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|Item 7.01|| |
Regulation FD Disclosure.
On June 29, 2022, Ventyx Biosciences, Inc. (“Ventyx”) issued a press release announcing topline Phase 1 data for its peripheral NLRP3 Inhibitor VTX2735. The press release is attached hereto as Exhibit 99.1 to this Current Report on Form 8-K and incorporated herein solely for purposes of this Item 7.01 disclosure.
Also on June 29, 2022, Ventyx published an updated corporate presentation which is attached as Exhibit 99.2 to this Current Report on Form 8-K and incorporated herein solely for purposes of this Item 7.01 disclosure.
In accordance with General Instruction B.2. of Form 8-K, all of the information furnished in this Item 7.01 and Item 9.01 (including Exhibit 99.1 and Exhibit 99.2) shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), and shall not be incorporated by reference in any filing under the Securities Act of 1933, as amended, or in any filing under the Exchange Act, except as shall be expressly set forth by specific reference in such a filing.
|Item 9.01|| |
Financial Statements and Exhibits.
|99.1||Press Release dated June 29, 2022.|
|99.2||Corporate Presentation dated June 29, 2022.|
|104||Cover Page Interactive Data File (embedded within the Inline XBRL document).|
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 hereunto duly authorized.
|VENTYX BIOSCIENCES, INC.|
/s/ Raju Mohan
|Raju Mohan, Ph.D.|
|Chief Executive Officer|
Date: June 29, 2022
Ventyx Biosciences Announces Positive Topline Phase 1 Data for its Peripheral NLRP3 Inhibitor VTX2735
Excellent safety, tolerability and pharmacokinetic profile
Robust dose-dependent target engagement as measured by ex vivo IL-1b release assay
Phase 2 trial planned in CAPS patients to efficiently establish clinical proof of concept
Clinical update in Q3 from Phase 1 trial of VTX958, our oral, selective allosteric TYK2 inhibitor
ENCINITAS, Calif., June 29, 2022 (GLOBE NEWSWIRE) Ventyx Biosciences, Inc. (Nasdaq: VTYX) (Ventyx), a multi-asset, clinical-stage biopharmaceutical company focused on advancing novel oral therapies that address a range of inflammatory diseases with significant unmet medical need, today announced positive data from the companys Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) trial of VTX2735, a peripheral NLRP3 inhibitor, and the first of two product candidates from its NLRP3 portfolio.
The Phase 1 study demonstrated an excellent exposure and safety profile and evidence of dose-dependent target engagement and pharmacodynamic activity, said Bill Sandborn, MD, President and Chief Medical Officer. Inhibition of the NLRP3 inflammasome is emerging as a potent anti-inflammatory mechanism with therapeutic potential in a broad range of indications with high unmet medical need. We look forward to sharing additional details from this trial and a broader discussion of the clinical opportunities available with VTX2735 at an investor event later this year.
The VTX2735 Phase 1 SAD/MAD clinical trial was a two-part, randomized, double-blind, placebo controlled, dose-escalation study designed to evaluate the safety, tolerability and pharmacokinetics of single and multiple ascending doses. The study enrolled 72 adult healthy volunteers in SAD cohorts up to 200 mg and MAD cohorts up to 200 mg daily for 14 days. VTX2735 was well-tolerated across all dose cohorts and all subjects completed the trial.
Drug exposures in both SAD and MAD cohorts increased linearly with dose. All drug-related adverse events (AEs) were considered mild, with no LFT abnormalities and no dose-related trend in the frequency of treatment-emergent AEs was observed. Drug exposures also correlated with markers of target engagement as evidenced by strong pharmacodynamic (PD) activity in ex vivo LPS- plus ATP-mediated IL-1b release assays from subject-derived plasma samples from both the SAD and MAD parts of the trial. VTX2735 demonstrated robust dose-related suppression of the induced pro-inflammatory cytokine IL-1b release relative to placebo. VTX2735 also demonstrated reduction from baseline in high sensitivity C-reactive protein (hsCRP) concentrations. Full PD analyses from the Phase 1 trial are ongoing.
