Bradykinin B2 receptor antagonist deucrictibant immediate-release capsule for treatment of HAE attacks: Phase 2

Bradykinin B2 Receptor Antagonist Deucrictibant Immediate-Release

Capsule for Treatment of HAE Attacks: Phase 2 Results

M. Maurer, J. Anderson, E. Aygören-Pürsün, M.L. Baeza, L. Bouillet, H. Chapdelaine, D.M. Cohn, A. Du-Thanh, O. Fain, H. Farkas, J. Greve, M. Guilarte, D. Hagin, R. Hakl, J.S. Jacobs, A. Kessel, S. Kiani-Alikhan, P. Králíčková, H.H. Li, R. Lleonart, M. Magerl, M.E. Manning, A. Reshef, B. Ritchie, G. Spadaro, M. Staevska, P. Staubach, M. Stobiecki, G. L. Sussman, M.D. Tarzi, A. Valerieva,

W.H. Yang, M.H. Jouvin, R. Crabbé, S. van Leeuwen, H. Chen, L. Zhu, J. Knolle, A. Lesage, P. Lu, M.A. Riedl

APAAACI 2023 International Conference

Singapore - 23-26 October 2023

This presentation includes data for an investigational product

not yet approved by regulatory authorities

Conflicts of interest disclosure

Consultancy fees, research grant support, speaker fees, and/or clinical trial fees

M.Mau.: Adverum, Attune, BioCryst, CSL Behring, KalVista, Pharming, Pharvaris, Takeda/Shire.

J.A.: BioCryst, BioMarin, CSL Behring, Cycle Pharmaceuticals, KalVista, Pharming, Pharvaris, 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. J.S.J.: BioCryst, CSL Behring, Cycle pharmaceuticals, Oasis pharmaceuticals, Pharming, Pharvaris, 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.

H.H.L.: BioCryst, BioMarin, CSL Behring, Intellia, KalVista, Pharming, Pharvaris, Takeda. M.Mag.: BioCryst, CSL Behring, KalVista, Novartis, Octapharma, Pharming, Shire/Takeda. M.E.M.: Allakos,

Amgen, AstraZeneca, BioCryst, Blueprint, CSL Behring, Cycle, Genentech, GSK, KalVista, Merck, Novartis, Pharming, Pharvaris, Sanofi/Regeneron, 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/MenariniGroup, 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.A.R.: Astria, BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, Grifols, Ionis, Ipsen, KalVista, Ono Pharma, Pfizer, Pharming, Pharvaris, RegenexBio, Sanofi-Regeneron, 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.

RAPIDe-1 was a Pharvaris-sponsored clinical trial. ClinicalTrials.gov Identifier: NCT04618211. EudraCT Number: 2020-003445-11.

Hereditary angioedema (HAE) is a bradykinin-mediated condition with unmet medical needs

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 20 September 2023). 9Cinryze® [summary of product characteristics], https://www.ema.europa.eu/en/documents/product-information/cinryze-epar-product-information_en.pdf (accessed 20 September 2023). 10Firazyr® [package insert], https://www.shirecontent.com/PI/PDFs/Firazyr_USA_ENG.pdf (accessed 20 September 2023).

11Kalbitor® [package insert], https://www.shirecontent.com/PI/PDFs/Kalbitor_USA_ENG.pdf (accessed 20 September 2023). 12Ruconest® [package insert], https://www.ruconest.com/wp-content/uploads/Ruconest_PI_Apr2020.pdf (accessed 20 September 2023). 13Burnette A et al. AAAAI 2023. 14Tuong LA et al. Allergy Asthma Proc 2014;35:250-4.15US 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 20 September 2023). 16Radojicic C et al. AAAAI 2023.

• 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 currently approved on-demandmedications8-13 leads to treatment of a number of HAE attacks being delayed or forgone13-16
• An unmet need exists for on-demand oral therapies that are effective and well-tolerated and may reduce the treatment burden enabling prompt administration

Deucrictibant is an orally bioavailable, selective, highly potent, competitive antagonist of bradykinin B2 receptor

• Antagonist of bradykinin B2 receptor (-tibant stem1)
• 2.4-foldlower molecular weight than icatibant
• Metabolic soft spot stabilized by introduction of a deuterium atom − Optimized for metabolic stability and exposure in humans
• Pure antagonistic activity at bradykinin B2 receptor
  (no partial agonistic activity as icatibant was found to exert at high concentrations, as reached locally at site of injection2)

Lesage A et al. Front Pharmacol 2020;11:916. Lesage A et al. Int Immunopharmacol 2022;105:108523.

1https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/who-pharm-s-nom-1570.pdf (accessed 20 September 2023). 2https://www.ema.europa.eu/en/documents/assessment-report/firazyr-epar-public-assessment-report_en.pdf (accessed 20 September 2023).

