Pharvaris N : Pharmacological Profile of Deucrictibant, a Small-molecule Bradykinin B2 Receptor Antagonist in Clinical Development for Hereditary Angioedema

Pharmacological profile of deucrictibant, a small molecule bradykinin B2 receptor antagonist in clinical development for hereditary angioedema

Anne Lesage, Ph.D., Pharvaris

Chief Early Development Officer

The 20st Annual Congress of

International Drug Discovery Science and Technology

May 22, 2024

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Disclaimer

This Presentation contains certain "forward‐looking statements" within the meaning of the federal securities laws that involve substantial risks and uncertainties. All statements contained in this Presentation

that do not relate to matters of historical fact should be considered forward-looking statements including, without limitation, statements containing the words "believe," "anticipate," "expect," "estimate," "may," "could," "should," "would," "will," "intend" and similar expressions. We have based these forward-looking statements largely on our current expectations and projections about future events and trends that we believe may affect our financial condition, results of operations, business strategy and financial needs. Such forward-looking statements involve unknown risks, uncertainties and other factors which may cause our actual results, financial condition, performance or achievements, or industry results, to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. Factors that might cause such a difference include, but are not limited to, uncertainty in the outcome of our interactions with regulatory authorities, including the FDA, with respect to clinical trials in the U.S. and our ability to resolve any issues to the satisfaction of the FDA or any regulatory agency in a timely manner, the expected timing, progress, or success of our clinical development programs, especially for deucrictibant, which is in late-stage global clinical trials, our ability to replicate the efficacy and safety demonstrated in the RAPIDe-1 and CHAPTER-1 Phase 2 study in ongoing and future nonclinical studies and clinical trials, risks the COVID-19 pandemic, which may adversely impact our business, nonclinical studies, and clinical trials, the outcome and timing of regulatory approvals and the value of our ordinary shares, the timing, costs and other limitations involved in obtaining regulatory approval for our product candidates, deucrictibant immediate-releasecapsules (PHVS416) and deucrictibant extended-releasetablets (PHVS719), or any other product candidate that we may develop in the future, our ability to establish commercial capabilities or enter into agreements with third parties to market, sell, and distribute our product candidates, our ability to compete in the pharmaceutical industry, including with respect to existing therapies, emerging potentially competitive therapies and with competitive generic products, our ability to market, commercialize and achieve market acceptance for our product candidates, our ability to raise capital when needed and on acceptable terms, regulatory developments in the United States, the European Union and other jurisdictions, our ability to protect our intellectual property and know-how and operate our business without infringing the intellectual property rights or regulatory exclusivity of others, our ability to manage negative consequences from changes in applicable laws and regulations, including tax laws, our ability to successfully remediate the material weaknesses in our internal control over financial reporting and to maintain an effective system of internal control over financial reporting, our expectations regarding the time during which we will be an emerging growth company under the JOBS Act or a foreign private issuer, changes and uncertainty in general market, political and economic conditions, including as a result of inflation and the current conflict between Russia and Ukraine, the Israel-Hamas war, and the other factors described under the headings "Cautionary Statement Regarding Forward-Looking Statements" and "Item 3. Key Information--D. Risk Factors" in our Annual Report on Form 20-F and other periodic filings with the Securities and Exchange Commission. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. We undertake no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

This presentation includes data for an investigational product not yet approved by regulatory authorities. Certain information contained in this Presentation relates to or is based on studies, publications, surveys and other data obtained from third-party sources and the Company's own internal estimates and research. While the Company believes these third-party sources to be reliable as of the date of this presentation, it has not independently verified, and makes no representation as to the adequacy, fairness, accuracy or completeness of, any information obtained from third-party sources. In addition, all of the market data included in this Presentation involves a number of assumptions and limitations, and there can be no guarantee as to the accuracy or reliability of such assumptions. Finally, while we believe our own internal research is reliable, such research has not been verified by any independent source.

