Aclaris Therapeutics, Inc. · NASDAQ:ACRS
Aclaris Therapeutics — Investor Day (September 2019)
121 slides from Aclaris Therapeutics's investor day presentation, Sep 27, 2019
Slide 1: Aclaris Therapeutics Research & Development Day
© Copyright 2019 Aclaris Therapeutics. All rights reserved EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE Aclaris Therapeutics Research & Development Day September 27, 2019
Slide 2: Cautionary Note Regarding Forward-Looking Statements
Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as "believe", "expect", "may", "plan," "pote
Slide 3: Aclaris Strategy
• Divest our commercial and near-term commercial assets • Shift from fully integrated dermatology company to development stage biotechnology company focused on immunology and inflammation – Leverage competitive differentiation in kinase development o World class leadership in ex-Pfizer kinase develo
Slide 4: Kinase market opportunity and positioning
• Market opportunity – Protein kinases comprise a major gene family within the human genome, consisting of approximately 500 proteins responsible for the selective phosphorylation of up to 30% of the genome. o Over 40 kinase inhibitors have been FDA approved for indications in oncology and chronic i
Slide 5: Overview of R&D day: key takeaways
• Key takeaways: – Strategic shift to inflammation – Leadership in kinase inhibitor development with a particular emphasis on the cysteinome o Dedicated to the design of innovative, kinase-targeted medicines o Novel kinase inhibitor in the clinic as well as in pre-IND advancement o Identification of
Slide 6: Market Overview of Select Inflammatory Indications
Market Overview of Select Inflammatory Indications *Auster M., et al. Something Big Is Getting Bigger [research note]. New York, NY: Credit Suisse Equity Research; 2019. (1) Estimates of total sales per indication from EvaluatePharma (2) CS projections: based on US branded pricing (3) Assumed peak t
Slide 7: Atopic dermatitis market
• Atopic dermatitis (AD) is a disease of unknown origin that usually starts in early infancy and is typified by pruritus, eczematous lesions, xerosis (dry skin), and lichenification on the skin (thickening of the skin and increase in skin markings). – Rates of AD are around 30% in the most developed
Slide 8: Inflammatory/autoimmune market
• Inflammatory/autoimmune markets have grown significantly in recent years • US Market size of ~$54 billion in 2018 - driven by biologics1 – In the US the number of patients with autoimmune diseases being treated per year is up 63% since 20132 – Although crowded and competitive, very attractive fiel
Slide 9: Inflammation Market Opportunity
• Many opportunities exist for novel agents to gain share: – Cycling through different therapies/medications is common. – Efficacy of biologics in the treatment of inflammatory / autoimmune disease can fade over time due to: o Development of anti-drug antibodies o Recalcitrant disease o Suboptimal d
Slide 10: Inflammation Market Opportunity: IBD
• Market opportunity1: – Including Crohn’s disease and ulcerative colitis, there are an estimated 1.7 million people in the US with IBD – Increased by 200,000 since 2011 – 70,000 new cases are diagnosed each year. – There may be as many as 80,000 children in the US with IBD. – Worldwide, IBD is esti
Slide 11: Pipeline: New Focus
Pipeline: New Focus Program Indication(s) Preclinical Phase 1 Phase 2 Phase 3 A-101(45%) Topical Common Warts ATI-450 MK2 Pathway Inhibitor Oral RA, Psoriasis ATI-1777 JAK1/JAK3 Inhibitor Soft Topical Atopic dermatitis ATI-2138 ITK/TXK/JAK3 Inhibitor Oral Psoriasis, Inflammatory Dermatoses ITK/JAK3
Slide 12: THWART 1&2: A-101 45% Topical Solution
THWART 1&2 : A-101 45% Topical Solution Hydrogen Peroxide (an investigational compound) compared to Vehicle in Subjects With Common Warts Eligibility • 1–6 common warts R A N D O M I Z E 1:1 A-101 45%, 2x/Week Vehicle, 2x/Week Randomized, Double-blind, Vehicle-controlled Multicenter Study Key Endpoi
Slide 13: Business Model
Business Model Discovery Development Partner Focus resources on innovative science Re-size to deliver an earlier pipeline Resources not spent on sales/marketing 13
Slide 14: Discovery Leaders
Discovery Leaders Former Executive Director, Pfizer Inflammation Research and Leader of Global Kinase Technology Team >95 publications and patents (>30 total on kinases) Joseph Monahan, PhD Exec. VP R&D (Head of Discovery) Former VP Research & Global Head, Pfizer Inflammation, co-leader of Pfizer Li
Slide 15: Catalysts
Catalysts Milestone 2019 2020 Q3 Q4 Q1 Q2 Q3 Q4 A-101 45% Common Warts Phase 3 Data (Thwart-1, Thwart-2) ✓ Inflammation / Immunology ATI-450 (MK2 Inhibitor) - Initiate Phase 1 Trial (SAD/MAD) ✓ ATI-450 (MK2 Inhibitor) - Phase 1 Data (SAD/MAD) ATI-450 (MK2 Inhibitor) - Initiate Phase 2 Trial in Rheum
