Pioneering science for patient choice - September 2021 - Pharvaris

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Pioneering science for patient choice - September 2021 - Pharvaris
Pioneering science for patient choice
                      September 2021

© 2021
Pioneering science for patient choice - September 2021 - Pharvaris
Disclaimer

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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
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                            © 2021                                                                                                                                             2
Pioneering science for patient choice - September 2021 - Pharvaris
Pharvaris: Fulfilling an unmet need in the treatment of hereditary
angioedema (HAE)

Competitive product profile           Large market opportunity             Strong fundamentals
Convenient, orally available, small   Large global HAE market of $2+       Experienced management team with
molecule targeting the validated      billion with predicted 13% CAGR      successful track record in HAE drug
bradykinin-B2 receptor pathway        over 5 years                         design and development

Clinical proof-of-mechanism with      Potential portfolio expansion into   World-wide operations: the
superior potency and duration         other BK-mediated angioedema         Netherlands, USA, and Switzerland
against surrogate endpoint, when      and diseases through B2-receptor     (headquarters)
compared to icatibant                 pathway expertise
                                                                           Runway for >2 years: €224.3 million
Favorable PK/PD profile supporting                                         as of June 30, 2021
both on-demand and prophylactic
treatment                                                                  Novel lead series with strong IP
                                                                           (issued US patent expires in 2038)

                      © 2021                                                                                     3
Pioneering science for patient choice - September 2021 - Pharvaris
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 Executive Officer           Chief Early Development Officer     Chief Business 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

                            © 2021                                                                                                      4
Pioneering science for patient choice - September 2021 - Pharvaris
On-demand and prophylaxis: Developing two oral products utilizing
 the same active ingredient
                                           PHVS416                       PHVS719
                        Softgel capsule formulation                      Extended-release tablet formulation

                                                                PHA121

Symptom resolution from validated mechanism                              Prophylaxis: Protection from attacks
                 More potent, longer half-life than icatibant            Mechanism addresses all bradykinin, regardless of pathway
                              Rapid onset of activity                    Extended release to maintain exposure
    Exposure exceeds the anticipated threshold therapeutic               Achieve steady-state concentration within 72 hours with
     plasma level (EC85) in 15 minutes, with or without food             BID/QD dosing

                          © 2021                                                                                                   5
Pioneering science for patient choice - September 2021 - Pharvaris
Wholly-owned pipeline focused on bradykinin B2 receptor mechanism
                                Candidate
                                Indication            Discovery   Preclinical   Phase 1   Phase 2   Phase 3    Next Milestone
              Solution

                                PHA121

                                PHVS416
 PHA121 API

                                                                                                              Phase 2 data 2022
              Softgel Capsule

                                On-demand HAE

                                PHVS416                                                                       Phase 2 start 2021
                                Prophylaxis HAE
              XR Tablet

                                PHVS719                                                                       Phase 1 start 2021
                                Prophylaxis HAE

  PHAxxx
  undisclosed

                                             © 2021                                                                                6
Pioneering science for patient choice - September 2021 - Pharvaris
Hereditary Angioedema (HAE)

          © 2021
Pioneering science for patient choice - September 2021 - Pharvaris
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

                                        © 2021                               8
Pioneering science for patient choice - September 2021 - Pharvaris
HAE attacks are unpredictable, debilitating and potentially lethal
   ▪ Attacks are unpredictable in                                                                      Annual attacks (overall)
     frequency, location, timing,
     and severity                                                              40%
                                                                                     Median: 14 attacks/year
                                                                                     • Females: 19 (range: 2-165 attacks/y)
                                                                                     • Males: 9 (range: 1-42 attacks/y)
        ‒ Multiple types of triggers                                           30%

                                                          Patients reporting
        ‒ If untreated, attacks last multiple days
        ‒ Attacks are commonly painful, leading                                20%

          to hospitalization or multiple sick days
                                                                               10%
        ‒ Half of patients experience a
          potentially life-threatening laryngeal
          attack at least once in their lifetime                               0%
                                                                                            0                   1-5           6-11   12-24   >24