RAPIDe-1: phase 2 trial of deucrictibant IR capsule as on-demand treatment for HAE-1/2 attacks

• Double-blind,placebo-controlled,cross-over trial with 3-dose levels
• • Study part I - randomized patients received a single dose of deucrictibant IR capsule at study Site for PK and safety assessment
  • Study part II - randomized patients treated up to 3 qualifying HAE attacks: 2 attack with deucrictibant IR capsule and 1 attack with placebo
• 74 HAE patients enrolled from 31 Sites

HAE: hereditary angioedema. IR: immediate-release. PK: pharmacokinetic.

ClinicalTrials.gov Identifier: NCT04618211, https://clinicaltrials.gov/ct2/show/NCT04618211 (accessed 20 September 2023). EudraCT Number: 2020-003445-11,https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-003445-11 (accessed 20 September 2023).

Primary endpoint: deucrictibant IR capsule

significantly reduced attack symptoms by VAS-3 at 4 hours

Change in composite VAS score from pre-treatment

Time (hours) after treatment

CI: Confidence interval. IR: immediate-release. mITT: modified intent-to-treat. SEM: standard error of the mean. VAS: visual analogue scale. †Nominal p-value; VAS assessed every 30 minutes up to 4 hours post-treatment, then at 5, 6, 8, 24, 48 hours; N = number of attacks in the mITT Analysis Set. Attacks in mITT Analysis Set refer to attacks treated with blinded study drug that had non-missing VAS result at pre-treatment and at least one non-missing VAS result post-treatment.VAS-3 = electronically captured, numerically assisted visual analogue scale. 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 is not included.

Difference from placebo in change from pre-treatment to 4 h post-treatment,least-squares mean (95% CI)

Deucrictibant IR capsule 10 mg	-16.75(-21.52,-11.97)	p < 0.0001†
Deucrictibant IR capsule 20 mg	-15.02(-20.22,-9.81)	p < 0.0001
Deucrictibant IR capsule 30 mg	-16.28(-21.27,-11.29)	p < 0.0001

Median VAS-3 at pre-treatment ranged

from 24.33 to 27.00 across different dose levels

achieving	in VAS-3
Percentage not	≥30% reduction

Deucrictibant IR capsule significantly shortened time to onset of symptom relief (≥30% reduction in VAS-3)

Median time in hours (95% CI)

Placebo	8.0 (7.6, 46.9)
Deucrictibant IR capsule 10 mg	2.1 (1.5, 2.9)	p < 0.0001†
Deucrictibant IR capsule 20 mg	2.7 (1.9, 3.5)	p = 0.0021
Deucrictibant IR capsule 30 mg	2.5 (1.9, 3.8)	p < 0.0001

Time (hours) after treatment

CI: Confidence interval. IR: immediate-release. mITT: modified intent-to-treat. VAS: visual analogue scale.

†Nominal p-value; VAS assessed every 30 minutes up to 4 hours post-treatment, then at 5, 6, 8, 24, 48 hours. N = number of attacks in the mITT Analysis Set. Median time based on Kaplan-Meier estimates. p-values based on a marginal Cox proportional hazards model.

achieving	in VAS-3
Percentage not	≥ 0% reduction

Deucrictibant IR capsule significantly reduced time to ≥ 0% reduction in VAS-3

Median time in hours (95% CI)

Placebo	22.8 (20.0, 24.1)
Deucrictibant IR capsule 10 mg	3.3 (2.4, 3.9)	p < 0.0001†
Deucrictibant IR capsule 20 mg	4.0 (2.9, 6.0)	p = 0.0003
Deucrictibant IR capsule 30 mg	4.0 (3.3, 5.8)	p < 0.0001

Time (hours) after treatment

CI: Confidence interval. IR: immediate-release. mITT: modified intent-to-treat. VAS: visual analogue scale.

†Nominal p-value; VAS assessed every 30 minutes up to 4 hours post-treatment, then at 5, 6, 8, 24, 48 hours. N = number of attacks in the mITT Analysis Set. Median time based on Kaplan-Meier estimates. p-values based on a marginal Cox proportional hazards model.

Deucrictibant IR capsule significantly reduced time to almost complete or complete symptom relief (all individual VAS ≤10)

Median time in hours (95% CI)

Placebo	42.0 (22.0, 48.1)
Deucrictibant IR capsule 10 mg	5.8	(3.6, 7.5)	p < 0.0001†
Deucrictibant IR capsule 20 mg	20.0	(4.5, 20.0)	p = 0.0127
Deucrictibant IR capsule 30 mg	20.0 (6.0, 20.1)	p = 0.0001

CI: Confidence interval. IR: immediate-release. mITT: modified intent-to-treat. VAS: visual analogue scale.

†Nominal p-value; VAS assessed every 30 minutes up to 4 hours post-treatment, then at 5, 6, 8, 24, 48 hours. N = number of attacks in the mITT Analysis Set. Median time based on Kaplan-Meier estimates. p-values based on a marginal Cox proportional hazards model.

Deucrictibant IR capsule substantially reduced use of rescue medication

Percentage without using rescue medications

Time (hours) after treatment

IR: immediate-release. mITT: modified intent-to-treat. N = number of attacks in the mITT Analysis Set.