Slide 16: Agenda
Agenda Introduction Neal Walker David Gordon KINect™ Platform Joe Monahan ATI-450: MK2 inhibitor Walter Smith Paul Changelian BREAK ATI-1777: Soft JAK inhibitor Paul Changelian ATI-2138: ITK/JAK3 inhibitor David R Anderson Gut restricted JAK and ITK/JAK inhibitors Jon Jacobsen LUNCH 16
Slide 17: The KINect Platform: Our Drug Discovery Engine
© Copyright 2019 Aclaris Therapeutics. All rights reserved EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE The KINect™ Platform: Our Drug Discovery Engine
Slide 18: Technology Platform
Technology Platform 18
Slide 19: The Kinase Opportunity and Challenge
The Kinase Opportunity and Challenge Creating New Medicines Targeting Previously Inaccessible Kinome Targets Science 2003 ~36 Marketed Drugs ~$48B* Annual Sales of Kinase Drugs Medically Important and Productive Target Class Most Members of the Kinome Remain Unexplored 518 Members >90% of the Human
Slide 20: The Aclaris Solution: The KINect Technology Platform
The Aclaris Solution: The KINect™ Technology Platform • Experienced and accomplished kinase drug discovery and development team • Demonstrated success in generating clinical candidates for difficult to drug kinases with novel approaches – reversible and covalent inhibitors • A portfolio of high inte
Slide 21: Confluence Discovery Technologies
Confluence Discovery Technologies Experienced, Successful Drug Discovery and Development Team ➢ Target Validation ➢ Structure Based Design ➢ Medicinal Chemistry ➢ Testing Funnel Design ➢ Compound Screening ➢ Lead Identification ➢ Compound Mechanism of Action Studies ➢ PK, CMC and Safety ➢ IND Submis
Slide 22: KINect Platform: Developing Kinase Drug Candidates
KINect™ Platform Developing Kinase Drug Candidates Rapidly & Efficiently Proprietary Portfolio • MK2 Inhibitor • JAK Inhibitors • ITK Inhibitors Strategic Partner(s) • Project 1 • Project 2 • Project 3 ASSET GENERATION KINect™ Platform – LEAD GENERATION TARGET SELECTION & VALIDATION >300 Cysteine Ki
Slide 23: KINect Platform Demonstrated Success
KINect™ Platform Demonstrated Success Reversible and Covalent Covalent ITK Inhibitors MK2 Pathway Inhibitor Tissue Restricted JAK Inhibitors • Oral anti-TNF, anti-IL-1, and IL-6 MK2 kinase inhibitor drug • Novel solution for a difficult to target kinase • ATI-450 (an investigational compound) curren
Slide 24: Covalent inhibitors exploit the cysteinome
KINect™ Technology Platform Covalent inhibitors exploit the cysteinome to gain selectivity and potency ABCAB CD A D B C E F Group 4 Group 1 Group 2 Group 3 Ac va on Loop (disordered) Staurosporine Groups 1-4 Grey, et. al., Nat. Rev. Cancer (2009) Group 5 T. Barf, et. al., J. Med. Chem. (2012) • 313
Slide 25: Discovery of covalent kinase inhibitors
KINect™ Technology Platform Discovery of covalent kinase inhibitors Maximizing reversible affinity and Minimizing reactivity with the intent to develop efficacious and safe drugs Precise placement of reactive group provides enormous rate enhancement for covalent bond formation Kinase Cysteine Revers
Slide 26: Novel library coupled with industry-leading expertise
KINect™ Platform Novel library coupled with industry-leading expertise • KINect™ proprietary compound library – Purposely designed physical library of kinase scaffolds with electrophilic substituents – Library has been validated by generating lead optimization starting points • Characterization of c
Slide 27: KINect Library Validation
27 KINect Library Validation Rapid Lead Identification for 10 Kinases of Interest • Validation with 10 kinase targets chosen for structural diversity & disease biology (8 shown here) • Lead chemical matter generated on all 10 targets in <2 months as lead optimization starting point • Time dependent
Slide 28: Competitive Landscape
Competitive Landscape KINect™ has Comprehensive Cysteinome Coverage Irreversible Kinase Technology Companies Technology Capabilities KINect™ Platform Celgene Avilomics Research Principia Biopharma Target Specific Yes Yes Yes Broad cysteinome coverage Yes No No Multiple scaffolds/templates 8-10 Paten
Slide 29: KINect Technology Platform: Summary
KINect™ Technology Platform: Summary • The Aclaris fully integrated kinase drug discovery team has successfully utilized multiple novel approaches to generate drug candidates for disease relevant kinases • The success of the MK2, ITK and JAK programs is linked to successful utility of the KINect™ pl
Slide 30: ATI-450: MK2 Inhibitor
© Copyright 2019 Aclaris Therapeutics. All rights reserved EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE ATI-450: MK2 Inhibitor (an investigational compound)
Slide 31: MK2 Inhibitor: Potential Oral Alternative to Biologics
