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INTRODUCTION & PIPELINE VTX958 | TYK2 Inhibitor | Phase 1 VTX002 |
S1P1R Modulator | Phase 2 VTX2735 | Peripheral NLRP3 Inhibitor | Phase 1 CNS NLRP3 Inhibitor | Pre-clinical Summary | Milestones & highlights
Our Leadership Team MANAGEMENT John Nuss, PhD J rn Drappa, MD, PhD
Raju Mohan, PhD Martin Auster, MD Chris Krueger, JD CHIEF SCIENTIFIC OFFICER CHIEF MEDICAL OFFICER CHIEF EXECUTIVE OFFICER, CHIEF FINANCIAL OFFICER CHIEF BUSINESS OFFICER FOUNDER BOARD OF DIRECTORS Sheila Gujrathi, MD Jigar Choksey Richard Gaster,
MD, PhD Raju Mohan, PhD EXECUTIVE CHAIR, VENTYX PRINCIPAL, THIRD POINT MANAGING PARTNER, VENBIO CHIEF EXECUTIVE OFFICER, VENTYX Aaron Royston, MD Somu Subramaniam William White MANAGING PARTNER, VENBIO MANAGING PARTNER, NEW CHIEF FINANCIAL OFFICER,
AKERO SCIENCE VENTURES THERAPEUTICS 4
Our Mission: To become a Leading Immunology Company Underpinned by
Strong Drug Discovery and Development Capabilities WITH THREE, DIFFERENTIATED, CLINICAL-STAGE CANDIDATES and a deep pipeline of preclinical programs that target immune-mediated and inflammatory disease indications OUR INTERNALLY-DISCOVERED SMALL
MOLECULE DRUGS allow us to own 100% commercial rights to our entire portfolio with long patent lives for all product candidates OUR EXPERIENCED TEAM AND OUR INTERNAL R&D ENGINE continue to generate candidates with potential to address diseases
with high unmet need 5
Broad Pipeline of Candidates With Multiple Near-Term Catalysts
Addressing Established Inflammatory and Immunology Markets with a Wholly Owned Product Portfolio TARGET PROGRAM PRECLINICAL PHASE 1 PHASE 2 PHASE 3 NEXT ANTICIPATED MILESTONES Complete Phase 1 MAD H1 2022 TYK2 VTX958 Initiate Phase 2 POC trial(s) H2
2022 Potential indications include psoriasis, psoriatic arthritis, Crohn's disease and others S1P1R Report topline Phase 2 data 2023 VTX002 Ulcerative Colitis Complete Phase 1 H1 2022 NLRP3 VTX2735 Peripheral Initiate Phase 2 POC trial(s) H2
2022 Potential indications include cardiovascular, hepatic, renal, and rheumatologic diseases Complete IND-enabling studies 2022 NLRP3 VTX3232 CNS-penetrant File IND Q4 2022 Neuroinflammatory diseases 6
Pipeline Targeting Large Well-Established Markets INDICATION* PATIENTS
IN THE U.S. GLOBAL DRUG REVENUE* (2020) TARGET POPULATION Psoriasis 25-30% ~8M ~$20B Dermatology MODERATE-TO-SEVERE Crohn's disease 30-40% ~700K ~$13B IBD MODERATE-TO-SEVERE Ulcerative colitis 30-40% ~1M ~$7B IBD MODERATE-TO-SEVERE Psoriatic
arthritis 40-60% ~1M ~$4B Rheumatology MODERATE-TO-SEVERE SLE Up to 500K ~$1B Rheumatology Sources: Evaluate Pharma, Company Estimates, Wall Street Research *Global drug revenue refers to the total market across all severity levels Notes: SLE =
systemic lupus erythematosus; *Group of indications based on current mid/late-stage trials for BMS's allosteric TYK2 inhibitor deucravacitinib; global commercial sales totaled $10.65B for biologics targeting IL-12/23 and IL-23 in 2020
ORALLY BIOAVAILABLE selective allosteric inhibitor of TYK2
VTX958 Program Summary Allosteric, Selective TYK2 Inhibitor Potentially
Differentiated Clinically Validated Target Large Addressable Markets TYK2 Inhibitor Multiple autoimmune Selective, allosteric TYK2 inhibitor Well established clinical efficacy in disorders in dermatology, psoriasis, IBD and