The Phase 1 results support progression of VTX2735 into Phase 2 clinical trials. The initial Phase 2 trial is being planned in cryopyrin-associated periodic syndrome (CAPS), a rare autoinflammatory condition characterized by IL-1b-mediated inflammation. This trial is intended to establish that VTX2735 can inhibit IL-1b in a similar fashion as IL-1b-targeted antibody therapy and other related IL-1b-antagonists, which have established clinical efficacy in CAPS and other inflammatory diseases, while further characterizing the profile of VTX2735 and its impact on IL-1b and IL-18, along with pyroptosis. It is expected that this trial will initiate in the fourth quarter of 2022. The profile of VTX2735 offers the opportunity to exploit the full therapeutic potential of systemic NLRP3 inhibition across a number of chronic inflammatory conditions, including atherosclerosis and cardiometabolic diseases.
VTX2735 is the first of Ventyxs two NLRP3 development candidates to enter the clinic. The second candidate, VTX3232, is an orally bioavailable, CNS-penetrant NLRP3 inhibitor and belongs to a structurally distinct chemical series than VTX2735. VTX3232 is currently in IND-enabling studies and is expected to start Phase 1 trials in the first quarter of 2023. True CNS-penetrant NLRP3 inhibitors, such as VTX3232, offer potential therapeutic utility in a broad range of neurodegenerative diseases, including Parkinsons disease.
I am very excited about the progress the Ventyx team has made on our NLRP3 inhibitor portfolio and the emerging clinical profile of VTX2735, said Raju Mohan, PhD, Chief Executive Officer. Todays update marks the first of two clinical updates expected this summer as we continue to advance our differentiated portfolio of clinical candidates across multiple immune-mediated diseases. We look forward to sharing data from the Phase 1 trial of VTX958, our oral, selective TYK2 inhibitor, in the third quarter.
About the NLRP3 Inflammasome
Activated NLRP3 acts as a danger sensor in the body to release the pro-inflammatory cytokines IL-1b, IL-18 and induce uncontrolled, lytic cell death (pyroptosis). These processes lead to chronic inflammation, and as such, NLRP3 has been implicated in a large number of diseases.
About Cryopyrin-Associated Periodic Syndromes
Cryopyrin-associated periodic syndromes (CAPS), also called cryopyrin-associated autoinflammatory syndromes, are three diseases related to a defect in the NLRP3 gene. CAPS encompasses neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS). The differences in these diseases lie in their severity and the organs involved.
About Ventyx Biosciences
Ventyx is a clinical-stage biopharmaceutical company focused on developing innovative oral medicines for patients living with autoimmune and inflammatory disorders. We believe our ability to efficiently discover and develop differentiated drug candidates will allow us to address important unmet medical need with novel oral therapies that can shift immunology markets from injectable to oral drugs. Our current pipeline includes three clinical-stage programs targeting TYK2, S1P1R and NLRP3, positioning us to become a leader in the development of oral immunology therapies. Ventyx is headquartered in Encinitas, California. For more information about Ventyx, please visit www.ventyxbio.com.
Ventyx cautions you that statements contained in this press release regarding matters that are not historical facts are forward-looking statements. These statements are based on Ventyxs current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding: the anticipated timing of commencement, enrollment and completion of clinical trials for Ventyxs product candidates; the anticipated timing of releasing data from the Phase 1 trial of VTX958; the potential of Ventyxs product candidates to address a broad range of immune-mediated diseases; the therapeutic potential of inhibition of the NLRP3 inflammasome; plans for advancing VTX2735 into a Phase 2 trial and the anticipated timing for starting such a trial; the therapeutic utility of CNS-penetrant NLRP3 inhibitors, such as VTX3232; and the anticipated timing for starting a Phase 1 trial for VTX3232. The inclusion of forward-looking statements should not be regarded as a representation by Ventyx that any of its plans will be achieved. Actual results may differ from those set forth in this press release due to the risks and uncertainties inherent in Ventyxs business, including, without limitation: potential delays in the commencement, enrollment and completion of clinical trials; disruption to our operations from the ongoing global outbreak of the COVID-19 pandemic, or from the ongoing military conflict in Ukraine, including clinical trial delays; Ventyxs dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; the success of Ventyxs clinical trials and preclinical studies for its product candidates; interim results not necessarily being predictive of final results; the potential of one or more outcomes to materially change as the trial continues and more patient data becomes available and following more comprehensive audit and verification procedures; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Ventyxs ability to obtain and maintain intellectual property protection for its product candidates; the use of capital resources by Ventyx sooner than expected; and other risks described in Ventyxs prior press releases and Ventyxs filings with the Securities and Exchange Commission (SEC), including in Part II, Item 1A (Risk Factors) of Ventyxs Quarterly Report on Form 10-Q, filed on May 12, 2022, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Ventyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.
