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such research has not been verified by any independent source. 2022 2
Pharvaris: Fulfilling an unmet need in the treatment of hereditary
angioedema (HAE) and other bradykinin-mediated diseases Competitive product profile Large market opportunity Strong fundamentals Convenient, orally available, small Large global HAE market of $2+ Novel lead series with strong IP (primary molecule
targeting the validated billion with predicted 13% CAGR CoM granted in multiple territories; initial bradykinin B2 receptor pathway over 5 years term to 2038) Clinical proof-of-mechanism with Potential portfolio expansion into World-wide operations:
the Netherlands, superior potency and duration USA, and Switzerland (headquarters) other BK-mediated angioedema against surrogate endpoint, when and diseases through B2-receptor Cash runway to early 1Q24: 209.4 million compared to icatibant
pathway expertise as of December 31, 2021 Favorable PK/PD profile supporting Experienced management team with both on-demand and prophylactic successful track record in HAE drug design treatment and development 2022 3
Experienced management with deep expertise in development and rare
diseases Berndt Modig Anne Lesage, Ph.D. Morgan Conn, Ph.D. Wim Souverijns, Ph.D. Chief Community Engagement Chief Early Development Officer Chief Business Officer Chief Executive Officer and Commercial Officer Includes the leaders behind the
discovery, development, and approval of Firazyr (icatibant), and a key Jochen Knolle, Ph.D. Peng Lu, M.D., Ph.D. Anna Nijdam member of the Takhzyro Chief Scientific and Operating Officer Chief Medical Officer Principal Accounting Officer
(lanadelumab) development team 2022 4
Hereditary Angioedema (HAE) 2022 2022
HAE is a rare, life-long condition characterized by attacks of swelling
Rare and potentially life-threatening genetic condition 1:10,000 to 1:50,000 Individuals affected by HAE globally At least 6,600 patients in the U.S. At least 8,900 patients in Europe Globally,
under-diagnosed/treated Nordenfelt et al, Acta Derm. Venereol 2016: 96: 540-545 2022 6
HAE attacks are unpredictable, debilitating and potentially lethal
Attacks are unpredictable in Annual attacks (overall) frequency, location, timing, and 40% severity Median: 14 attacks/year Females: 19 (range: 2-165 attacks/y) Males: 9 (range: 1-42 attacks/y) Multiple types of triggers
30% If untreated, attacks last multiple days 20% Attacks are commonly painful, leading to hospitalization or multiple sick days 10% Half of patients experience a potentially life-threatening laryngeal 0% attack at least once
in their lifetime 0 1-5 6-11 12-24 >24 Nordenfelt et al, Acta Derm. Venereol 2016: 96: 540-545 2022 7 Patients reporting
The swelling of an HAE attack is caused by excess levels of bradykinin:
PHA121 is designed to block signaling by bradykinin Most genetic causes lead to elevated levels of bradykinin HMWK: high-molecular-weight kininogen; cHMWK: cleaved high-molecular-weight kininogen Busse 2020 J Allergy Clin Immunol Pract 2022
HAE patients actively switch products seeking improvement in efficacy,
safety/tolerability, and convenience 1 2 3 but safety & tolerability while convenience has Efficacy is patient's are pushing patients to become a key driver for prime concern explore alternatives patient
preference Patients desire HAE therapy that can deliver on ALL fronts Source: Company research 2021 2022 9
HAE is a valuable, growing market (US approved) On-Demand Prophylaxis
$2B+ market in 2018 growing ~13% annually $772M 2018 open ground B2 receptor Significant unmet need for an oral solution + generic Most approved products are injectable Efficacious, but often with injection-site $251M
$253M reactions (leads some patients to delay 3Q21 (est) 3Q21 (est) treatment and risk attacks) C1-INH $152M Time consuming to receive $137M 3Q21 3Q21 Difficult to carry and/or store One oral product recently approved $633M $28M
3Q21 plasma Early sales validate patient demand for 3Q21 kallikrein oral therapy $76M 3Q21 Source: Sales trends from quarterly filings (ASX: CSL; NYSE: TAK; AMS: PHARM; NASDAQ: BCRX); EvaluatePharma 2022 10
Product Strategy 2022 2022 11 CONFIDENTIAL
On-demand and prophylaxis: Developing two oral products utilizing the
same active ingredient PHA121 PHVS416 PHVS719 Softgel capsule formulation Extended-release tablet formulation Aim to maintain compound exposure Potential to provide fast, easy, and to prevent attacks, providing an easy reliable symptom relief for