Nordenfelt et al, Acta Derm. Venereol 2016: 96: 540-545

                                        © 2021                                                                                                     9
Pioneering science for patient choice - September 2021 - Pharvaris
The swelling of an HAE attack is caused by excess levels of
bradykinin

     ▪ Most genetic causes lead to elevated levels of
       bradykinin

Busse 2020 J Allergy Clin Immunol Pract                 HMWK: high-molecular-weight kininogen; cHMWK: cleaved high-molecular-weight kininogen

                                   © 2021                                                                                             10
PHA121 is designed to block signaling by bradykinin

                                                                    ▪ Therapies are approved for treatment (‘on demand’) or prevention
                                                                      (‘prophylaxis’) of attacks
                                                                           • Replacement of C1-INH, inhibition of plasma kallikrein enzyme,
                                                                             inhibition of bradykinin binding to B2 receptor
                                                                    ▪ Most approved products are injectable, one oral product recently
                                                                      approved
                                                                           • Efficacious, but often with injection-site reactions (leads some
                                                                             patients to delay treatment and risk attacks)
                                                                           • Time consuming to receive
                                                                           • Difficult to carry and/or store
                                                                    ▪ Icatibant, an injectable inhibitor of the bradykinin B2 receptor, is
                                                                      the predominant therapy used for treatment of attacks
                                                                           • Properties prevent its use in prophylactic setting
HMWK: high-molecular-weight kininogen; cHMWK: cleaved high-molecular-weight kininogen                                                     Evaluate Pharma

                             © 2021                                                                                                                  11
HAE patients actively switch products for improved efficacy or
convenience
(US approved)                        On-Demand                                         Prophylaxis
                                                                                                                          ▪ $2B+ market in 2018 growing ~13%
                                                          $772M                                                             annually
                                                          2018
   B2 receptor
                                     + generic                                                                            ▪ Significant unmet need for an oral
                                                                                                                            solution
                                                            $287M
                                                                                                                          ▪ Most approved products are injectable
                                                                                                              $307M
                                                            2020
                                                                                                              2020            ▪ Efficacious, but often with injection-site
         C1-INH                                                                                                                 reactions (leads some patients to delay
                                                                    $212M
                                                                    2020
                                                                                                                 $206M
                                                                                                                 2020
                                                                                                                                treatment and risk attacks)
                                                                                                                              ▪ Time consuming to receive
                                                                                                                              ▪ Difficult to carry and/or store
                                                                                                                  $777M
         plasma                                            $37M
                                                           2020
                                                                                                                  2020
                                                                                                                          ▪ One oral product recently approved
       kallikrein
                                                                                                                  $39M        ▪ First half sales validate patient demand
                                                                                                                  1H21
                                                                                                                                for oral therapy
Source: Sales trends from quarterly filings (ASX: CSL; NYSE: TAK; AMS: PHARM; NASDAQ: BCRX); EvaluatePharma

                                   © 2021                                                                                                                                    12
Programs

           © 2021   CONFIDENTIAL
Pharvaris compounds are potent, orally available competitive inhibitors
of the bradykinin B2 receptor
                                Antagonism of bradykinin-induced contraction (human umbilical vein preparation)

                                  icatibant, pA2 8.7 nM                                  compound, pA2 0.21 nM

            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

                              © 2021
PHA121 was well tolerated in Phase 1 SAD and MAD trials

▪ PHA121 (oral solution) has completed SAD and MAD Phase 1 studies
   • Single ascending dose: 1-50 mg; double-blind, placebo-controlled
   • Food effect: 22-50 mg; fasting, high-fat diet, normal diet
   • Bradykinin challenge: 12/22 mg; Proof-of-mechanism
   • Multiple ascending dose: 12-50 mg; double-blind, placebo-controlled

▪ All doses were well tolerated in SAD, SADext, and MAD studies (oral solution)
   • No SAEs or severe AEs were reported and no treatment discontinuations
   • Total incidence of AEs is similar between active and placebo groups
   • Most AEs observed were of mild severity
   • No clear differences for AE patterns between different dosing regimens vs. placebo