Investor Relations Contact
CORPORATE PRESENTATION June 29, 2022 Exhibit 99.2
Forward Looking Statements Ventyx cautions you that statements contained in this presentation regarding matters that are not historical facts are forward-looking statements. These statements are based on the Company’s current beliefs and expectations. Such forward-looking statements include, but are not limited to, statements regarding: clinical development plans and related timing for Ventyx’s product candidates; anticipated timing of data announcements; anticipated efficacy, safety, dosing and clinical differentiation of Ventyx’s product candidates; potential indications for Ventyx's product candidates; market opportunities; the anticipated timing of IND submission for VTX3232; projected catalysts relating to Ventyx’s product candidate pipeline; and anticipated cash runway. The inclusion of forward-looking statements should not be regarded as a representation by Ventyx that any of its plans will be achieved. Actual results may differ from those set forth in this presentation due to the risks and uncertainties inherent in Ventyx’s business, including, without limitation: potential delays in the commencement, enrollment and completion of clinical trials; disruption to our operations from the ongoing global outbreak of the COVID-19 pandemic, including clinical trial delays; the Company’s dependence on third parties in connection with product manufacturing, research and preclinical and clinical testing; the results of preclinical studies and early clinical trials are not necessarily predictive of future results; supply chain constraints; the success of Ventyx’s clinical trials and preclinical studies for its product candidates; interim results do not necessarily predict final results and one or more of the outcomes may materially change as the trial continues and more patient data become available and following more comprehensive audit and verification procedures; regulatory developments in the United States and foreign countries; unexpected adverse side effects or inadequate efficacy of our product candidates that may limit their development, regulatory approval and/or commercialization, or may result in recalls or product liability claims; Ventyx’s ability to obtain and maintain intellectual property protection for its product candidates; Ventyx may use its capital resources sooner than it expects; and other risks described in the Company’s prior communications and the Company’s filings with the Securities and Exchange Commission (SEC), including under the heading “Risk Factors” in the Company’s Quarterly Report on Form 10-Q files on May 12, 2022, and any subsequent filings with the SEC. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof, and Ventyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date hereof. All forward-looking statements are qualified in their entirety by this cautionary statement, which is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. This presentation includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. Industry publications and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our products include several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reliable, such assumptions have not been verified by any third party. The industry in which we operate is subject to a high degree of uncertainty and risk due to a variety of important factors that could cause results to differ materially from those expressed in the estimates made by third parties and by us. Trademarks in this presentation are the property of their respective owners and used for informational and education purposes only.
VTX958 | TYK2 Inhibitor | Phase 1 VTX002 | S1P1R Modulator | Phase 2 VTX2735 | Peripheral NLRP3 Inhibitor | Phase 1 Complete VTX3232 | CNS-penetrant NLRP3 Inhibitor | Pre-clinical Summary | Milestones & highlights INTRODUCTION & PIPELINE
