Pharvaris N : Treatment with oral bradykinin B2 receptor antagonist deucrictibant immediate-release capsule improves hereditary angioedema attack symptoms

Treatment with oral bradykinin B2 receptor antagonist deucrictibant immediate-release capsule improves hereditary angioedema attack symptoms

John Anderson1, Joshua S. Jacobs2, H. Henry Li3, Michael E. Manning4, Emel Aygören-Pürsün5, Maria Luisa Baeza6, Laurence Bouillet7, Hugo Chapdelaine8, Danny M. Cohn9, Aurélie Du-Thanh10, Olivier Fain11, Henriette Farkas12, Jens Greve13, Mar Guilarte14, David Hagin15, Roman Hakl16, Aharon Kessel17, Sorena Kiani-Alikhan18, Pavlina Králícková19, Ramon Lleonart20, Markus Magerl21, Avner Reshef22, Bruce Ritchie23, Giuseppe Spadaro24, Maria Staevska25, Petra Staubach26, Marcin Stobiecki27, Gordon L. Sussman28, Michael D. Tarzi29, Anna Valerieva25, William H. Yang30, Marie-Helene Jouvin31, Rafael Crabbé32, Simone van Leeuwen33, Huaihou Chen31, Li Zhu34, Jochen Knolle35, Anne Lesage36, Peng Lu34, Marcus Maurer21, Marc A. Riedl37

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

Introduction

• Approved therapies for hereditary angioedema (HAE) attacks are administered parenterally with substantial treatment burden due to administration time and risk of pain or other injection site reactions1-4, with treatment of many attacks being delayed or forgone.5-6
• An unmet need exists for on-demand oral therapies that are effective and well-tolerated and may reduce the treatment burden enabling prompt administration as recommended by international clinical guidelines.7-9
• Deucrictibant immediate-release (IR) capsule (PHVS416) is an investigational formulation containing deucrictibant (PHA121), a highly potent, specific, and orally bioavailable competitive antagonist of the bradykinin B2 receptor.10-11
• In the Phase 2 RAPIDe-1 trial (NCT0461821112) deucrictibant IR capsule reduced time to

onset of symptom relief and to attack resolution measured through the visual analogue	Figure 1. RAPIDe-1 trial design schematic
scale-3(VAS-3) and substantially reduced use of rescue medication.13-14

Onset of symptom relief = The time point when TOS PRO first reaches at least "A little better" for all symptom complexes affected at baseline, and no new symptom in any other symptom complex is reported. Relief is confirmed if the improvement is sustained at 2 consecutive time points.

Table 1. Time to onset of symptom relief measured through TOS

Methods

Results

• RAPIDe-1was a Phase 2, double-blind,placebo-controlled, randomized, crossover, dose- ranging trial of deucrictibant IR capsule for the acute treatment of angioedema attacks in patients with HAE-1/2.
• A primary analysis was performed including 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 VAS results at both pre-treatment and ≥1 post-treatment time point).
• Mean Symptom Complex Severity (MSCS) score and Treatment Outcome Score (TOS) are validated composite scores based on patient-reported symptoms of attacks at the affected body sites, included in ecallantide clinical trials15-17. Changes in MSCS score and in TOS from pre-treatment to 4 hours post-treatment were secondary endpoints of RAPIDe-1.

• MSCS is a point-in-time measure of symptom severity:

Figure 2. MSCS score measured up to 4 h post-treatment

• • Patient-ratedseverity of each affected symptom on a categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe)
  • Calculated as average score from all affected body sites (symptom complexes)
  • Decrease in score reflects improvement in symptom severity
• TOS is a measure of symptom response to treatment:
• • Patient assessment of response for each affected body site on categorical scale (significant improvement [100], improvement [50], same [0], worsening [-50], significant worsening [-100])
  • Calculated as weighted average of the response at all body sites using pre-treatment severity as weight
  • Increase in score reflects improvement in symptom from pre-treatment
  • Complex Assessment questions evaluate patient-reported change in attack symptoms from pre-treatment
    (a lot better or resolved - a little better - same - a little worse - a lot worse)

Figure 3. TOS measured up to 4 h post-treatment

Almost complete or complete symptom relief = The time point when TOS PRO first reaches "A lot better or resolved" for all symptom complexes affected at baseline, and no new symptom in any other symptom complex is reported.

Table 2. Time to almost complete or complete symptom relief measured through TOS

Conclusions

• In the Phase 2 RAPIDe-1 trial deucrictibant IR capsule improved symptoms and reduced time to symptom relief and to resolution of HAE attacks
• Clinical meaningful improvement of symptoms was observed during the first hours after treatment with deucrictibant IR capsule
• 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

1Berinert® [package insert], https://labeling.cslbehring.com/pi/us/berinert/en/berinert-prescribing-information.pdf (accessed 18 July 2023). 2Firazyr® [package insert], https://www.shirecontent.com/PI/PDFs/Firazyr_USA_ENG.pdf (accessed 18 July 2023). 3Kalbitor® [package insert],

https://www.shirecontent.com/PI/PDFs/Kalbitor_USA_ENG.pdf (accessed 18 July 2023). 4Ruconest® [package insert], https://www.ruconest.com/wp-content/uploads/Ruconest_PI_Apr2020.pdf (accessed 18 July 2023). 5Tuong LA et al. Allergy Asthma Proc 2014;35:250-4.6US 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). 7Betschel S et al. Allergy Asthma Clin Immunol 2019;15:72. 8Busse PJ et al. J Allergy Clin Immunol Pract 2021 2021;9:132-50.9Maurer M et al. Allergy 2022;77:1961-90.10Lesage A et al. Front Pharmacol 2020;11:916. 11Lesage A et al. Int Immunopharmacol 2022;105:108523. 12https://clinicaltrials.gov/ct2/show/NCT04618211 (accessed 18 July 2023). 13Maurer M et al. AAAAI 2023;411; 14Farkas H et al. 13th C1-inhibitor Deficiency and Angioedema Workshop 2023;O-19.15Vernon MK et al. Qual Life Res 2009;18:929-39.16Cicardi M et al. N Engl J Med 2010:363:523-31.17Levy RJ et al. Ann Allergy Asthma Immunol 2010;104:523-9.

Research grant support, consultancy fees, speaker fees, and/or clinical trial fees - 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. 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.

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