Pioneering science for patient choice - September 2021 - Pharvaris
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Pioneering science for patient choice
September 2021
© 2021
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
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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
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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
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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.
© 2021 2
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
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
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
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
Hereditary Angioedema (HAE)
© 2021
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
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
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 10PHA121 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 11HAE 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 12Programs
© 2021 CONFIDENTIALPharvaris 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
© 2021PHA121 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 15PHA121
PK/PD in humans
© 2021 CONFIDENTIALPHA121 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 17Inhibition 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 18Oral 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 19Oral 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 20Single 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 21PHVS416/On-Demand
Softgel capsule formulation of PHA121
© 2021 CONFIDENTIALPHVS416: 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 23HAE 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 24On-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 IC50PHVS719/Prophylaxis
Extended-release tablet formulation of
PHA121
© 2021Entering 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 27HAE 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 28Multiple-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 29PHVS719: 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 30Prophylaxis: 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 31Upcoming 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 32Nasdaq: PHVS © 2021
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