Efficacy and safety of bradykinin B2 receptor antagonism with deucrictibant immediate-release capsule for treatment of hereditary angioedema attacks: results of RAPIDe-1 phase 2 trial

Efficacy and safety of bradykinin B2 receptor antagonism with deucrictibant immediate-release capsule for treatment of hereditary angioedema attacks: results of RAPIDe-1 phase 2 trial

Marc A. Riedl1, John Anderson2, Joshua S. Jacobs3, H. Henry Li4, Michael E. Manning5, Emel Aygören-Pürsün6, Maria Luisa Baeza7, Laurence Bouillet8, Hugo Chapdelaine9, Danny M. Cohn10, Aurélie Du-Thanh11, Olivier Fain12, Henriette Farkas13, Jens Greve14, Mar Guilarte15, David Hagin16, Roman Hakl17, Aharon Kessel18, Sorena Kiani-Alikhan19, Pavlina Králícková20, Ramon Lleonart21, Markus Magerl22, Avner Reshef23, Bruce Ritchie24, Giuseppe Spadaro25, Maria Staevska26, Petra Staubach27, Marcin Stobiecki28, Gordon L. Sussman29, Michael D. Tarzi30, Anna Valerieva26, William H. Yang31, Marie-Helene Jouvin32, Rafael Crabbé33, Simone van Leeuwen34, Huaihou Chen32, Li Zhu35, Jochen Knolle36, Anne Lesage37, Peng Lu35, Marcus Maurer22

1La Jolla, CA, United States of America; 2Birmingham, AL, United States of America; 3Walnut Creek, CA, United States of America; 4Chevy Chase, MD, United States of America; 5Scottsdale, AZ, United States of America; 6Frankfurt, Germany; 7Madrid, Spain; 8Grenoble, France; 9Montréal, QC, Canada; 10Amsterdam, The Netherlands; 11Montpellier, France; 12Paris, France; 13Budapest, Hungary; 14Ulm, Germany; 15Barcelona, Spain; 16Tel Aviv, Israel; 17Brno, Czech Republic; 18Haifa, Israel; 19London, United Kingdom; 20Hradec Kralove, Czech Republic; 21Barcelona, Spain; 22Berlin, Germany; 23Ashkelon, Israel; 24Edmonton, AB, Canada; 25Napoli, Italy; 26Sofia, Bulgaria; 27Mainz, Germany; 28Krakow, Poland; 29Toronto, ON, Canada; 30Brighton, United Kingdom; 31Ottawa, ON, Canada; 32Lexington, MA, United States of America (former Pharvaris employees); 33Bassins, Switzerland; 34Woerden, The Netherlands; 35Lexington, MA, United States of America; 36Frankfurt, Germany; 37Schilde, Belgium

Introduction

• Excess bradykinin is the cause of signs and symptoms of swelling during HAE attacks1 and efficacy and tolerability of bradykinin B2 receptor antagonism for treatment of HAE attacks has been proven in clinical trials and ~15 years of post-marketingexperience2-4
• International guidelines recommend that HAE attacks are treated as early as possible5-7
• Burden associated with parenteral administration of approved on-demandmedications8-12 leads to treatment of many HAE attacks being delayed or forgone12-15
• An unmet need exists for on-demand oral therapies that are effective and well-tolerated and may reduce the treatment burden enabling prompt administration

Methods

• RAPIDe-1*(NCT0461821116) was a Phase 2, double-blind,placebo-controlled, randomized, crossover, dose-ranging trial of deucrictibant immediate-release (IR) capsule (PHVS416) for treatment of angioedema attacks in patients with HAE-1/2.
• Key inclusion criteria: diagnosis of HAE-1/2; ≥3 attacks in the last 4 months or ≥2 attacks in the last 2 months prior to screening; access to and experience with use of on-demand medications.
• Key exclusion criteria: pre-enrolment use of: C1-inhibitor(C1-INH) for acute use or short- term prophylaxis (7 days); C1-INH for long-term prophylaxis, oral kallikrein inhibitors, attenuated androgens, anti-fibrinolytics (2 weeks); monoclonal antibodies for HAE (12 weeks); pregnancy or breast-feeding; conditions interfering with participant's safety/ability to participate in the study.
• A primary analysis included 147 qualifying HAE attacks treated by 62 participants with double-blinded placebo or deucrictibant IR capsule 10, 20, or 30 mg (modified intent-to- treat analysis, mITT = all randomized participants with ≥1 treated HAE attack and non- missing VAS results at both pre-treatment and ≥1 post-treatment time point of that attack).