all attacks and effective way for patients to live 2022 12
Wholly-owned pipeline focused on bradykinin B2 receptor mechanism
Candidate Indication Discovery Preclinical Phase 1 Phase 2 Phase 3 Next Milestone PHA121 Phase 2 topline data PHVS416 in 4Q2022 On-demand HAE (RAPIDe-1 trial) Phase 2 topline data PHVS416 in 4Q2022 HAE Prophylaxis (PoC) (CHAPTER-1 trial) Phase 1
topline PK PHVS719 data in 1Q2022 HAE Prophylaxis PHAxxx undisclosed 2022 13 PHA121 API XR Tablet Softgel Capsule Solution
Programs 2022 2022 CONFIDENTIAL
Pharvaris compounds are potent, orally available competitive inhibitors
of the bradykinin B2 receptor Competitive antagonism of bradykinin-induced contraction (human umbilical vein preparation) Pharvaris Icatibant compound Increasing antagonist concentration Increasing antagonist concentration pA 8.7 nM pA 0.21 nM 2 2
PHA121 is 25-fold more potent than icatibant at the endogenous human B2 receptor Lesage et al, Frontiers in Pharmacology, 2020 (11), 916, doi: 10.3389/fphar.2020.00916 2022 15
PHA121 PK/PD in humans 2022 2022 CONFIDENTIAL
PHA121 was well tolerated in Phase 1 SAD and MAD trials PHA121 (oral
solution) has completed SAD and MAD All doses were well tolerated in Phase 1 studies SAD, SADext, and MAD studies (oral solution) Single ascending dose: 1-50 mg; double-blind, placebo-controlled No SAEs or severe AEs were reported
Food effect: 22-50 mg; fasting, high-fat diet, normal diet with no treatment discontinuations Total incidence of AEs was similar Bradykinin challenge: 12/22 mg; Proof-of-mechanism between active and placebo groups
Multiple ascending dose: 12-50 mg; double-blind, placebo- Most AEs observed were of mild controlled severity No clear differences for AE patterns No clinically significant changes were observed for between different dosing regimens vs.
placebo physical exams, vitals, ECG, and safety lab assessments 2022 17
PHA121 demonstrates a well-behaved dose-proportional PK profile 1 mg
PHA-022121 fasted 250 22 mg PHA121 1000 250 (fasted) 2 mg PHA-022121 fasted 200 22 mg PHA121 4.5 mg PHA-022121 fasted 200 100 (HCHF meal) 150 12 mg PHA-022121 fasted 22 mg PHA121 100 22 mg PHA-022121 fasted 150 10 (standard meal) 40 mg PHA-022121
fasted 50 EC 85 100 1 0 0.00 0.50 1.00 50 0.1 EC 85 0 0.01 0 4 8 12 16 20 24 0 12 24 36 48 60 Time (h) Time (h) Approximately dose-proportional PK with single and Rapid exposure under both fasted and fed status (EC 85 multiple oral
administration within 15 min); T delayed by ~2 hours with food max Half-life approximately 3.4-5.6 hours (approximately Lower C and comparable AUC under fed max 0-24h three-fold longer than icatibant) (standard and high-calorie,
high-fat) compared to fasted status https://epostersonline.com/acaai2020/node/1384 2022 18 Plasma concentrations of PHA-022121 (ng/mL) Plasma concentrations of PHA-022121 (ng/mL)
In multiple-dose studies, when dosed with food, BID doses of PHA121
solution maintain exposure above predicted efficacious levels C (mean) on Day 10 Exposure following last dose (Day 10) trough prior to final dose 250 200 150 EC 85 100 50 EC85 0 12 mg 22 mg 33 mg 55 mg BID BID BID BID Steady state reached within 72
hours; plasma trough levels on Day 10 remained well above EC 85 https://ir.pharvaris.com/static-files/81a9499d-0769-4b89-8ecd-8ace5ca521d3 2022 19 CONFIDENTIAL PHA121 C PLASMA EXPOSURE (ng/ml) trough
Inhibition of bradykinin-induced hemodynamic effects is a validated
surrogate assessment In healthy volunteers, pre-dosing a bradykinin-B2-receptor antagonist blocks the Bradykinin (BK) hemodynamic effects of bradykinin Bradykinin effects restored as single-dose eliminated BP HR Used to select
clinical dose in the original icatibant development program, as reviewed by FDA and EMA Proportion of attacks treated Icatibant's clinical dose, established with the BK challenge, has demonstrated successful resolution of HAE attacks in
randomized clinical trials and over 10 One dose years of data post-approval 93.1% Two doses Icatibant Outcome Survey: Longitudinal survey over 10 years; more than 5000 HAE 6.0% attacks treated with 30 mg SC Three or more 0.9%
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000ClinPharmR.pdf; Maurer et al 2020: Long-term effectiveness and safety of icatibant for the on-demand treatment of hereditary angioedema attacks: 10 years of the icatibant outcome
survey (EAACI Poster #1118, June 6-8, 2020): https://clinicaltrials.gov/ct2/show/NCT01034969 2022 20