psoriatic arthritis TYK2 functional selectivity can IBD, renal and rheumatology with biologics targeting IL-12/IL-23 potentially differentiate clinical total $45B WW and IL-23* pathways profile vs. less selective TYK2 inhibitors
These pathways also the target of allosteric TYK2 inhibitors Phase 3 PoC in psoriasis has been demonstrated** by BMS' allosteric TYK2 inhibitor deucravacitinib Deucravacitinib in Phase 2/3 for Crohn's disease, psoriatic
arthritis, lupus Includes approved drugs Stelara (JNJ), Tremfya (JNJ), Skyrizi (ABBV), Ilumya (Sun Pharma) and others in late-stage development (mirikizumab (LLY), brazikumab (AZN) **Deucravacitinib efficacy reported on
16-week primary endpoint of PASI-75 (75% reduction of psoriasis affected area and severity) at AAD 21; p<0.0001 vs placebo and Otezla in POETYK-1; p=0.0003 vs. Otezla in POETYK-2; See slide 14 for more detail on $45B worldwide market
Allosteric Inhibitor VTX958 Binds Selectively to the TYK2 JH2 Domain
Features of VTX958 IL-12, JH2 Allosteric Inhibition Inhibited Inactive Active IL-23, IFNa Structural Domains in the Selectivity for TYK2 JH2 JAK/TYK2 Family vs. JAK1 JH2 domain (>4,000 X) FERM/SH2 Receptor interaction No binding to JAK2/3 JH2 JH2
Allosteric Domain domains Much less conserved amongst the JAK family with structurally No binding to TYK2 kinase distinct binding pockets JH1 and JH1 Kinase Domain JH2 Highly conserved and No kinase enzyme inhibitors targeting the kinase JH1
inhibition of any JAK domain have poor selectivity family member ATP Binding to JH1 allows phosphorylation of substrates TYK2 Selective Targeting the JH2 (allosteric) TYK2 Inhibitor domain of TYK2 affords TYK2 inhibitors with selectivity against
other JAK isoforms 10
VTX958 More Selective than Deucravacitinib for TYK2 JH2 Domain Inhibits
TYK2 Pathways (IL-12, IL-23, IFN ) while Avoiding the JAK1/2/3 Pathways DEUCRAVACITINIB VTX958 IL-2, IL-4 IL-10,IL-22 IFN / IL-12/23 IFN IL-13, IL-15 IL-6 TYK2-JH2 Binding K 0.009 nM 0.058 nM d JAK1-JH2 Binding K 0.43 nM 240 nM
d TYK2 JAK1 JAK1 TYK2 JAK1 JAK1 Selectivity (fold) 48 >4,000 JAK2 JAK3 JAK2 other JAK TYK2 essential signaling pathways JAK1 dependent signaling pathways Source: Ventyx internal data 11
VTX958 Selectively Targets IL-12, IL-23 and IFNa VTX958 Has No
Measurable Inhibition VTX958 Potently Inhibits TYK2 Pathways of JAK1-Mediated Pathways Selective and potent inhibition of IL-12/23 and Type I Lack of inhibition of IL-6, IL-10 and other protective interferon axis allows targeting pathways driving
immune- cytokines may avoid potential AEs associated with less mediated diseases selective inhibitors PROINFLAMMATORY INNATE & TH1/TH17 CYTOKINES PLEIOTROPIC CYTOKINES WITH PROTECTIVE FUNCTIONS Psoriasis Patient PBMC IL-23 IFN IL-22 IL-10
IFN IL-4 IL-6 IL-12 DRUG DRUG IC (nM) IC (nM) IC (nM) IC (nM) IC (nM) IC (nM) IC (nM) IC (nM) 50 50 50 50 50 50 50 50 35 5 12 >10,000 >10,000 >10,000 >10,000 >10,000 deucravacitinib 10 10 5 deucravacitinib 114 20 350 249 464
Potent activity against IL-23, a key cytokine implicated in psoriasis and other indications KEY TAKEAWAYS Broad therapeutic window with VTX958 may allow for higher exposures in Phase 2/Phase 3 studies Source: Ventyx internal data;
conducted in peripheral blood mononuclear cells (PBMC) 12