Figure 1. RAPIDe-1 trial design schematic

Results

Figure 2. Pharmacokinetic profile of single dose of deucrictibant IR capsule 10, 20 or 30 mg in HAE patients

Median VAS-3 at baseline ranged from 24.33 to 27.00 across deucrictibant IR capsule doses (10, 20, and 30 mg). † Nominal p-value; N = The number of attacks in the mITT Analysis Set. Figure is based on descriptive summary of mean and SEM (standard error of the mean). Least-squares mean differences, CIs, and p-values come from a mixed-effects model with repeated measures (MMRM). Data after rescue medication use not included.

Figure 3 and Table 1. Results of primary endpoint (reduction of attack symptoms by VAS-3)

N = Number of attacks included in the mITT Analysis Set. p-values for deucrictibant IR capsule 20mg and 30mg are based on statistical tests in the pre-specified multiple comparison procedure, other p-values are nominal. aHazard ratios and p-values are based on marginal Cox proportional hazards models. bMinimal clinically important difference for MSCS = -0.30.cp-values are based on mixed- effects models for repeated measures. dMinimal clinically important difference for TOS = 30.

Table 2. Results of key secondary efficacy endpoints

N = Number of attacks in the mITT Analysis Set.

Figure 4. Additional secondary endpoint: use of rescue medication

N = Number of participants (Part I) and number of attacks (Part II) in the Safety Analysis Set. The Safety Analysis Set includes all randomized participants who received ≥1 dose of study drug between Part I and Part II.

Table 3. Treatment-related adverse events within 48 hours after administration of study drug

Conclusions

• The Phase 2 RAPIDe-1 trial for treatment of attacks in patients with HAE-1/2 met primary and all key secondary endpoints, providing evidence on the efficacy and safety of deucrictibant IR capsule in treating HAE attacks and supporting its further development as a potential on-demand therapy for HAE.
• The U.S. FDA has placed a hold on clinical trials of deucrictibant for long-term prophylaxis in the United States of America. For the latest information and updates visit: https://ir.Pharvaris.com/.

References

1Busse PJ et al. N Engl J Med 2020;382:1136-48;2Cicardi M et al. N Engl J Med 2010;363:532-41;3Lumry WR et al. Ann Allergy Asthma Immunol 2011;107:529-37;4Maurer M et al. Clin Exp Allergy 2022;52:1048-58.5Betschel S et al. Allergy Asthma Clin Immunol 2019;15:72; 6Busse PJ et al. J Allergy Clin Immunol Pract 2021;9:132-50;7Maurer M et al. Allergy 2022;77:1961-90;8Berinert® [package insert], https://labeling.cslbehring.com/pi/us/berinert/en/berinert-prescribing-information.pdf (accessed 18 July 2023); 9Firazyr® [package insert],

https://www.shirecontent.com/PI/PDFs/Firazyr_USA_ENG.pdf (accessed 18 July 2023); 10Kalbitor® [package insert],

https://www.shirecontent.com/PI/PDFs/Kalbitor_USA_ENG.pdf (accessed 18 July 2023); 11Ruconest® [package insert], https://www.ruconest.com/wp-content/uploads/Ruconest_PI_Apr2020.pdf (accessed 18 July 2023); 12Burnette A et al. AAAAI 2023; 13Tuong LA et al. Allergy Asthma Proc 2014;35:250-4;14US Food and Drug Administration, Center for Biologics Evaluation and Research. The voice of the patient- Hereditary angioedema. May 2018. https://www.fda.gov/media/113509/download (accessed 18 July 2023); 15Radojicic C et al. AAAAI 2023.

