SEC Filing - Pharvaris N.V.

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6-K

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, D.C. 20549

FORM 6-K

REPORT OF FOREIGN PRIVATE ISSUER

PURSUANT TO RULE 13A-16 OR 15D-16

UNDER THE SECURITIES EXCHANGE ACT OF 1934

For the month of January 2022

Commission File Number: 001-40010

Pharvaris N.V.

(Translation of registrant’s name into English)

J.H. Oortweg 21

2333 CH Leiden

The Netherlands

(Address of principal executive office)

Indicate by check mark whether the registrant files or will file annual reports under cover of Form 20-F or Form 40-F.

Form 20-F ☒ Form 40-F ☐

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(1): ☒

Indicate by check mark if the registrant is submitting the Form 6-K in paper as permitted by Regulation S-T Rule 101(b)(7): ☐

PHARVARIS N.V.

On January 10, 2022, Pharvaris N.V. made available an investor presentation on its website. A copy of the investor presentation is attached hereto as Exhibit 99.1.

EXHIBIT INDEX


Exhibit No.		Description

99.1		Investor Presentation, dated January 10, 2022

SIGNATURES

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto duly authorized.


	PHARVARIS N.V.

Date: January 10, 2022	By:	/s/ Berndt Modig

	Name:	Berndt Modig
	Title:	Chief Executive Officer

EX-99.1

Disclaimer This Presentation may contain certain “forward‐looking statements” within the meaning of the federal securities laws that involve substantial risks and uncertainties. All statements other than statements of historical factors contained in this Presentation, including statements regarding our future financial condition, results of operations and/or business achievements, including, without limitation, statements containing the words “believe,” “anticipate,” “expect,” “estimate,” “may,” “could,” “should,” “would,” “will,” “intend” and similar expressions are forward-looking statements. 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, the expected timing, progress or success of our clinical development programs, risks associated with the COVID-19 pandemic, 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 weakness in our internal control over financial reporting and to maintain an effective system of internal control over financial reporting, and the other factors described under the heading “Risk Factors” in our registration statement 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. 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. © 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

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 8

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

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

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 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

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 (https://www.kalvista.com/sites/default/files/presentations/zoom_0.mp4) © 2022 26

Prophylactic proof-of-concept study underway with PHVS416 Candidate Phase 1 Phase 2 Phase 3 Indication Utilizing the food effect observed in Phase 1, PK/PD modeling PHVS416 Data 4Q22 suggests that PHA121 can maintain exposure >EC 85 Prophylaxis HAE with twice-daily dosing of PHVS416 PHVS719 Data 1Q22 Prophylaxis HAE Pharvaris is targeting to use PHVS719 for pivotal studies in HAE prophylaxis § Combining exposure/efficacy data from PHVS416 Phase 2 (CHAPTER-1) study and exposure data from PHVS719 Phase 1 study © 2022 28 XR Softgel Tablet

HAE CHAPTER-1 study recruiting: Prevention of attacks in HAE patients § Primary objective: assessing safety and efficacy of 12 WEEKS PHA121 in preventing HAE attacks in patients with HAE type 1 or type 2 Placebo 2 placebo capsules § Placebo-controlled, 3 parallel arms, two doses § Primary endpoint: Number of investigator- PHA121 1 PHVS416 capsule (10 mg) 1 placebo capsule confirmed HAE attacks • Secondary endpoints include moderate or severe HAE PHA121 2 PHVS416 attacks, HAE attacks requiring acute treatment (20 mg) capsules § 30 HAE patients across 24 sites in US, Canada, BID dosing after meals Europe, Israel, and UK § Topline data anticipated 4Q22 https://clinicaltrials.gov/ct2/show/NCT05047185, https://haechapter-1.com/ © 2022 29 Screening Period Randomization

PHVS719 PK study underway: Assessing QD potential § Open-label, crossover comparison in 8 adult § Primary objective to assess PK under male healthy volunteers fasting conditions • Secondary objectives to assess food effect; § Sequential dosing (random order) of: compare exposure to PHVS416; evaluate safety • PHVS416: 20 mg dose (fasted) and tolerability • PHVS719 prototypes § Key performance parameters o XR1: 20 mg dose (fasted, fed) • Mean plasma concentration maintained above o XR2: 40 mg dose (fasted, fed) 13.8 ng/mL at 12 or 24 hours Study Site • Extended-release profile enabling QD option for prophylactic use PHVS416 XR1 (fed) XR1 (fasted) XR2 (fed) XR2 (fasted) Randomized order § Topline results expected 1Q22 © 2022 30 CONFIDENTIAL

Prophylaxis: PHVS719 aims to combine efficacy and convenience compared to approved therapies and oral pipeline PHVS719 KVD824 ORLADEYO® TAKHZYRO® HAEGARDA® CINRYZE® FDA Approval (Phase 1/2) (Phase 2) 2020 2018 2017 2008 Mechanism B2R pKi pKi pK mAb C1INH C1INH Dose ≤40 mg 300-900 mg 150 mg, 110 mg 300 mg 60 IU/kg 1000-2500 IU Form XR tablet Delayed-release tablet Hard capsule SC, 2 mL SC, 6 mL IV, 10-25 mL Storage room temp room temp fridge room temp fridge/room temp Frequency Daily Twice daily Once daily Semi-monthly Semi-weekly Semi-weekly Attack reduction (mean) 44% 87% 84% 84.5% ≥50% reduction 58% 100% 90% ≥70% reduction 50% 89% 83% ≥90% reduction 23% 67% 58% Patients, attack-free 44% -- 40% (study) (77-87% SS) Steady-state ~3 d ~3 d (est.) 6-12 days 10 weeks ~14 d (est.) ~7 d (est.) GI effects, QTc on Injection-site reaction, Headache, nausea, Side effects higher doses, injection-site reaction thromboembolic events thromboembolic events moderate DDI Source: Takhzyro, Haegarda, Cinryze, Orladeyo prescribing information; Aygoren-Pursun 2018. NEJM 379(4), 352-62; ICER 2018 Final Evidence Report – Long-Term Prophylaxis in HAE; Kalvista corporate presentation 2020-12-16 and quarterly report 2021-09-09 © 2022 31

Pharvaris poised for multiple milestones in 2022 HAE On-Demand HAE Prophylaxis (type 1 and type 2) (type 1 and type 2) RAPIDe-1 Ph2 topline data CHAPTER-1 Ph2 topline data PHVS416 soft capsule (anticipated 4Q22) (anticipated 4Q22) Ph1 topline PK data PHVS719 XR tablet not applicable (anticipated 1Q22) €209.4 million cash (YE21) provides runway into early 1Q24 © 2022 32