▪ No clinically significant changes were observed for physical exams, vitals, ECG, and safety
  lab assessments
                  © 2021                                                                        15
PHA121

PK/PD in humans

             © 2021   CONFIDENTIAL
PHA121 demonstrates a well-behaved dose-proportional PK profile
                                                                                        1 mg PHA-022121 fasted                                                250             22 mg PHA121
                                      1000                                                                                                                                                      250
    Plasma concentrations of PHA-022121

                                                                                        2 mg PHA-022121 fasted                                                                (fasted)

                                                                                                                        Plasma concentrations of PHA-022121
                                                                                                                                                                                                200
                                                                                        4.5 mg PHA-022121 fasted                                              200             22 mg PHA121
                                          100
                                                                                                                                                                              (HCHF meal)       150
                                                                                        12 mg PHA-022121 fasted
                                                                                                                                                                              22 mg PHA121      100
                                           10                                           22 mg PHA-022121 fasted                                               150
                                                                                                                                                                              (standard meal)
                 (ng/mL)

                                                                                                                                     (ng/mL)
                                                                                        40 mg PHA-022121 fasted                                                                                  50
                                                                                                                                                                                                                         EC85
                                            1                                                                                                                 100                                 0
                                                                                                                                                                                                      0.00   0.50        1.00

                                           0.1                                                                                                                 50
                                                                                                                                                                                                                          EC85
                                          0.01                                                                                                                  0
                                                 0   12            24              36            48                60                                               0   4   8 Time (h) 12        16                 20          24
                                                                        Time (h)

▪            Approximately dose-proportional PK with single and multiple oral administrations
▪            Rapid exposure under both fasted and fed status (EC85 within 15 min); Tmax delayed by ~2 hours with food
▪            Half-life approximately 3.4-5.6 hours (approximately three-fold longer than icatibant)
▪            Lower Cmax and comparable AUC0-24h under fed (standard and high-calorie, high-fat) compared to fasted status
▪            MAD data indicate that projected therapeutic levels achieved within first day; steady-state exposure reached within 72
             hours
https://epostersonline.com/acaai2020/node/1384

                                                          © 2021                                                                                                                                                                     17
Inhibition of bradykinin-induced hemodynamic effects is a validated
surrogate assessment

                    Proportion of attacks treated                                                                   ▪ Used to select the dose in the original
                                                                                                                      development program for icatibant, as
                                                                                                                      reviewed by FDA and EMA
                                                                                                                    ▪ Clinical dose established with the BK
                    One dose                                                                                          challenge has demonstrated
                     93.1%
                                                                                     Two doses                        successful resolution of HAE attacks in
                                                                                       6.0%
                                                                                                                      randomized clinical trials and over 10
                                                                                 Three or more
                                                                                                                      years of data post-approval
                                                                                     0.9%
                                                                                                                             • Icatibant Outcome Survey: Longitudinal
                                                                                                                               survey over 10 years; more than 5000 HAE
                                                                                                                               attacks treated with 30 mg SC

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

                                  © 2021                                                                                                                                  18
Oral PHA121 inhibits challenge by bradykinin in vivo

    Modelled after icatibant
    BK challenge in healthy
    volunteers (PoC Phase 1)

                                                                     Pre-clinical BK challenge study in
                                                                     freely moving monkeys
                                                                     • Clear dose-dependent activity
                                                                     • Longer duration, faster onset of
                                                                       activity than icatibant

https://education.aaaai.org/sites/default/files/L37%20Lesage_1.pdf

                                   © 2021                                                                 19
Oral pre-treatment with PHA121 blocks the effect of IV bradykinin-
induced hemodynamic changes in human studies

                       PHA121 or placebo (po)                                                                            Human BK
                     Bradykinin                                                                                          challenge                   PHA121              Icatibant
                        (BK)         BK      BK      BK        BK               BK
                                                                                                                           EC50 (ng/mL)                   2.4                 9.5
                       Predose 0      +1     +4       +8       +12              +24      hours                             EC85 (ng/mL)                  13.8                53.8