BOARD OF DIRECTORS Sheila Gujrathi, MD Executive Chair, Ventyx Raju Mohan, PhD Chief Executive Officer, Founder Martin Auster, MD Chief Financial Officer Chris Krueger, JD Chief Business Officer John Nuss, PhD Chief Scientific Officer William Sandborn, MD PRESIDENT, Chief Medical Officer MANAGEMENT William White Chief Financial Officer, Akero Therapeutics Jigar Choksey Principal, Third Point Richard Gaster, MD, PhD Managing Partner, venBio Raju Mohan, PhD Chief Executive Officer, Ventyx Aaron Royston, MD Managing Partner, venBio Somu Subramaniam Managing Partner, New Science Ventures Our Leadership Team
Our experienced team and our internal R&D engine continue to generate candidates with potential to address diseases with high unmet need 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 With three, differentiated, clinical-stage candidates and a deep pipeline of preclinical programs that target immune-mediated and inflammatory disease indications Our Mission: To become a Leading Immunology Company Underpinned by Strong Drug Discovery and Development Capabilities
TARGET PROGRAM PRECLINICAL PHASE 1 PHASE 2 PHASE 3 NEXT ANTICIPATED MILESTONES TYK2 VTX958 Report topline Phase 1 data Q3 2022 Initiate Phase 2 POC trials H2 2022 S1P1R VTX002 Report topline Phase 2 data 2023 NLRP3 Peripheral VTX2735 Initiate POC trial in CAPS Q4 2022 NLRP3 CNS-penetrant VTX3232 File IND Q4 2022 Initiate Phase 1 trial Q1 2023 Potential indications include psoriasis, psoriatic arthritis, Crohn’s disease and others Ulcerative Colitis Potential indications include cardiovascular, hepatic, renal, and rheumatologic diseases Neuroinflammatory diseases Addressing Established Inflammatory and Immunology Markets with a Wholly Owned Product Portfolio Broad Pipeline of Candidates With Multiple Near-Term Catalysts
Indication* PATIENTS in the U.S. Global drug revenue* (2020) Target Population Psoriasis Dermatology ~8M ~$20B 25-30% moderate-to-severe Crohn’s disease IBD ~700K ~$13B 30-40% moderate-to-severe Ulcerative colitis IBD ~1M ~$7B 30-40% moderate-to-severe Psoriatic arthritis Rheumatology ~1M ~$4B 40-60% moderate-to-severe SLE Rheumatology Up to 500K ~$1B Pipeline Targeting Large Well-Established Markets 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 *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 Multiple autoimmune disorders in dermatology, IBD, renal and rheumatology total $45B WW sales* Selective, allosteric TYK2 inhibitor TYK2 functional selectivity can potentially differentiate clinical profile vs. less selective TYK2 inhibitors Potentially Differentiated TYK2 Inhibitor Well established clinical efficacy in psoriasis, IBD and psoriatic arthritis with biologics targeting IL-12/IL-23 and IL-23* pathways 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 Allosteric, Selective TYK2 Inhibitor Large Addressable Markets Clinically Validated Target
Inactive Active IL-12, IL-23, IFNα Inhibited VTX958 JH2 JH1 TYK2 Features of VTX958 JH2 Allosteric Inhibition Selectivity for TYK2 JH2 vs. JAK1 JH2 domain (>4,000 X) No binding to JAK2/3 JH2 domains No binding to TYK2 kinase JH1 and No kinase enzyme inhibition of any JAK family member FERM/SH2 Receptor interaction JH2 Allosteric Domain Much less conserved amongst the JAK family with structurally distinct binding pockets JH1 Kinase Domain Highly conserved and inhibitors targeting the kinase domain have poor selectivity ATP Binding to JH1 allows phosphorylation of substrates Structural Domains in the JAK/TYK2 Family Selective TYK2 Inhibitor Targeting the JH2 (allosteric) domain of TYK2 affords TYK2 inhibitors with selectivity against other JAK isoforms Allosteric Inhibitor VTX958 Binds Selectively to the TYK2 JH2 Domain
VTX958 More Selective than Deucravacitinib for TYK2 JH2 Domain Source: Ventyx internal data Deucravacitinib VTX958 TYK2-JH2 Binding Kd 0.009 nM 0.058 nM JAK1-JH2 Binding Kd 0.43 nM 240 nM Selectivity (fold) 48 >4,000 JAK1 JAK3 IL-2, IL-4 IL-13, IL-15 JAK1 JAK2 IFNγ IL-10,IL-22 IL-6 JAK1 other JAK JAK1 dependent signaling pathways TYK2 essential signaling pathways JAK1 TYK2 IFNα/β JAK2 TYK2 IL-12/23 Inhibits TYK2 Pathways (IL-12, IL-23, IFNα) while Avoiding the JAK1/2/3 Pathways