Research grant support, consultancy fees, speaker fees, and/or clinical trial fees - M.A.R.: Astria, BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, Grifols, Ionis, Ipsen, KalVista, Ono Pharma, Pfizer, Pharming, Pharvaris, RegenexBio, Sanofi-Regeneron, Takeda. J.A.: BioCryst, BioMarin, CSL Behring, Cycle Pharmaceuticals, KalVista, Pharming, Pharvaris, Takeda. J.S.J.: BioCryst, CSL Behring, Cycle pharmaceuticals, Oasis pharmaceuticals, Pharming, Pharvaris, Takeda. H.H.L.: BioCryst, BioMarin, CSL Behring, Intellia, KalVista, Pharming, Pharvaris, Takeda. M.E.M.: Allakos, Amgen, AstraZeneca, BioCryst, Blueprint, CSL Behring, Cycle, Genentech, GSK, KalVista, Merck, Novartis, Pharming, Pharvaris,

Sanofi/Regeneron, Takeda. E.A.P.: BioCryst, Biomarin, Centogene, CSL Behring, KalVista; Pharming, Pharvaris, Shire/Takeda. M.L.B.: BioCryst, CSL Behring, Shire HGT. L.B.: BioCryst, Blueprint, CSL Behring, Novartis, Shire/Takeda. H.C.: CSL Behring, Dyax, Green Cross, Merck, Novartis, Pharvaris, Sanofi, Sobi, Takeda. D.M.C.: BioCryst, CSL Behring, Pharming, Pharvaris, Shire/Takeda. A.D-T.: BioCryst, Takeda. O.F.: BioCryst, CSL Behring, Takeda. H.F.: BioCryst, CSL Behring, KalVista, ONO Pharmaceutical, Pharming, Pharvaris, Takeda. J.G.: CSL Behring, Shire/Takeda. M.G.: CSL Behring, Novartis, Takeda; participated in advisory boards organized by BioCryst, CSL Behring, Novartis, Pharming, Pharvaris, Takeda. D.H.: none.

R.H.: BioCryst, CSL Behring, KalVista, Pharming Pharvaris, Shire/Takeda. A.K.: CSL Behring, Pharming, Takeda. S.K.-A.: BioCryst, Biotest, CSL Behring, Ionis Pharmaceuticals, KalVista, Pharvaris, Shire/Takeda, X4 Pharmaceuticals. P.K.: none. R.L.: BioCryst, CSL Behring, Takeda. M.Mag.: BioCryst, CSL Behring, KalVista, Novartis, Octapharma, Pharming, Shire/Takeda. A.R.: BioCryst, CSL Behring, Pharming, Pharvaris, Shire/Takeda, Stallergens, Teva. B.R.: BioCryst, CSL-Behring, Ionis, KalVista, Pharvaris, Takeda. G.S.: Pharvaris, Takeda. M.Sta.: Pharming, Pharvaris, Sobi. P.S.: CSL Behring, Novartis, Pfleger, Shire/Takeda. M.Sto.: BioCryst, CSL Behring, KalVista, Pharming, Shire/Takeda. G.L.S.: Aimmune, Amgen, CSL

Behring, DBV, Genentech, Green Cross, Kedrion, Leo, Novartis, Novo, Pediapharm, Sanofi. M.D.T.: none. A.V.: Astra Zeneca, Berlin-Chemie/Menarini Group, CSL Behring, Novartis, Pharming, Pharvaris, Shire/Takeda, Sobi, Teva. W.H.Y.: Aimmune, ALK, AnaptysBio, AstraZeneca, BioCryst, CSL Behring, DBV Technologies, Dermira, Genentech, GlaxoSmithKline, Glenmark, Merck, Novartis, Pharming, Regeneron, Roche, Sanofi, Shire/Takeda. M.-H.J.: employee of Pharvaris at the time the analyses were conducted, holds stocks in Pharvaris. R.C.: employee of CG Consultancy and consultant to Pharvaris, holds stocks in Pharvaris. S.v.L.: employee of SLC Consultancy and consultant to Pharvaris, holds stocks in Pharvaris.

H.C.: employee of Pharvaris at the time the analyses were conducted, holds stocks in Pharvaris. L.Z.: employee of Pharvaris, holds stocks in Pharvaris. J.K.: employee of JCK Consult and consultant to Pharvaris, holds stocks/stock options in Pharvaris. A.L.: employee of GrayMatters Consulting and consultant to Pharvaris, holds stocks/stock options in Pharvaris. Advisor to Kosa Pharma, holds stocks in Kosa Pharma. P.L.: employee of Pharvaris, holds stocks/stock options in Pharvaris. M.Mau.: Adverum, Attune, BioCryst, CSL Behring, KalVista, Pharming, Pharvaris, Takeda/Shire.

RAPIDe-1 was a Pharvaris-sponsored clinical trial. ClinicalTrials.gov Identifier: NCT04618211.