              Phase 1 BK challenge study in healthy volunteers
              • Potency ~4x higher than icatibant based on plasma concentration from
                published data
                   • ~24x more potent on molecule-by-molecule basis (170 pM for PHA121 vs. 4.1 nM for icatibant)
                           • Consistent with in vitro measurement: PHA121 demonstrates Kb 150 pM (recombinant) and
                             350 pM (endogenous) at the human bradykinin B2 receptor
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000ClinPharmR.pdf; https://doi.org/10.1016/j.jaci.2019.12.094; https://epostersonline.com/acaai2020/node/1369

                                  © 2021                                                                                                                                             20
Single PHA121 dose predicted to provide a similar pharmacodynamic
effect as two injections of icatibant
    Simulation of PK/PD resulting from single vs. double doses of                                                                            Estimated duration of effect
              icatibant versus single doses of PHA121                                                                                         (icatibant versus PHA121)
                                                                                                                                                      Icatibant            PHA121              PHA121
                                                                                                                                    Response          30 mg SC            12 mg PO            22 mg PO
                                                                                                                                    Time (h) plasma level above EC50 at 75% confidence level
                                                                                                                                           DBP             6                 11.5                  14
                                                                                                                                        MABP               6                  12                 15.5
                                                                                                                                             HR           6.5                 10                   13
                                                                                                                                    Time (h) plasma level above EC85 at 50% confidence level
                                                                                                                                           DBP            5.5                 7.5                  10
                                                                                                                                        MABP              5.5                  7                   10
                                                                                                                                             HR           5.5                 6.5                 9.5
                                                                                                                                DBP: diastolic blood pressure; MABP: mean arterial blood pressure; HR: heart rate

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022150Orig1s000ClinPharmR.pdf; https://epostersonline.com/acaai2020/node/1369

                                 © 2021                                                                                                                                                                  21
PHVS416/On-Demand

Softgel capsule formulation of PHA121

              © 2021        CONFIDENTIAL
PHVS416: formulation and PK tailored for convenient on-demand treatment

▪ Soft capsule formulation of PHA121 containing the oral
  solution used in clinical studies
▪ In preclinical studies, demonstrated the same PK profile
  as the solution formulation
▪ Expected to provide appropriate PK profile for on-demand
  treatment of HAE

                  © 2021                                                  23
HAE RAPIDe-1 study underway: On-demand treatment of acute
  attacks in Type 1 or 2 HAE patients
                                                                               ▪ Primary objective: to evaluate angioedema
                                                                                 symptom relief within four hours in acute
                                                                                 attacks of patients with HAE type 1 or 2
                                                                               ▪ Placebo-controlled, three doses
                                                                               ▪ Primary endpoint: ∆VAS at 4hr post-dose
                                                                                  • VAS, MSCS, TOS will be assessed up to 48 hr
                                                                                    post-dose

                                                                               ▪ Up to 72 HAE patients to enroll from ~30
                                                                                 sites in Canada, Europe, and US

www.hae-rapide.com; https://clinicaltrials.gov/ct2/show/NCT04618211;
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-003445-11         VAS: visual analogue score; MCSC: mean symptom complex severity; TOS: treatment outcome score

                                      © 2021                                                                                                                           24
On-Demand: PHVS416 aims to provide clear differentiation for
convenience and efficacy
        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
PHVS719/Prophylaxis

Extended-release tablet formulation of
  PHA121

               © 2021
Entering prophylactic studies in 2021, initially with PHVS416

                       Candidate
                       Indication            Phase 1    Phase 2    Phase 3   Utilizing the food effect observed in Phase 1,
             Softgel

                       PHVS416                          Starting             PK/PD modeling suggests that PHA121 can
                       Prophylaxis HAE                   2021                reach exposure >4.5x EC50 with twice-daily
                       PHVS719                                               dosing of PHVS416
      Tablet