MK2 Inhibitor – Potential ORAL Alternative to Injectable, Anti-Cytokine Biologics and JAK Inhibitors for Immuno-Inflammatory Diseases • MK2* is an attractive drug target because it drives pro-inflammatory cytokine expression associated with the p38 MAP kinase pathway • The effects of inhibiting MK2
Slide 32: Intracellular Pathways Regulate Cytokine Production
Intracellular Pathways Regulate Cytokine Production sTNFR (Enbrel) aTNF (HUMIRA, REMICADE) TNFa and IL1 Transcription Translocation p38 p38 P P TXF MK2 MK2 TNF P P INFLAMMATORY STIMULI IL-1 aIL-1 (Ilaris) Translation Transduction mRNA Stability Derepression mRNA Translocation MK2 pathway also regula
Slide 33: MK2 Post-Transcriptionally Regulates TNFα
Inactive kinase Active kinase MK2 Post-Transcriptionally Regulates TNFα and Other Key Pro-Inflammatory Cytokines MK2 Regulates Post-Transcriptional mRNA Stability Resting Conditions Pro-TNFα mRNA High mRNA stability TNFα expression Inflammation / Stress Conditions • Tristetraprolin (TTP) is a post-t
Slide 34: Historical Development of p38 Inhibitors
• 1st generation failed due to safety profile – Off-target effects – poor kinase selectivity – On-target tox liabilities • 2nd generation were very selective with fewer off-target toxicities – On-target tox liabilities remain – In the clinic – tachyphylaxis in rheumatoid arthritis (RA) & inflammator
Slide 35: p38 MAPK Substrates
p38 MAPK Substrates Transcription Factor DNA Binding Regulatory Protein RNA Binding Atf2 BAF60c BimEL-BCL2L11 FBP2/3 C/EBPβ CDt1 Caspase-3-CASP3 HuR-ELAV1 CHOP-GADD153-DDIT3 E47-TCF3 Caspase-8-CASP8 KSRP ERa-ESR1 SRC3-NCOA3 Cdc25A SP45-RBM17 Fos–c-fos H3-H3F3A Cdc25B Membrane FOXO3a HBP1 Cyclin D1-C
Slide 36: The Path From p38 to MK2
The Path From p38 to MK2 • p38 was the original therapeutic target for suppressing TNFα and other pro- inflammatory cytokines • Historically p38 inhibitors could not overcome toxicity and demonstrated a lack of sustained activity in certain diseases such as RA and IBD. This lack of sustained activit
Slide 37: ATI-450 Blocks MK2 Activation
ATI-450 ATI-450 Blocks MK2 Activation, BUT NOT p38 Phosphorylation of Other Substrates • ATI-450 “captures” MK2 in an inactive state – preventing p38MAPK from phosphorylating/activating MK2 • ATI-450 is substrate selective. It is designed to only interact with the p38-MK2 complex and not other p38 s
Slide 38: Capturing MK2 in an Inactive State
Capturing MK2 in an Inactive State Crystal structure of the p38α/MK2 complex ATI-450 (yellow) docked in the pocket • In the nucleus, inactive MK2 and p38 dock in a high affinity complex that exhibits a binding pocket formed by juxtaposed walls of both proteins • Aclaris MK2 inhibitors bind to both w
Slide 39: ATI-450 is Highly Selective for MK2
ATI-450 is Highly Selective for MK2 vs other p38 Substrates CDD-110, a global p38 inhibitor, inhibits MK2 and PRAK (MK5) with equal potency ATI-450 inhibits MK2 ≥700X more potently than it does either PRAK or ATF2 (a p38 activated transcription factor) CDD-110 (µM) CDD000450 (uM) 0.0001 0.001 0.01 0
Slide 40: ATI-450 Selectivity
• >350-fold binding selectivity on all kinases in this panel except p38α and p38β • In total, ATI-450 tested vs 193 kinases at 5 µM and found selective ATI-450 Selectivity 0 20 40 60 80 100 120 1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 51 53 55 57 59 61 63 65 67 69 71 73
Slide 41: ATI-450: Anti-inflammatory Data
ATI-450: MK2 inhibitor - Anti-inflammatory Data (an investigational compound) 41
Slide 42: Mouse Model: ATI-450 Durable Response
Protocol: • p38 inhibitor (CDD-111) or ATI-450 administered to mice in feed starting day 1 and continuing through day 28 • LPS challenges and blood TNFa levels determined at Days 4, 14, 21 and 28 • Drug levels in blood were quantified to control for changes in drug metabolism • p38 inhibitor lost ef
Slide 43: Animal Models Supporting MK2 Inhibitors
Animal Models Supporting the Development of MK2 inhibitors in Inflammatory Diseases Therapeutic area Model (all used ATI-450) Reference Rheumatoid Arthritis / Osteoarthritis / Psoriatic Arthritis Rat streptococcal cell wall arthritis model - Protection against bone deterioration - Protection against
Slide 44: Potential Effect in Rheumatoid Arthritis
ATI-450 by blocking MK2 – Potential Effect in Rheumatoid Arthritis MK2 is a key regulator of essential pathogenic signals in chronic inflammatory and autoimmune diseases Cells Cytokines Mediators Monocyte/Macrophage TNFα COX-2 Osteoclast IL1β iNOS Epithelial Cells IL1a MMP-9 Synovial Fibroblast IL6
Slide 45: Rat Streptococcal Cell Wall Arthritis
Rat Model: ATI-450 Activity in Rat Streptococcal Cell Wall Arthritis 0.8 1 1.2 1.4 1.6 1.8 2 2.2 2.4 2.6 2.8 0 5 10 15 20 Paw Volume - ml Study Day Vehicle CDD450 - 10 MPK CDD450 - 5 MPK CDD110 - 1.5 MPK Oral dosing initiated vehicle ATI-450 Protocol • On Day 0, rats were injected IP with SCW prep.