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HAE: A rare, life-long genetic condition with significant burden from unpredictable, debilitating, and potentially lethal attacks of swelling

• Unpredictable frequency, location, timing, and severity
• • Multiple types of triggers
  • If untreated, attacks last multiple days
• Attacks are commonly painful, leading to hospitalization or multiple sick days
• • Half of people living with HAE experience a potentially life- threatening laryngeal attack at least once in their lifetime
• 1:10,000 to 1:50,000 Individuals affected by HAE globally
• • At least 6,600 people living with HAE in the U.S.
  • At least 8,900 people living with HAE in Europe
  • Globally, under-diagnosed/treated

	40%
	30%
reporting	20%
Patients	10%
	0%

Annual attacks (overall)

Median: 14 attacks/year

• Females: 19 (range: 2-165 attacks/y)
• Males: 9 (range: 1-42 attacks/y)

0

1-5

6-11

12-24

>24

Source: Nordenfelt et al, Acta Derm. Venereol 2016: 96: 540-545; Busse 2020 J Allergy Clin Immunol Pract; Bork et al 2021 J Allergy Clin Immunol

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Excess levels of bradykinin lead to swelling characteristic of angioedema attacks

HAE due to C1INH	HAE Type 1
deficiency	HAE Type 2

Hereditary
			HAE-FXII
			HAE-PLG
	HAE with normal		HAE-KNG
		HAE-HSST
	C1INH
		HAE-ANGPT
			HAE-MYOF
			HAE-unknown
	C1INH deficiency		Lymphoproliferative disorders, B-
Acquired		cell malignancies
(AAE C1-INH)		Autoimmune disorders
Drug-induced		Other
			Other disorders
			ACE-inhibitor
	Idiopathic		Histamine independent	bold = known or potential role for
		Histamine dependent	bradykinin involvement in disease

Source: Busse 2020 J Allergy Clin Immunol Pract; Bork et al 2021 J Allergy Clin Immunol; Zanichelli et al 2012 Allergy; Longhurst et al 2016 Clin. Exp. Immunol.; Otani, Banerji 2017 Immunol. Allergy Clin. N. Am.; Bova et al 2018 Int. Arch. Allergy Immunol.; Petersen, "Prophylaxis of angioedema attacks due to acquired C1-Inhibitor deficiency with PHA121, a novel oral bradykinin B2 receptor antagonist" C1-Inhibitor Workshop 2023 (https://2023.haenetworkshop.hu/program/index.php, https://www.linkedin.com/feed/update/urn:li:activity:7060638305842778112/); Shi et al 2021 Clin Immunol. 230 (doi.org/10.1016/j.clim.2021.108819), Reshef et al., 2024 J Allergy Clin Immunol, doi.org/10.1016/j.jaci.2024.03.024.

Notes: HMWK: high-molecular-weight kininogen; cHMWK: cleaved high-molecular-weight kininogen; FXII(a): Factor XII(a); ACE(i): angiotensin-converting enzyme (inhibitor); tPA: tissue plasminogen activator; KNG1: gene

encoding HMWK; PLG: gene encoding plasminogen; FXII: gene encoding FXII; ANGPT: gene encoding angiopoietin; MYOF: gene encoding myoferlin; HSST: gene encoding heparan sulfate sulfotransferase; SCLS: systemic capillary leak syndrome

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Targeting the culprit in HAE: bradykinin

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Deucrictibant: A novel, orally bioavailable bradykinin B2 receptor antagonist for bradykinin-mediated angioedema

• Potent and selective inhibitor of the bradykinin B2 receptor
• The first orally available bradykinin B2 receptor antagonist
• The compound contains a deuterium that was introduced into a metabolic soft spot, to stabilize the molecule.
• Currently in late-stage development for hereditary angioedema