In preclinical in vivo studies, oral PHA121 inhibits challenge by
bradykinin with longer duration and faster onset than SC icatibant https://education.aaaai.org/sites/default/files/L37%20Lesage_1.pdf 2022 21
In healthy volunteers, oral pre-treatment with PHA121 blocks the effect
of bradykinin-induced hemodynamic changes PHA121 or placebo (po) Bradykinin BK BK BK BK BK (BK) Human BK challenge PHA121 +12 0 +1 +4 +8 hours +24 Predose EC (ng/mL) 2.4 50 EC (ng/mL) 13.8 85 Predose +1 h after dose Systolic BP Potency ~4x higher
than icatibant based on Mean Arterial BP plasma concentration (published data) Diastolic BP ~24x more potent on molecule-by-molecule basis (170 pM for PHA121 vs. 4.1 nM for icatibant) BK BK Consistent with in vitro measurement:
PHA121 demonstrates K 150 pM (recombinant) and 350 pM b PK/PD modeled using a nonlinear mixed-effect E model max (endogenous) at the human bradykinin B2 receptor comparing effect (inhibition of the baseline, average-to-peak) to PK (two-compartment
model, first-order oral absorption) 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 2022 22
A single PHA121 dose predicted to provide similar pharmacodynamic
effect as two injections of icatibant Estimated duration of effect (icatibant versus PHA121) PK (exposure) Icatibant PHA121 PHA121 Response 30 mg SC 12 mg PO 22 mg PO Time (h) plasma level above EC at 50% confidence level 85 DBP 5.5 7.5 10 PHA121,
PO MABP 5.5 7 10 22 mg PD HR 5.5 6.5 9.5 Icatibant, SC (effect) 2x30 mg Q6h DBP: diastolic blood pressure; MABP: mean arterial blood pressure; HR: heart rate The PK/PD model was used to simulate PK profiles (N=1000) and calculate probability of
durations of effect as well as to visualize effect-time profiles https://epostersonline.com/acaai2020/node/1369; https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000ClinPharmR.pdf 2022 23
PHVS416/On-Demand Softgel capsule formulation of PHA121 2022
HAE RAPIDe-1 study underway: On-demand treatment of acute attacks in
Type 1 or 2 HAE patients Study Site Home Treatment Primary objective: to evaluate angioedema Non-attack Attack 1 Attack 2 Attack 3 symptom relief within four hours in acute PHVS416 PHVS416 placebo attacks of patients with HAE type 1 or 2
PHA121 placebo PHVS416 PHVS416 (10 mg) placebo PHVS416 PHVS416 Placebo-controlled, three doses Primary endpoint: VAS at 4hr post-dose placebo PHVS416 PHVS416 PHA121 PHVS416 placebo PHVS416 VAS, MSCS, TOS will be assessed
up to 48 hr (20 mg) placebo PHVS416 PHVS416 post-dose PHVS416 PHVS416 placebo Up to 72 HAE patients to enroll from ~30 sites PHA121 placebo PHVS416 PHVS416 in US, Canada, Europe, Israel, and UK (30 mg) placebo PHVS416 PHVS416 Topline
data anticipated 4Q2022 www.hae-rapide.com; https://clinicaltrials.gov/ct2/show/NCT04618211; https://hae-rapide.us/; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-003445-11 VAS: visual analogue score; MCSC: mean symptom complex
severity; TOS: treatment outcome score 2022 25 Screening Period Randomization
On-Demand: PHVS416 aims to provide clear differentiation for efficacy
and convenience Clinical data PHVS416 Icatibant KVD900 berotralstat BERINERT RUCONEST KALBITOR FDA Approval (Phase 2) 2011 (end of Phase 2) (EOP2, dropped) 2009 2014 2009 Mechanism B2R B2R pKi pKi C1INH C1INH pKi Dose 30 mg
30 mg 6x100 mg 750 mg 20 IU/kg 50 IU/kg 3x10 mg Form Soft capsule SC Tablet Oral, suspension IV (10 mL/2.5 min) IV (14 mL/5 min) SC, 3 doses Storage Room temp Room temp Room temp Room temp Room temp Fridge Administered Patient Patient Patient
Patient Patient HCP/Patient HCP Time to 2x IC50 <15 min 10 min <30 min 48 min Half-life (h) 3.4-5.6 1.4 ~2 93 18 2.5 2 Single-dose resolution 93% 64% 80-89%% 90% 67-86% 5d 24h 24h Rescue or re-dose? 7% 21% 30% 11-20% 11% 14-33% VAS PGI-C VAS
PGI-C Initial relief (h) 0.8-1.5 1.6 /6 5 0.25 1.5 -- 50% VAS reduction (h) 2 6 8 -- 3.5 -- Almost-complete 8 23 8.4 -- -- symptom relief (h) Anaphylaxis, Injection site Nasopharyngitis, Thromboembolic Headache, rabbit Side effects pruritus, rash,
reaction diarrhea, headache events allergy nausea Source: Firazyr, Ruconest, Kalbitor prescribing information; Pharming release 2018-12-07; BioCryst release 2018-09-04; Kalvista corporate presentation 2021-02-09;
https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-004489-32; Lumry 2013 Allergy Asthma Proc. 34(2), 155-161; EAACI 2020 Poster #1118; Zanichelli et al, C1 Inhibitor Workshop 2021
PHVS719/Prophylaxis Extended-release tablet formulation of PHA121