Slide 46: Joint and Bone Preservation
Rat Model: ATI-450 Activity in Rat Streptococcal Wall Arthritis Model: Disease Modifying Activity – Joint and Bone Preservation Control Vehicle ATI-450 (5mpk) • Significant deterioration of the ankle joint observed in disease (middle panel) • Bone protection with ATI-450 (right panel) • Bone mineral
Slide 47: Adoptive Transfer Mouse Model of Crohn's Colitis
Mouse Model: Orally Dosed ATI-450 in an Adoptive Transfer Mouse Model of Crohn’s Colitis • Collaboration with Dr. Kevin Haigis, Harvard Medical School • Adoptive transfer of CD4+CD45RBhi T cells (naïve T cells) into RAG-1-/- mouse (no endogenous T or B cells); Synchronously develop intestinal coliti
Slide 48: Crohn's Colitis Histology
Mouse Model: Orally Dosed ATI-450 in a Crohn’s Colitis Adoptive Transfer Model Histology shows • decreased lymphoid infiltrate • preserved crypt architecture Orally administered ATI-450 suppresses the manifestations of adoptive T-cell colitis mouse model Normal Control (disease is expressed) ATI-450
Slide 49: Cryopyrin-Associated Periodic Syndromes
• Cryopyrin-Associated Periodic Syndromes (CAPS) are orphan, genetic disorders caused by NLRP3 inflammasome-activating mutations – IL1β-dominant pro-inflammatory cytokine profile – Symptoms: – Systemic inflammation, fevers, CNS symptoms, hearing/vision loss, retarded growth, skeletal deformities, jo
Slide 50: ATI-450 Protects Against Weight Loss in NOMID Mice
Mouse Model: ATI-450 Protects Against Weight Loss in NOMID Mice • Attenuated body weight loss • Prevented death (no death in treated mice) • Prevented development of splenomegaly • Inhibited osteoclast formation • Inhibited bone loss Weight change (%) NOMID (n=11) NOMID+ATI-450 (n=10) ** -25 -20 -15
Slide 51: ATI-450 Suppresses Inflammation in NOMID Mice
Mouse Model: ATI-450 Suppresses Inflammation in NOMID Mice Orally dosed ATI-450 in NOMID mice suppresses the expression of IL1β, IL18, IL6 IL1β (bone marrow fluid) CDD-450 - + - + 0 10 20 30 40 50 60 70 (pg ) (ng/ml ) 0 0.5 1.0 1.5 2.0 2.5 3.0 Normal NOMID CDD-450 - + - + Normal NOMID IL6 (serum) (p
Slide 52: ATI-450 Inhibits RANKL-induced Osteoclastogenesis
• In CAPS, osteoclastogenesis gives rise to low bone mass (osteopenia) •(a) When bone marrow derived macrophages (BMDM) from NOMID mice are stimulated with RANKL (RANK ligand), they differentiate into osteoclasts •(b) ATI-450 blocks this macrophage differentiation Mouse Model: ATI-450 Inhibits RANKL
Slide 53: ATI-450 Inhibits IL1β in CAPS Patient PBMCs
Ex Vivo Data: ATI-450 Inhibits IL1β Expression in PBMCs from a CAPS Patient • To evaluate how findings in mice might translate into humans, peripheral blood mononuclear cells were isolated from CAPS patients and healthy controls. In CAPS patients (Muckle Wells Syndrome; MWS), disease (reflected by I
Slide 54: ATI-450: Development Status and IND-Related Studies
ATI-450: MK2 inhibitor - Development Status and IND-Related Studies (an investigational compound) 54
Slide 55: ATI-450 IND Status
ATI-450 IND Status • IND open and currently in Ph 1 single and multiple ascending doses • GLP toxicology ✓28-day rat – no-observed-adverse-effect-level (NOAEL) ✓28-day minipig ✓13-week studies in rat and minipig (in-life completed) • Safety pharmacology – all studies complete; no issues ✓CNS assessm
Slide 56: ATI-450 Pharmaceutical Development
ATI-450 Pharmaceutical Development • IP ✓Covered in USP 9,115,089 ✓Four additional patent families around other MK2 pathway inhibitors filed • Drug Substance ✓GMP synthesis: >6kg available ✓Ph IIB/III launch ready API manufacturing route and specification being optimized • Formulation ✓Tablet 56
Slide 57: Single and Multiple Ascending Dose Trial
ATI-450: Single and Multiple Ascending Dose Trial Single Dose Cohort • 10mg • 30mg • 50mg • 100mg Multiple Dose Cohort • 10mg BID • 30mg BID or 50mg QD • 50mg BID or 100mg QD Fed Fasting arm Methotrexate DDI arm Dose Selection • Safety • PK • PD (inhibition of TNFα, IL-1, IL-6, IL-8 & Hsp27) Rheumat
Slide 58: ATI-450 Rheumatoid Arthritis Phase 2 Trial
ATI-450 Development Rheumatoid Arthritis Phase 2 Clinical Trial • ~ 20 patients Active Disease • 12 wks: high dose v placebo • Assess CRP dynamics • Clinical Disease Activity • MRI: wrist synovitis Establish Principle • Demonstrate proof of concept Rheumatoid Arthritis Psoriasis Psoriatic Arthritis
Slide 59: ATI-450: MK2 Inhibitor in Oncology
ATI-450: MK2 inhibitor in Oncology (an investigational compound) 59
Slide 60: ATI-450 in Oncology: Dual Mechanisms
Breast Cancer • Stromal cells secrete MK2-dependent inflammatory cytokines • Cytokines drive tumor proliferation and inhibit function of immune cells • MK2 Inhibition broadly blocks tumor growth ATI-450 in Oncology – Dual Mechanisms Pancreatic Cancer • Chemotherapy induces kinase targets (figure bel
Slide 61: ATI-450 in Oncology: Aclaris Strategy
ATI-450 in Oncology – Aclaris Strategy • Preclinical studies suggest MK2 inhibition may be functioning in two ways: – Impact on the tumor microenvironment (TME) resulting in diminished production of inflammatory cytokines by stromal cells – Synergy with chemotherapeutic agents that induce tumor cell
Slide 62: Inhibiting the Stromal MK2 Pathway in Breast Cancer
Inhibiting the Stromal MK2 Pathway May Limit Breast Cancer Metastases and Chemotherapy-Induced Bone Loss Sheila Stewart Ph.D., Washington University School of Medicine 62
Slide 63: Modeling Bone and Visceral Metastasis in the Mouse
Modeling Bone and Visceral Metastasis in the Mouse • 70% of all metastatic breast cancer patients harbor bone metastasis1 • Patients with bone metastases suffer numerous co-morbidities including significant risk for bone fractures1 • Currently no spontaneous mouse model exists to study bone metastas
Slide 64: ATI-450 Reduces Visceral Organ Tumor Burden
Mouse Model: ATI-450 Reduces Visceral Organ Tumor Burden Intra-cardiac tumor cell injection model (mouse) Vehicle ATI-450 Day 13 Visceral Tumor Burden *Stewart lab / Murali et al. 2018. Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss.