VTX958 Phase 1 SAD Results Support Clinical Advancement Safety
Pharmacokinetics Pharmacodynamics No dose-saturation observed; Dose-dependent VTX958-mediated Well-tolerated across PK and absorption profiles effect on TYK2 signaling observed in all cohorts; all AEs observed suggest continued absorption both in
vivo gene expression studies were mild and not dose- or throughout GI tract and ex vivo stimulation assays time-of-dose dependent NOTE: SAD = single ascending dose; AE= adverse event; dose-related exposures are observed at all doses 13
Targeting a Best-in-Class Exposure Profile With VTX958 Allosteric TYK2
Inhibitors - Target Coverage VTX958 Target Profile Maximize TYK2 pathway suppression (IC and IC ) 50 90 Deucravacitinib (BMS) 6mg QD NDI-034858 (Nimbus) 30mg QD with once-daily oral dosing Wide safety margin enabling ~9 hours
IC ~5 hours IC 50 90 higher doses and exposures: coverage coverage - Potential for improved efficacy in PsO + PsA with TYK2 IC 90 TYK2 IC 50 greater TYK2 inhibition - Higher exposures may be necessary to achieve efficacy in Crohn's
disease TYK2 IC 50 6 12 18 24 6 12 18 24 Time (hours) Time (hours) Source: Adapted from Chimalakonda et al., 2020. Source: Adapted from Nimbus 2022 JPM conference presentation. Note: Exposure curves are adapted from corporate presentations and
publications, as noted 14 Plasma Concentration (nM) Derived Concentrations (ng/mL)
VTX958 Profile Expected to Drive Clinical Differentiation Psoriasis
Competitive Landscape Targeting Best-in-Disease Oral Profile with VTX958 KEY TAKEAWAYS 100% 86-91% 76-90% Current oral options in PsO are substantially less efficacious 80% than biologics VTX 958 Greater TYK2 suppression may 54-59%
60% produce improved efficacy compared to other oral agents, 71-87% 78-85% with potential to approach 40% 59- 29-33% leading biologics 64% 44- 44-46% Significant opportunity for a 46% 20% 23-28% best-in-disease oral agent in psoriasis, a
>$20B global market 0% IL-17 IL-23 p19 Otezla Deucravacitinib Next-Gen Allosteric (Biologic) (Biologic) PDE4 (Oral) TYK2 (Oral) TYK2 Inhibitors (Oral) Note: Solid area represents pbo-adjusted response rate; dashed area indicates total observed
response rate; primary endpoint cut-off ranges from Week 10 to Week 16 Sources: Company reports and FDA labels for approved anti-IL-17 and anti-IL-23 biologics 15 PASI-75 (% responders) at Primary Endpoint Cut-off
Unlocking the Opportunity in Crohn's Disease * Several-fold
Higher Doses Required in Crohn's Agent PsO Dose Crohn's Dose Greater Exposures Needed for TYK2 Inhibitor Efficacy in Crohn's 150mg Q12W 600mg IV Q4W (induction) Skyrizi (IL-23) Biologics data suggest substantially
Subcutaneous 360mg SC (maintenance) higher exposures are required for efficacy in Crohn's vs. PsO 100mg Q8W 200mg / 600mg / 1200mg** Maximizing TYK2 target coverage Tremfya (IL-23) Subcutaneous IV Q4W induction expected to
differentiate VTX958 from other TYK2 inhibitors Selectivity, safety and tolerability 40mg / 90mg Q12W 260mg / 390mg / 520mg Stelara (IL-12/23) considerations may limit the Crohn's Subcutaneous IV induction dose opportunity for other
TYK2 inhibitors Optimized profile of VTX958 may unlock 80mg (SC induction) 160mg (SC induction) a major market opportunity in Crohn's, a Humira (TNF ) 40mg Q2W maintenance 40mg Q2W maintenance >$13B global market Source: FDA