Deucrictibant

PHA-022121 PHA121

We aspire to develop novel, oral alternatives that improve the standard of care

for people living with HAE and other bradykinin-mediated diseases

Source: Lesage et al, Frontiers in Pharmacology 2020, doi: 10.3389/fphar.2020.00916; Lesage et al, Int. Immunopharmacology 2022, doi.org/10.1016/j.intimp.2022.108523; https://ir.pharvaris.com/static-files/0361cd85-6000-490b-932b-d305e1f3ca1b;https://ir.pharvaris.com/static-files/81a9499d-0769-4b89-8ecd-8ace5ca521d3;https://ir.pharvaris.com/static-files/33217945-6893-4f49-8a93-c80ea6fb2a31;https://doi.org/10.1016/j.jaci.2019.12.094; Maurer et al., 2023 AAAAI,https://ir.pharvaris.com/static-files/351671e4-35b8-4bc3-a50d-ef96e17059ab;Riedl et al., 2024 AAAAI, https://ir.pharvaris.com/static-files/42de033b- 052a-4067-ad10-2c946c9aa2c7

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Deucrictibant is a competitive inhibitor of the bradykinin B2 receptor

Competitive antagonism of bradykinin-induced contraction

(human umbilical vein preparation)

Icatibant

Deucrictibant

Increasing antagonist concentration	Increasing antagonist concentration
pA2 8.7 nM	pA2 0.35 nM

deucrictibant is 25-fold more potent than icatibant at the endogenous human B2 receptor

Source: Lesage et al, Frontiers in Pharmacology 2020, doi: 10.3389/fphar.2020.00916; Lesage et al, Int. Immunopharmacology 2022, doi.org/10.1016/j.intimp.2022.108523

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Development of translational bradykinin challenge model in monkey

Deucrictibant, icatibant, or

(mmHg)

Transient BK effect

vehicle

110

100

Bradykinin

BK

BK

BK

BK

BK

BK

BK

pressure

90

(BK)

80

blood

70

60

predose

0

+1

+2

+3

+4

+5

+6

+7

hours

arterial

50

Mean

40

-400

-200

0

200

400

600

800

• Conscious, freely moving monkeys
• BK bolus was administered iv using infusion line and remote-control pump
• Mean arterial blood pressure (MABP) was measured using telemetry
• BK induced a transient MABP decrease of 20-40 mmHg

Source: Lesage et al, Kinin 2022, https://ir.pharvaris.com/static-files/f6622f7e-e405-4901-9bc9-5051a3588126

Time after BK injection, sec

BK challenge Predose

BK challenge 2h after PHA121

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In preclinical in vivo studies, oral deucrictibant inhibits challenge by bradykinin with longer duration and faster achievement of peak of effect than SC icatibant

		50							Vehicle
								PHA121 0.1 mg/kg
MABP
								PHA121 0.3 mg/kg
		40							PHA121 1 mg/kg
in
								PHA121 3 mg/kg
decreaseinduced-	(mmHg)	10
		30							PHA121 10 mg/kg
		20
BK
		0
		Predose	+1h	+2h	+3h	+4h	+5h	+6h	+7h

Maximal activity at

1 h

Source: https://education.aaaai.org/sites/default/files/L37%20Lesage_1.pdf; Lesage et al., 2021, 12th C1-Inhibitor deficiency and angioedema workshop presentation https://ir.pharvaris.com/static-files/76beb63f-4ccf-482a- 933d-d2b47ec4e09d

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In healthy volunteers, oral pre-treatment with deucrictibant blocks the effect of bradykinin-induced hemodynamic changes

Deucrictibant or placebo (po)

Bradykinin		BK	BK	BK	BK	BK
(BK)
Predose	0	+1	+4	+8	+12	+24	hours

Predose	+1 h
	(post- dose)

Systolic BP

Mean Arterial BP

Diastolic BP

		BK
BK

PK/PD modeled using a nonlinear mixed-effect Emax model comparing effect (inhibition of the baseline average-to-peak) to PK (two-compartment model, first-order oral absorption)

EC50 (ng/mL)	2.4
EC85 (ng/mL)	13.8

PK (exposure)

PD (effect)

PHA-022121,

Icatibant, SC22 mg PO 2x30 mg Q6h

A single deucrictibant dose predicted to provide similar PD effect as two injections of icatibant

Source:https://epostersonline.com/acaai2020/node/1369;https://doi.org/10.1016/j.jaci.2019.12.094;https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000ClinPharmR.pdf

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