Slide 65: ATI-450 and Paclitaxel Increases Overall Survival
Mouse Model: ATI-450 and Paclitaxel (PTX) Increases Overall Survival *Murali et al. 2018. Inhibition of the stromal p38MAPK/MK2 pathway limits breast cancer metastases and chemotherapy-induced bone loss. Cancer Res 78:1 PTX plus ATI-450 extends survival vs. single arm treatments Importantly these ag
Slide 66: ATI-450 Reduces Metastases and Preserves Bone
Mouse Model: ATI-450 Reduces Metastases and Preserves Bone (a), (b) ATI-450 (MK2Pi) significantly reduces bone and visceral metastases in mice (c) ATI-450 preserves bone quality - as well as or better than - zoledronic acid (ZOL) and better than paclitaxel (PTX) *Murali et al. 2018. Inhibition of th
Slide 67: MK2 Pathway in Pancreatic Ductal Adenocarcinoma
Inhibiting the MK2 pathway Inhibits Tumor Growth in Mouse Models of Pancreatic Ductal Adenocarcinoma (PDAC) Kian Lim M.D./Ph.D., Washington University School of Medicine 67
Slide 68: ATI-450 Pancreatic Cancer Update
• SOC for PDAC is switching from gemcitabine to FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin)1 • Regimen has high toxicity, thus additional agents must be well tolerated and overcome resistance mechanisms • Irinotecan is the main driver of cellular stress/induced apoptosis - resis
Slide 69: ATI-450 Pancreatic Cancer Update: KPPC model
• Lim lab shows that chemotherapy induced stress in PDAC cells driven by irinotecan (SN38) • SN38 activates MK2/Hsp27 pathway and blockade by MK2 RNAi or ATI-450 increases SN38 induced apoptosis • ATI-450 does not inhibit tumor growth directly, does suppress tumor growth in vivo (sc models) – move t
Slide 70: ATI-450 and FOLFIRINOX in KPPC Mouse Model
Combination of ATI-450 and Folfirinox Improves Efficacy in Autochthonous Mouse Model of Pancreatic Cancer (KPPC) • Combination of ATI-450 plus low dose FOLFIRONOX improves survival compared to each drug alone in autochthonous mice • Data supports the investigation of the addition of ATI-450 to FOLFI
Slide 71: Cancer: Next Steps
Cancer: Next Steps ATI-450 data for MK2 inhibition in breast and pancreatic tumor mouse models has resulted in robust interest in clinical trials both as monotherapy and in combination with current standard of care Ongoing: • Pancreatic Cancer Models (Laboratory of Dr. Kian Lim, MD, PhD) – Human PDX
Slide 72: MK2 Inhibitor ATI-450 Summary
• Novel mechanism designed to block inflammation – Multiple inflammatory cytokines impacted – Key RA inflammatory cell types impacted – Lock MK2 in a catalytically inactive state – a unique MOA – Broad IP issued or filed • Oral option for numerous diseases currently treated by biologics – Robust eff
Slide 73: ATI-1777: Soft, Topical JAK1/3 Inhibitor
EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE © Copyright 2019 Aclaris Therapeutics. All rights reserved ATI-1777: Soft, Topical JAK1/3 Inhibitor (an investigational compound)
Slide 74: Rationale for a Soft Topical JAK Inhibitor
To deliver topical therapy for atopic dermatitis (AD) in a way that meets the medical, aesthetic, and compliance needs of patients and physicians Desirable Drug Properties: • Efficacy which will at least be as good as topical competitors and a differentiated safety profile • Minimize the toxicity of
Slide 75: Why a Soft Topical; why Atopic Dermatitis?
• Aclaris’ goal is to deliver a “soft” topical JAK inhibitor to achieve efficacy in skin while minimizing systemic exposure – A soft drug is designed to be rapidly metabolized to an inactive form • AD is the primary clinical target – There is an unmet need for effective and safe topical treatment fo
Slide 76: Designing a Drug Physicians and Patients May Prefer
Aclaris is developing novel “soft” JAK inhibitors for topical use • Potent in enzyme and cell assays • JAK1/3 selective • Favorable physicochemical properties for a topical product • Designed to be active in skin but rapidly metabolized once it reaches the systemic circulation • ATI-1777 is our lead
Slide 77: Oral and Topical JAK Inhibitors are Clinically Effective in AD
Oral and Topical JAK Inhibitors are Clinically Effective in AD • Rates of AD are around 30% in the most developed nations and exceed 10% in many countries. Worldwide cumulative prevalence of 15-20%1 • AD strongly driven by Th2 cells → IL-4/13 • IL-4R uses JAK1/3, IL-13R uses JAK1/2 • Orally dosed ba
Slide 78: ATI-502 Pilot Study of Topical JAK1/3 Inhibitor
ATI-502-AD-201 Topical: Pilot Study of Topical JAK1/3 Inhibitor • ATI-502 Topical Solution, 0.46% (not soft) • Patients with Moderate to severe AD: Physician Global Assessment (PGA) 3/4 • 28 days open label treatment • 17 completers: 7/17 (41.2%) achieved PGA ≤ 1 (at least 2-point change) 78
Slide 79: Designing a Better Topical Drug for Atopic Dermatitis