VTX958 Selectively Targets IL-12, IL-23 and IFNα Source: Ventyx internal data; conducted in peripheral blood mononuclear cells (PBMC) Pleiotropic Cytokines with Protective Functions Drug IL-22 IC50 (nM) IL-10 IC50 (nM) IFNγ IC50 (nM) IL-4 IC50 (nM) IL-6 IC50 (nM) VTX958 >10,000 >10,000 >10,000 >10,000 >10,000 deucravacitinib 114 20 350 249 464 Selective and potent inhibition of IL-12/23 and Type I interferon axis allows targeting pathways driving immune-mediated diseases VTX958 Has No Measurable Inhibition of JAK1-Mediated Pathways Lack of inhibition of IL-6, IL-10 and other protective cytokines may avoid potential AEs associated with less selective inhibitors VTX958 Potently Inhibits TYK2 Pathways Potent activity against IL-23, a key cytokine implicated in psoriasis and other indications Broad therapeutic window with VTX958 may allow for higher exposures in Phase 2/Phase 3 studies KEY TAKEAWAYS Proinflammatory Innate & Th1/Th17 Cytokines Psoriasis Patient PBMC Pso Patient PBMC Drug IL-12 IC50 (nM) IL-23 IC50 (nM) IFNα IC50 (nM) VTX958 35 5 12 deucravacitinib 10 10 5
VTX958 Phase 1 SAD Results Support Clinical Advancement NOTE: SAD = single ascending dose; AE= adverse event; dose-related exposures are observed at all doses Well-tolerated across all cohorts; all AEs observed were mild and not dose- or time-of-dose dependent No dose-saturation observed; PK and absorption profiles suggest continued absorption throughout GI tract Dose-dependent VTX958-mediated effect on TYK2 signaling observed in both in vivo gene expression studies and ex vivo stimulation assays Safety Pharmacokinetics Pharmacodynamics
Targeting a Best-in-Class Exposure Profile With VTX958 Note: Exposure curves are adapted from corporate presentations and publications, as noted Allosteric TYK2 Inhibitors – Target Coverage Plasma Concentration (nM) Time (hours) Derived Concentrations (ng/mL) Time (hours) Deucravacitinib (BMS) 6mg QD NDI-034858 (Nimbus) Source: Adapted from Nimbus 2022 JPM conference presentation. Source: Adapted from Chimalakonda et al., 2021. Maximize TYK2 pathway suppression (IC50 and IC90) Wide safety margin enabling higher doses and exposures: Potential for improved efficacy in PsO + PsA with greater TYK2 inhibition Higher exposures may be necessary to achieve efficacy in Crohn’s disease VTX958 Target Profile
VTX958 Profile Expected to Drive Clinical Differentiation 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 Psoriasis Competitive Landscape PASI-75 (% responders) at Primary Endpoint Cut-off Current oral options in PsO are substantially less efficacious than biologics Greater TYK2 suppression may produce improved efficacy compared to other oral agents, with potential to approach leading biologics Significant opportunity for a best-in-disease oral agent in psoriasis, a >$20B global market KEY TAKEAWAYS Targeting Best-in-Disease Oral Profile with VTX958
Unlocking the Opportunity in Crohn’s Disease *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. Several-fold Higher Doses Required in Crohn’s* Agent PsO Dose Crohn’s Dose Skyrizi (IL-23) 150mg Q12W Subcutaneous 600mg IV Q4W (induction) 360mg SC (maintenance) Tremfya (IL-23) 100mg Q8W Subcutaneous 200mg / 600mg / 1200mg** IV Q4W induction Stelara (IL-12/23) 40mg / 90mg Q12W Subcutaneous 260mg / 390mg / 520mg IV induction dose Humira (TNFα) 80mg (SC induction) 40mg Q2W maintenance 160mg (SC induction) 40mg Q2W maintenance Greater Exposures Needed for TYK2 Inhibitor Efficacy in Crohn’s Biologics data suggest substantially higher exposures are required for efficacy in Crohn’s vs. PsO Maximizing TYK2 target coverage expected to differentiate VTX958 from other TYK2 inhibitors Selectivity, safety and tolerability considerations may limit the Crohn’s opportunity for other TYK2 inhibitors Optimized profile of VTX958 may unlock a major market opportunity in Crohn’s, a >$13B global market