                                             Starting
       XR

                       Prophylaxis HAE        2021

▪ Planning to commence a Phase 2 clinical trial using PHVS416 for prophylaxis in 2021 (HAE CHAPTER-1)
    • US IND open; initiating 2021
▪ Expect to test PHVS719 formulation in a Phase 1 trial starting in 2021
    • Anticipate that PHVS719 will be included in pivotal trial

                                    © 2021                                                                                    27
HAE CHAPTER-1 study: Prevention of attacks in HAE patients

                                   12 WEEKS                           ▪ Primary objective: assessing safety and efficacy
                                                                        of PHA121 in preventing HAE attacks in patients
         R
         A        Placebo                  2 placebo capsules           with HAE type 1 or type 2
 S       N
 C
 R
     P
         D
         O
                                                                      ▪ Placebo-controlled, 3 parallel arms, two doses
     E
 E       M
 E
     R
     I
         I
                PHA-022121
                 LOW DOSE
                                      1 PHVS416 + 1 placebo capsule   ▪ Primary endpoint: Number of investigator-
 N       Z
 I
     O
     D
         A                                                              confirmed HAE attacks
 N       T
 G       I
                PHA-022121
                                                                          • Secondary endpoints include moderate or severe
         O                                2 PHVS416 capsules
         N
                HIGH DOSE                                                   HAE attacks, HAE attacks requiring acute treatment

                             BID dosing after meals
                                                                      ▪ 30 HAE patients across 24 sites in US, Canada,
                                                                        and Europe

             © 2021                                                                                                         28
Multiple-dose studies show BID doses of PHA121 solution maintain
exposure above predicted efficacious levels

        Exposure following last dose (Day 10)                                              PK Parameters on Day 10 (mean ± SD)

                                                                                                          PHA121         PHA121       PHA121       PHA121
                                                                                            Day 10
                                                                                                         12 mg BID      22 mg BID    33 mg BID    50 mg BID

                                                                                                     N       8              8            8           6
                                                                              EC85
                                                                                            Cmax (ng/mL) 114 ± 48.4     243 ± 94.5   286 ± 66.3   693 ± 480
                                                                                          Ctrough (ng/mL) 20.6 ± 12.0   33.9 ± 20.8 43.1 ± 28.6   257 ± 248

 Plasma trough levels at steady state (Day 10) remained well above EC85 for all doses tested
 https://ir.pharvaris.com/static-files/81a9499d-0769-4b89-8ecd-8ace5ca521d3

                              © 2021                                             CONFIDENTIAL                                                                 29
PHVS719: Modeling of dissolution profile suggests formulation may
support twice-a-day dosing; goal of once-a-day
                       Simulation of BID dosing                  Simulation of QD dosing
PK (exposure)

                                                                                                    Targeting maintenance of PHA121
                                                                                                    concentrations above levels predicted
  PD (effect)                                                                                       to provide protection against attacks

                Simulation of pharmacokinetics (exposure) and pharmacodynamics (inhibition of
                bradykinin effect) for once-daily (QD) or twice-daily (BID) dosing of a prototype
                extended-release formulation, based on observed in vitro release characteristics

                           © 2021                                                                                                           30
Prophylaxis: PHVS719 aims to combine convenience and efficacy
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                      600-900 mg                   150 mg, 110 mg                      300 mg                            60 IU/kg          1000-2500 IU
               Form                             Tablet                          Oral                      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           thromboembolic
                                                                                                         moderate DDI                                                      events                  events

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

                                    © 2021                                                                                                                                                                       31
Upcoming milestones over next 18 months

                          HAE On-Demand              HAE Prophylaxis
                         (type 1 and type 2)        (type 1 and type 2)

                       RAPIDe-1 Ph2 underway   CHAPTER-1 Ph2 starting 2021
PHVS416 soft capsule
                            (data 2022)               (data 2022)

                                                 Ph1 PK starting end 2021
  PHVS719 XR tablet        Not applicable
                                                       (data 2022)

            © 2021                                                           32
Nasdaq: PHVS

© 2021
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