✓Design potent/selective JAK enzyme inhibitors ✓Confirm cellular potency and selectivity ✓Design compounds to be metabolically unstable ✓Create patient-friendly formulation ✓Design topical pharmacodynamic model ✓Demonstrate minimal systemic exposure ➢Evaluate in early clinical studies Designing a Be
Slide 80: ATI-1777: Enzymatic Potency and Selectivity
ATI-1777: Enzymatic Potency and Selectivity ATI-1777 is highly selective for the JAK family over other kinases in the kinome 0 .1 1 1 0 1 0 0 1 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 5 0 1 0 0 E n z y m e p o te n c ie s o f A T I-1 7 7 7 w ith in J A K fa m ily C o n c e n tra tio n o f A T I-1 7 7 7 (n M )
Slide 81: Cellular JAK/STAT Assays
Cellular JAK/STAT Assays Human peripheral blood mononuclear cells stimulated by different cytokines, signal through different pairings of JAK kinases to phosphorylate downstream signal transducers and activators for transcription (STATs) • IL-2 stimulation requires JAK1 and JAK3 to phosphorylate STA
Slide 82: ATI-1777: Cellular Potency and JAK Selectivity
ATI-1777: Cellular Potency and JAK Selectivity in Human Cells Functional selectivity assessed by stimulating hPBMCs with IL-2 (STAT5), IFN-γ (STAT1), and GM-SCF (STAT5) - measuring IC50s for inhibiting P-STAT generation In human cells, ATI-1777 exhibited selectivity for JAK1/3 over JAK2 signaling -1
Slide 83: Porcine Topical Pharmacodynamic Model
Porcine Model: Building a Robust Topical Pharmacodynamic Model • Compound in topical formulations applied to skin • JAK-dependent cytokines injected intradermally • Biopsies harvested/RNA prepared • Chemokine genes robustly induced (CCL8, CXCL10) • ATI-1777 in various formulations blocks induced RNA
Slide 84: ATI-1777 Blocked IL-15 Induced CCL8
Porcine Model: ATI-1777 in Two Formulations Blocked IL-15 Induced CCL8 Naive Sol3 Sol3 1777-2% Sol4 Sol4 1777-2% Ruxo Cream Ruxo-1.5% 1 10 100 C C L 8 , F o l d C h a n g e PD Effects of ATI-1777 in Pigs • After 1 hour, application sites were injected with porcine IL-15 (JAK1/3 dependent cytokine) •
Slide 85: Clinical Ruxolitinib Systemic Exposure After Topical Application
Clinical Ruxolitinib Systemic Exposure After Topical Application 1. Downmodulation of key inflammatory cell markers with a topical Janus kinase 1/2 inhibitor. 2015. British Journal of Dermatology 173:989–997 2. Pharmacokinetics and Pharmacodynamics of Orally Administered Ruxolitinib (INCB018424 Phos
Slide 86: Minipig Model: ATI-1777 Nonclinical Safety
• No adverse effects noted for each of 4 tested formulations (10% BSA QD) • Bleeds at 0.5, 1, 2, 4, 8, 12, and 24 hours post-application: Days 1 and 6 • Most plasma samples were BLQ (<0.50 ng/mL) – well below cellular IC50 Minipig Model: ATI-1777 Nonclinical Safety Program TK Data Tolerability/Toxic
Slide 87: Rodent Model: ATI-1777 In Vivo PK Properties
Rodent Model: ATI-1777 In Vivo PK Properties • ATI-1777 is rapidly cleared after IV administration • Measured clearance higher than liver blood flow (indicating extrahepatic clearance) • IV half life was <0.5 hr • Profile consistent with that of a “soft” drug *Data on file 87
Slide 88: 7-Day Oral Dose-Range Finding Study in Rats
7-Day Oral Dose-Range Finding Study in Rats (non-GLP): Toxicokinetic Parameters Rodent Model: ATI-1777 Nonclinical Safety Program M ale Fem ale M ale Fem ale M ale Fem ale M ale Fem ale 1 10 100 1000 10000 100000 ATI-1777 Day 1 mean plasma Cmax in SD rats after oral dosing C m a x ( n g / m L ) Whol
Slide 89: Summary of Formulation Development
• API free base selected for progression into formulation development activities • Based on the solubility and compatibility data: creams, polyethylene glycol (PEG) based ointments, foams, gels (both aqueous and non-aqueous) and solutions were developed • Solution 4 (SOL4), a 2 wt% (API) emollient-c
Slide 90: ATI-1777: Summary
ATI-1777: Soft Topical JAK Inhibitor Summary • Potent inhibitor of JAK1 and JAK3 – JAK1/3 receptor selectivity minimizes JAK2 toxicities • Results in pre-clinical rodent and pig models – Topical activity demonstrated in both animal models – Designed for rapid metabolism to potentially minimize syste
Slide 91: ATI-2138: ITK/TXK/JAK3 Inhibitor
EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE © Copyright 2019 Aclaris Therapeutics. All rights reserved ATI-2138: ITK/TXK/JAK3 Inhibitor (an investigational compound)
Slide 92: ATI-2138 for Autoimmune Disease
• ATI-2138 is an investigational oral compound which interrupts T cell receptor (TCR) signaling and cytokine signaling in lymphocytes • Evaluating for the potential treatment for a number of T cell mediated autoimmune diseases ATI-2138: ITK/TXK/JAK3 Inhibitor for Autoimmune Disease 92
Slide 93: ITK/TXK Function and Expression
