/day) XR tablet for prophylaxis of attacks in adolescents and adults with HAE. Results from the Phase 2 CHAPTER-1 study support the CHAPTER-3 study design.

On-Demand

• Durability Of Response to a Single Dose of Oral Deucrictibant for On-Demand Treatment of Hereditary Angioedema Attacks, a poster presentation by Anna Valerieva, M.D., Ph.D. A post-hoc analysis of the placebo-controlled RAPIDe-1 trial and the RAPIDe-2 extension study assessed the durability of effects in HAE attacks treated with a single dose of deucrictibant. In both studies, the majority of attacks were treated with a single dose of deucrictibant. In RAPIDe-1, 95-100% of the attacks and, in RAPIDe-2, 98-100% of the attacks that achieved symptom relief and resolution had a durable response without symptom reoccurrence.
  Dr. Lu continued, “The ideal on-demand treatment for people living with HAE should offer both rapid symptom relief and complete symptom resolution with a single dose; this can only be achieved if the response to treatment is sustained without attack symptom reoccurrence. We believe the recently presented data on durability of response could be compelling to multiple stakeholders in the HAE community, including those living with HAE, their prescribing physicians, and the payor community. We aim to further evaluate deucrictibant’s ability to rapidly and completely address bradykinin-mediated angioedema attack symptoms in our ongoing Phase 3 RAPIDe-3 clinical study.”
• Long-Term Safety and Efficacy of Oral Deucrictibant for Treatment of Hereditary Angioedema Attacks: Results of the RAPIDe-2 Extension Study, an oral presentation by Marc A. Riedl, M.D., M.S. Following the closure of Part A of RAPIDe-2, a Phase 2/3 study of deucrictibant for the on-demand treatment of HAE attacks, an analysis of 465 attacks from 19 participants, including 14 upper airway attacks from seven participants, was conducted. The final results from Part A of the RAPIDe-2 extension are consistent with the Phase 2 RAPIDe-1 randomized study. Deucrictibant continued to be well tolerated across all doses. The median time to onset of symptom relief was 1.1 hours, and 97.8% of attacks achieved onset of symptom relief in 12 hours. The median time to complete attack resolution was 10.6 hours, and 86.9% of attack achieved complete resolution at 24 hours. Eighty-nine percent of the attacks that achieved symptom resolution at 24 hours were treated with a single dose of deucrictibant.
• Safety and Efficacy of Oral Deucrictibant for Treatment of Upper Airway and Laryngeal Hereditary Angioedema Attacks: Results from the RAPIDe-2 Extension Study, a poster presentation by Ramón Lleonart, M.D. The final data from Part A of the RAPIDe-2 study showed that safety and efficacy outcomes of treatment with deucrictibant IR were consistent for both HAE attacks affecting the upper airways, including laryngeal attacks, and HAE attacks occurring in other locations. Deucrictibant was generally well tolerated with no treatment-related treatment-emergent adverse events reported across upper airway and non-upper airway attacks. Fourteen upper airway attacks were treated by 7 participants; the median time to onset of symptom relief, as measured by Patient Global Impression of Change (PGI-C) of “a little better”, was 1.4 hours (n=14) for upper airway attacks compared to 1.1 hours for non-upper airway attacks (n=451). Endpoint measurements taken throughout the span of an entire attack until and including complete resolution were similar for both upper airway and non-upper airway attacks. Importantly, 92.9% of the upper airway attacks were treated with a single dose of deucrictibant.

Expansion Beyond HAE

• Clinical Validation of a Novel Biomarker Assay to Characterize Bradykinin-Mediated Angioedema in Prospective and Biobank Plasma Samples, an oral presentation by Evangelia Pardali, Ph.D. Assays for an early and accurate diagnosis of bradykinin-mediated angioedema are lacking. Cold activation of plasma from people living with HAE resulted in increased levels of bradykinin compared to cold-activated plasma of healthy volunteers, resulting in a qualified kinin assay that can be used to reliably characterize people with bradykinin-mediated angioedema and could become a key tool aiding identification, study, and management of bradykinin-mediated pathologies including angioedema.
• Acquired Angioedema Due to C1-Inhibitor Deficiency: Patient Experience and Assessment of Patient-Reported Outcome Measures, a poster presentation by Andrea Zanichelli, M.D., Ph.D. There are currently no approved therapies for the treatment of AAE-C1INH attacks, nor patient-reported outcome measures validated in AAE-C1INH. Concept elicitation and cognitive interviews were performed to develop a conceptual model of AAE-C1INH that could reveal important disease concepts supporting a clinical outcome assessment strategy, as well as evaluating the comprehension and interpretation of PGI-C, PGI-Severity (PGI-S), patient global assessment of change (PGA-C), and PGA-Status (PGA-S), and explore perceptions of meaningful change using these measures. One hundred percent of participants considered PGI-C “better” to be a meaningful change four hours post-treatment.
• Epidemiology of Bradykinin-Mediated Angioedema in the European Population, a poster presentation by Emel Aygören-Pürsün, M.D. A systematic literature review was conducted to summarize epidemiologic data on bradykinin-mediated angioedema, including HAE due to C1 inhibitor deficiency (HAE-C1INH Type 1 and Type 2), HAE due to other mutations in people with normal C1 levels and function (HAE-nC1INH), and AAE-C1INH, in the European Union (EU) and United Kingdom (UK). The review of 14 peer-reviewed scientific articles allowed to estimate the prevalence of HAE-C1INH (Type 1/2) as ranging between 0.05-0.33/10,000 individuals, the prevalence of HAE-nC1INH ranging between <0.01-0.07/10,000 individuals, and the prevalence of AAE-C1INH ranging between 0.01-0.02/10,000 individuals in European countries.