VTX958 Clinical Development Plan NOTE: SAD = single ascending dose; MAD = multiple ascending dose; PoC = proof-of-concept Phase 1 SAD All 7 cohorts completed Safety and exposure data allow exploration of high exposure multiples in MAD trial Phase 1 MAD Explore safety and exposure data on repeat dosing Elucidate PD profile with multiple dose exposure across therapeutic range Select Phase 2 doses Phase 2 PoC Phase 2 trials planned in additional indications (psoriatic arthritis, Crohn’s disease and others) VTX958’s selectivity may allow for differentiation in multiple indications DOSING COMPLETE Q4 2021 H2 2022 H2 2022 Phase 2 PoC Initial Phase 2 trial in moderate-to-severe psoriasis patients TYK2 inhibition is a de-risked mechanism for treatment of psoriasis Planning Additional Phase 2 trials CMC & Toxicology Chronic toxicology studies in process to support Phase 2/3 trials Solid oral dose form developed for Phase 2/3 trials Report topline data Q3 2022
PERIPHERALLY RESTRICTED S1P1R MODULATOR with potential for treatment of ulcerative colitis
Phase 2 S1P1R Modulator for Ulcerative Colitis VTX002 Program Summary Ulcerative colitis is lead indication totaling up to $7B in worldwide revenue Selective S1P1R modulator Differentiated on key parameters Demonstrated pharmacodynamic activity in Phase 1 trial Pursuing clinical development plan in both treatment-naïve and biologic-experienced patients Potentially Differentiated S1P1R Modulator S1P1R modulators approved for MS and UC with clinical trials ongoing in other indications BMS’ ozanimod approved for UC in May 2021 Large Addressable Markets Clinically Validated Target
Sustained lymphocyte reduction up to 65% across multiple doses in MAD trial VTX002 Differentiates on Multiple Key Parameters vs. Competitors Notes: SAE=significant adverse event; MAD=multiple ascending dose No SAEs, elevated LFTs, abnormal PFTs or macular edema No long-acting circulating metabolites Optimal half life (t~20h) No CYP inhibition; no food effect; favorable profile for patients with co-morbidities Potential to avoid first-dose cardiac monitoring in label Very low CNS penetration; not a repurposed MS drug; potential to avoid macular edema Safety Profile No Drug-Drug Interactions Ability to Dose Titrate Peripherally Restricted Fast Onset of Action Faster Lymphocyte Recovery Potential for Differentiated Clinical Profile in UC Patients
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) *Ph2 UC ALC reduction from baseline: 1mg ozanimod (49%), 2mg etrasimod (40%)
Pharmacodynamics Pharmacokinetics Phase 1 MAD Results: Dose-Dependent Exposure and Lymphocyte Reduction Source: NEJM (2016), Gastroenterology (2020) *Ph2 UC ALC reduction from baseline: 1mg ozanimod (49%), 2mg etrasimod (40%) T1/2 of ~20 hours Dose-proportionate exposure after single and multiple doses of VTX002 with steady-state reached after 4 to 7 days of target-dose exposure Demonstrated consistent, sustained reduction of lymphocytes up to 65% across multiple dose groups Absolute Lymphocyte Count (ALC) Reductions of 40-50% Correlated with Clinical Efficacy Observed in UC* ****p< 0.0001 **** **** **** **** 45 mg 35 mg 20 mg 10 mg 2 mg Placebo
Phase 2 Induction Trial in Moderate-to-Severe Ulcerative Colitis Baseline Week 13* Week 52 12-Week Treatment Period Patients with LOR Placebo VTX002, 60 mg VTX002, 30 mg VTX002, 60 mg VTX002, 30 mg Placebo Week 13 * includes 7-day titration Screening Period 39-Week LTE Treatment Period 13-Week Treatment Period R OLE* – VTX002, 60 mg NR Powered for primary endpoint of clinical remission Trial may serve as the first of two pivotal trials required for registration KEY TAKEAWAYS N=180; 1:1:1 Trial Design Note: Phase 2 tablet doses of 30mg and 60mg provide comparable VTX002 exposure as Phase 1 suspension doses of 20mg and 40mg, respectively *Induction and OLE non-responder dosing includes 7-day titration period followed by 12 weeks of placebo or VTX002 dose