ITK/TXK Function and Expression • ITK and TXK are members of the TEC family of kinases • ITK and TXK have overlapping functions • Expression restricted to T cells, NK cells, and mast cells • ITK and TXK are downstream of the T cell receptor • ATI-2138 is designed to reduce T cell differentiation, pr
Slide 94: ATI-2138 Impacts Clinically Important Pathways
• ATI-2138 function is analogous to IL-12/23/17 antibodies • Potential Indications: – Psoriasis – Psoriatic arthritis – IBD – Ankylosing spondylitis ATI-2138: Impacts Clinically Important Pathways IL-12 IL-23 Naïve CD4+ T cell ITK/TXK TH1 ITK/TXK IFNγ IL-2 TNFα IL-17A IL-17F IL-17AR IL-17FR Ustekinu
Slide 95: JAK signaling and JAK inhibitors
• Cytokine receptors pair with JAK kinases to phosphorylate STATs • Multiple inhibitors of JAK kinases have been approved for and are currently in clinical trials for inflammatory diseases JAK signaling and JAK inhibitors Gadina, M. et al., J. Leukoc Biol., 2018, 104, 499 95
Slide 96: Examples from the Organ Transplant Field
• Combination regimens are better able to block complex immunologic cascades involved with inflammatory responses, and avoid the use of higher, more toxic doses of individual drugs • Main pathways targeted in all transplant drug cocktails are the T cell receptor (blocked with cyclosporine / tacrolim
Slide 97: Combination of TCR and Cytokine Signaling Synergy
• Tofacitinib was originally developed as a drug for transplant rejection • The combination of tofacitinib and cyclosporine was significantly more active than either drug alone • By inhibiting both the TCR and cytokine signaling pathways with the same agent greater effects may be observed than eithe
Slide 98: ATI-2138 Covalently Inhibits ITK, TXK and JAK3
Pre-clinical Data: ATI-2138 Covalently Inhibits ITK, TXK and JAK3 CYS442 ATI-2138 modeled into ITK kinase domain 3QGY ATI-2138 • Design guided by modeling and proprietary crystal structures • ATI-2138 was designed to interact with ATP site and covalently modify CYS – CYS442 in ITK • Other oral drugs
Slide 99: ATI-2138: Activity in Enzyme Based Assays
• Broad panel kinase panel screening of 194 kinases at 1µM • IC50 values determined for kinases with >85% inhibition • Weak potency against kinases that lack a CYS residue – Inhibition is reversible in these cases • Varying potency within TEC family of kinases – Most potent for ITK • Crossover onto
Slide 100: ATI-2138 Activity in Cell Based Assays
ATI-2138 potently inhibits ITK/TXK and JAK3 in cells and in whole blood Pre-clinical Data: ATI-2138 Activity in Cell Based Assays Assay ATI-2138 (µM) Assay Description hJurkat pPLCγ-1 IC50 0.007 Assesses ITK/TXK activity hPBMC pSTAT-5 IC50 0.02 Assesses JAK1/3 activity Ramos pPLCγ-2 IC50 0.052 Asses
Slide 101: ATI-2138 Inhibited ITK/TXK and JAK3 Signaling In Vivo
• ATI-2138 potently inhibited TCR signaling in vivo • At higher doses can inhibit both TCR and JAK3 pathways Mouse Model: ATI-2138 Inhibited ITK/TXK and JAK3 Signaling In Vivo PO dose of ATI-2138 3hr Female CD-1 mice 3hr Stimulate with αCD3 (ITK/TXK) or IL-2 (JAK3) Measure INFγ levels in mouse VEH 1
Slide 102: Prolonged Effect on ITK/TXK Inhibition
• Due to covalent inhibition of targets, pharmacodynamic effects persisted after compound is cleared from plasma compartment Mouse Model: ATI-2138 Had a Prolonged Effect on ITK/TXK Inhibition PO dose of ATI-2138 Time Female CD-1 mice 3hr Stimulate with αCD3 (ITK/TXK) Measure IFNγ levels in mouse 0 1
Slide 103: Rat Adjuvant Induced Arthritis Model
Measure ankle diameter Weigh every other day Rat Model: ATI-2138 Demonstrated Activity in Rat Adjuvant Induced Arthritis (AIA) model Male Lewis Rat Day 0 Inject with adjuvant Day 6 Begin PO dosing of ATI-2138 Day 12 Day 23 Histology, BMD Vehicle ATI-2138-10-QD ATI-2138 30 QD ATI-2138 5 BID ATI-2138
Slide 104: ATI-2138 Protected Bone in Rat AIA Model
• ATI-2138 reduced bone mineral density loss in rat AIA disease model Rat Model: ATI-2138 Protected Bone in the Rat Adjuvant Induced Arthritis AIA Disease Model VEH QD ATI-2138-10-QD ATI-2138-30-QD ATI-2138-5-BID ATI-2138-15-BID 120 140 160 180 200 220 ATI-2138 bone mineral density in rat AIA study
Slide 105: Measuring ATI-2138 Occupancy of ITK
• Relationship between PK and PD is complex for covalent inhibitors – PD effects continue after compound has been cleared from plasma – Recovery rate of target proteins determines duration of effect • Target occupancy may be assessed ex vivo using probe molecules • OC50 – concentration of an inhibit
Slide 106: ATI-2138: Potential Indications
• Moderate-severe psoriasis • Approved oral therapies – OTEZLA (apremilast) – Approved in psoriatic arthritis and moderate-to-severe plaque psoriasis in 2014 – Annual sales of $472M, $1.02B, $1.28B, $1.61B, from 2015-2018 respectively.1 – Sold to Amgen for $13.4B • Probable new entries – JAK inhibit
Slide 107: Current Development Programs: Covalent ITK/TXK/JAK3 Inhibitors