labels for approved drugs/indications; Skyrizi represents dose submitted for FDA approval. Note: maintenance dose unless otherwise specified. **Represents Phase 2 doses; specific Phase 3 doses not disclosed. 16
VTX958 Clinical Development Plan Phase 1 SAD Phase 1 MAD Phase 2 PoC
All 7 cohorts Explore safety and completed exposure data on Phase 2 PoC Phase 2 trials planned in repeat dosing Safety and additional indications Initial Phase 2 trial in exposure data allow (psoriatic arthritis,
Crohn's Elucidate PD profile moderate-to-severe disease and others) exploration of high with multiple dose psoriasis patients exposure multiples exposure across VTX958's selectivity may in MAD trial TYK2 inhibition is a
therapeutic range allow for differentiation in de-risked mechanism for multiple indications Select Phase 2 doses treatment of psoriasis DOSING COMPLETE Complete Q4 Do 2 s0 in 2g 1 H1 2022 H2 2022 H2 2022 CMC & Toxicology Planning
Chronic toxicology studies in process to support Phase 2/3 trials Additional Phase 2 trials Solid oral dose form developed for Phase 2/3 trials NOTE: SAD = single ascending dose; MAD = multiple ascending dose; PoC = proof-of-concept
PERIPHERALLY RESTRICTED S1P1R MODULATOR with potential for treatment of
VTX002 Program Summary Phase 2 S1P1R Modulator for Ulcerative Colitis
Potentially Differentiated S1P1R Modulator Clinically Validated Target Large Addressable Markets Selective S1P1R modulator S1P1R modulators approved for Ulcerative colitis is lead MS and UC with clinical trials indication
totaling up to $7B Differentiated on key parameters ongoing in other indications in worldwide revenue Demonstrated pharmacodynamic BMS' ozanimod approved for activity in Phase 1 trial UC in May 2021 Pursuing
clinical development plan in both treatment-na ve and biologic-experienced patients 19
VTX002 Differentiates on Multiple Key Parameters vs. Competitors
Potential for Differentiated Safety Profile No Drug-Drug Interactions Clinical Profile in UC Patients Sustained lymphocyte reduction up to 65% No SAEs, elevated LFTs, abnormal No CYP inhibition; no food effect; favorable across multiple doses in MAD
trial PFTs or macular edema profile for patients with co-morbidities Fast Onset of Action Ability to Dose Titrate Peripherally Restricted Faster Lymphocyte Recovery Very low CNS penetration; not a No long-acting circulating metabolites Potential to
avoid first-dose cardiac repurposed MS drug; potential to Optimal half life (t~20h) monitoring in label avoid macular edema Notes: SAE=significant adverse event; MAD=multiple ascending dose 20
VTX002 Differentiates on Multiple Key Parameters vs. Competitors
Differentiating Parameter Ozanimod Etrasimod VTX002 Receptor Selectivity S1P 1,5 S1P 1,4,5 S1P 1,5 Lymphocyte Suppression in Healthy Volunteers 1 mg, ~60% 2 mg, 69% 40 mg, ~65% Lymphocyte Suppression in UC Patients* 1 mg, 49% 2 mg, 40% TBD CYP450
Interactions Yes No No Liver Enzyme Elevations Yes No No Active Metabolites Yes No No Half-life 19 h, Met 10-13 d 33 h ~20 h Fast Lymphocyte Recovery Time No Yes Yes First Dose Heart Rate Reduction Yes Yes Yes Dose Titration Yes No Yes First Dose
Monitoring No TBD TBD Source: NEJM (2016), Gastroenterology (2020) 21 *Ph2 UC ALC reduction from baseline: 1mg ozanimod (49%), 2mg etrasimod (40%)