Addressable UC Patient Population in US VTX002 TARGET POPULATION ~1M UC PATIENTS 300K+ moderate-to-severe UC patients ~100K biologic-treated patients >50K Existing agents leave room for new treatments Novel oral agents may expand penetrance of treated moderate-to-severe UC population beyond current ~25-30% S1P well positioned to emerge as leading oral therapeutic class based on its attractive class efficacy/safety profile Underpenetrated Market for Biologic Refractory Patients
SELECTIVE NLRP3 INFLAMMASOME INHIBITORS for systemic and CNS indications
Rationale for Targeting the NLRP3 Inflammasome NLRP3 = NOD-like receptor family, pyrin domain-containing protein 3; IL-1β = interleukin-1β NLRP3 Inflammasome Inhibitors Target IL-1β, a Key Driver of Inflammatory Disease The NLRP3 inflammasome can become overactive in the presence of persistent tissue damage or crystal deposits Inflammasome activation results in release of IL-1β & IL-18 recruiting neutrophils and driving Th17 response This leads to pyroptosis and further tissue damage IL-1β signaling, downstream of inflammasome activation, is a clinically-validated, anti-inflammatory target with biologics Ilaris® ($873M sales in 2020) approved for CAPS and other orphan periodic fever syndromes In vivo Evidence Gain-of-function mutations in the NLRP3 gene, associated with certain severe orphan inflammatory diseases, are classified as cyropyrin-associated periodic syndromes (CAPS) Genetic Evidence Clinical Validation of Downstream Target
NLRP3 Inhibitor Program Summary Peripheral NLRP3 Inhibitor: VTX2735 CNS NLRP3 Inhibitor: VTX3232 Selective NLRP3 inhibitor Well tolerated in GLP safety and tox assessment Phase 1 completed with attractive safety/tolerability profile and evidence of pharmacodynamic activity Phase 2 trial in CAPS planned Q4 2022; additional indications are being evaluated Selective compounds generated with high CNS bioavailability Novel and proprietary lead series Plan to file IND in Q4 2022 Potential to be first, truly CNS-directed NLRP3 inhibitor to enter clinic
VTX2735 is a Selective & Orally Bioavailable NLRP3 Inhibitor MCC950 is an NLRP3 inhibitor and a control compound used in in vitro and in vivo studies IL-1β IC50 (nM) On Target human monocytes 2 human whole blood 75 Off Target AIM2 >10000 NLRC4 >10000 NF-kb >10000 Non-Human Primate PK Mouse Pharmacodynamic Assay In Vitro Potency & Selectivity IV Clearance: 1.6 mL/min/kg; Oral Bioavailability: 80% Well-tolerated preclinically in IND-enabling GLP studies Oral bioavailability (80%) in NHP and dose-proportional exposure that predicts potential for wide safety margins based on PK/PD modeling KEY TAKEAWAYS
Summary of VTX2735 Phase 1 Results Excellent Safety and Pharmacodynamic Activity Concentration-Dependent Suppression of IL-1β Ex Vivo Safety All AEs considered mild No LFT abnormalities No dose-related increase in frequency of AEs observed PK Dose-proportionate increases in exposure (Cmax and AUC) Target Coverage Ability to cover IL-1β IC50, IC90 Potential wide therapeutic window (safe across wide exposure range) PD Robust dose and concentration-dependent suppression of IL-1β ex vivo *PK: Pharmacokinetics; PD: Pharmacodynamics Data from Day 10 of Phase 1 MAD, 1 to 8h post-dose Ex vivo LPS plus ATP-mediated IL-1β release assay
IC50 in Blood Monocyte Assay (nM) VTX2735 Has Broad Activity Against Multiple NLRP3 Mutations *Source: UCSD (Dr. Hal Hoffman’s lab); CAPS=Cryopyrin-Associated Periodic Syndromes VTX2735 blood assay data from CAPS patients suggest inhibitory activity across several mutations: FCAS, MWS and NOMID subset of CAPS patients. CPD CHALLENGE FCAS1 L353P FCAS2 (L353P) FCAS3 (L353P) FCAS4 A439V/G564R FCAS.MWS E525K/V198M NOMID F309Y VTX2735 LPS 117 56 166 14 24 17 MCC950 LPS >10K >10K >10K 1,264 >10K >10K 75% of all CAPS patients In North America MOST SEVERE KEY TAKEAWAY What is CAPS? An ultra-orphan auto-inflammatory disease caused by various mutations in NLRP3 and characterized by inappropriate release of IL-1β and symptoms of recurrent systemic inflammation Potential for Differentiation in CAPS Setting*