Current Development Programs - Covalent ITK/TXK/JAK3 Inhibitors ID Company Phase Indication(s) Mechanism PF-06651600 Pfizer II/III Alopecia Areata, IBD JAK3, TEC family JTE-051 Akros II Psoriasis, RA ITK only CPI-818 Corvus I T cell lymphoma ITK only PRN694 Principia Preclinical IBD, Psoriasis ITK/T
Slide 108: ATI-2138: Program Summary and Status
• ATI-2138 is an investigational immunosuppressive compound that targets the TCR and the JAK3 pathways – Potent covalent inhibitor of ITK/TXK and JAK3 in enzyme and cell assays – In vitro and in vivo evidence of covalent target modification – PD effects persisted after drug is cleared from the plasm
Slide 109: Gut Restricted Inhibitors of ITK and/or JAK Kinases for IBD
EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE © Copyright 2019 Aclaris Therapeutics. All rights reserved Gut Restricted Inhibitors of ITK and/or JAK Kinases as Drugs for IBD
Slide 110: Inflammatory Bowel Diseases (IBD)
• IBD: Ulcerative colitis (CD) and Crohn’s disease (CD) • UC inflammation restricted to inner most layers of the colon (mucosa/submucosa) • CD inflammation can occur anywhere along digestive tract • Orally delivered, gut-restricted drugs may be efficacious in UC and CD – and potentially result in fe
Slide 111: Advent of JAK Therapy for IBD
Advent of JAK Therapy for IBD Tofacitinib Approval for UC • Ph 3 trial design – 8 wks induction, 10 mg BID – If responsive, subjects then randomized to placebo, 5 mg or 10 mg BID • 1-year remission rates – Placebo – 11% – 5mg BID – 34% – 10 mg BID – 41% • AEs – 5 CV events, 5 skin cancer, increased
Slide 112: Gut-restricted program rationale and candidate profile
• Therapeutic Indications: IBD (UC and CD), Celiac Disease • Biological Rationale: – JAK3 required by key cytokines associated with IBD, Celiac Disease – ITK dependent T cells drive all autoimmune disease – JAK inhibitors clinically active in UC and CD (XELJANZ (tofacitinib) recently approved for UC
Slide 113: Gut-restricted program development plan
• Identify potent covalent JAK3/ITK and reversible JAK inhibitors • Covalent ITK/JAK3 ATX-002 and ATX-001 (investigational compounds) in hand √ • Reversible pan-JAK1 ATX-025 (non-covalent JAK inhibitor) and ATX-023 in hand √ • Initial studies were done with ATX-002 and ATX-025 • Show compounds have
Slide 114: Preclinical Data: Compound Potencies in Cells
Preclinical Data: Compound Potencies in Cells Kinases ITK/TXK JAK1/3 JAK1/2 JAK2/2 Tyk2/JAK2 ATX# Jurkat IL-2 IFNg GMCSF IL-12 002 27 42 >4,000 >4,000 >4,000 023 ND 60 270 963 >4000 025 >4,000 50 151 38 61 • ATX-002 is covalent inhibitor of ITK, TXK and JAK3, demonstrating potent inhibition of cell
Slide 115: Compound Exposure after Oral Dosing
0 2 4 6 8 10 1 10 100 1000 ATX-023 Intestinal vs. Systemic PK 5 mpk PO in Mice Time C o n c e n t r a t i o n A T X - 0 2 3 ( n g / m L o r n g / g ) Colon Plasma Mouse Model: Compound Exposure after Oral Dosing 0 2 4 6 8 1 10 100 1000 10000 ATX-002 Intestinal vs. Systemic PK 5 mpk PO in Mice Time C
Slide 116: ATX-002 and ATX-025 Inhibit OXA Induced Cytokines
Mouse Model: ATX-002 and ATX-025 Inhibit OXA Induced Cytokines • Shaved mice primed topically with 4% oxazolone. Seven days after priming: – 0 hr: Mice dosed PO with ATX-002 or ATX-025, 30 mg/kg – 2 hr: Mice injected intrarectally with 100 ml, 1% OXA – 4 hr: Colons harvested, and lysate analyzed cyt
Slide 117: Oxazolone Model of Colitis
• Standard model of oxazolone induced colitis performed with ATX-001 which is an ITK/JAK3 inhibitor – Day 0 – Topical Oxa prime – Day 5 - Begin PO dosing, BID – Day 6 – IR Oxa challenge – Days 7 and 8 in-life DAI scoring – Terminal histology • DAI (Disease activity index) – Body weight – Stool consi
Slide 118: Adoptive Transfer T Cell Colitis Model
Mouse Model: Bolder Biopath Adoptive Transfer T Cell Colitis Model • Adoptive transfer of naïve T cells into SCID mice results in colitis • In-life readout is weight loss over 48 days (shown) • Colon weight/length and terminal histology at end • Translatable model as antibody to IL-12/23 (surrogate
Slide 119: Gut Restricted Drug Development - Summary
• Potent compounds found in both series: – ITK/TXK/JAK3 covalent and JAK1/3 non-covalent • Compounds have gut-restricted PK post oral dosing • Compounds active in short-term PD and efficacy models (OXA), with alternative models in development (e.g., TNBS-induced colitis) • Lead compounds being studi
Slide 120: Catalysts
Catalysts Milestone 2019 2020 Q3 Q4 Q1 Q2 Q3 Q4 A-101 45% Common Warts Phase 3 Data (Thwart-1, Thwart-2) ✓ Inflammation / Immunology ATI-450 (MK2 Inhibitor) - Initiate Phase 1 Trial (SAD/MAD) ✓ ATI-450 (MK2 Inhibitor) - Phase 1 Data (SAD/MAD) ATI-450 (MK2 Inhibitor) - Initiate Phase 2 Trial in Rheum
Slide 121: Thank You
EMPOWERING PATIENTS THROUGH REVELATIONARY SCIENCE © Copyright 2019 Aclaris Therapeutics. All rights reserved THANK YOU