CNS-Penetrant NLRP3 Inhibitor VTX3232 In Vitro Potency & Selectivity IL-1β IC50 (nM) NLRP3 huWB 13 AIM2 BMDM >10000 NLRC4 BMDM >10000 NF-kb BMDM >10000 Rat PK (PO, 5mg/kg) T½ = 4.4 h; Oral Bioavailability = 75% Dog PK (PO, 5mg/kg) T½ = 8 h; Oral Bioavailability = 100% WB IC50 CSF Conc. ~20 x WB IC50 at 24 h Novel, potent, brain-penetrant inhibitor of NLRP3 13 nM IC50 in human whole blood IL-1β release assay Unique structural chemotype vs. peripheral NLRP3 inhibitors Provisional application filed June 2021 IND filing in Q4 2022; Phase 1 start in Q1 2023 KEY TAKEAWAYS
NLRP3 Program Clinical Development Plan COMPLETE IND-enabling Studies September 2021 IND approved Q4 2021 Initiate Phase 2 CAPS Further indications TBD Q4 2022 VTX2735 PERIPHERALLY-RESTRICTED VTX3232 CNS-PENETRANT INHIBITOR IND-Enabling Studies Potential indications include Parkinson’s, Alzheimer’s, etc. 2022 COMPLETE Phase 1 Healthy volunteers
Our Comprehensive NLRP3 Portfolio Targets a Broad Range of Major Inflammatory Diseases NLRP3 Alzheimer’s Disease Parkinson’s Disease ALS Multiple Sclerosis Neuroinflammatory Diseases CNS-directed NLRP3 inhibitors are designed to treat a range of neuro-degenerative disorders, such as Alzheimer’s and Parkinson’s disease Our solution: VTX3232 Cardiovascular Rheumatic Fibrotic Diseases Rare Genetic Diseases Systemic Diseases Peripheral NLRP3 inhibitors are designed to treat cardiovascular, rheumatic, fibrotic and rare genetic diseases Our solution: VTX2735
Projected Pipeline Catalysts and Summary
Projected Catalysts Over Next 24 Months *Following completion of our Phase 1 trial, we intend to initiate Phase 2 trials in psoriasis, psoriatic arthritis, Crohn’s disease and potentially other indications ** Following regulatory acceptance of planned Q4 2022 IND filing, we intend to initiate and conduct a Phase 1 SAD/MAD trial in healthy volunteers in Q1 2023 PROGRAMS H1’2021 H2’2021 H1’2022 H2’2022 2023 VTX958 Allosteric TYK2 inhibitor addressing a broad range of autoimmune disorders VTX002 Selective S1P1R modulator targeting UC and other immune disorders Phase 1 SAD Phase 1 MAD Phase 2 in Multiple Indications* Phase 2 Ulcerative Colitis 13-Week Induction IND-enabling Phase 1 SAD/MAD Phase 2 CAPS Initiation IND-enabling Candidate Selection Phase 1 SAD/MAD** VTX2735 Peripheral NLRP3 inflammasome inhibitor for multiple inflammatory and immune conditions VTX3232 CNS-directed NLRP3 inflammasome inhibitor for neurodegenerative diseases
Investment Highlights Efficient & Productive Immunology Platform Internal R&D engine designed to generate candidates to address autoimmune and inflammatory diseases with high unmet need 100% commercial rights to entire portfolio; long patent life for all product candidates Potentially Differentiated Medicines Multiple selective, oral, small molecule product candidate portfolio: VTX958: allosteric TYK2 inhibitor for multiple autoimmune indications VTX002: peripherally-restricted S1P1R modulator for ulcerative colitis VTX2735: peripheral NLRP3 inhibitor for multiple autoimmune indications VTX3232: CNS-targeted NLRP3 inhibitor for multiple neurodegenerative indications Target Major Inflammatory & Immunology Disease Markets Our portfolio can address I&I markets, such as psoriasis, IBD, and other indications Opportunity to disrupt existing markets dominated by biologics with varying degrees of efficacy and safety in order to: Capture refractory patients Expand market share of moderate-to-severe patient populations with patient-friendly oral therapy Capital-Efficient Business Model Over $339 million raised from dedicated biotech investors Cash & equivalents and marketable securities balance of $273.1M as of March 31, 2022; Runway into H1 2024
Contact us for additional information: email@example.com VENTYX BIOSCIENCES, INC. 662 ENCINITAS BOULEVARD, SUITE 250 ENCINITAS, CA 92024