Aclaris Therapeutics, Inc. · NASDAQ:ACRS
Aclaris Therapeutics — Q1 2024 Earnings Presentation
22 slides from Aclaris Therapeutics's earnings presentation, May 7, 2024
Slide 1: Empowering Patients Through Kinome Innovation
EMPOWERING PATIENTS THROUGH KINOME INNOVATION Overview of ITK Portfolio May 7, 2024 © Copyright © Copyright 2024 2020 Aclaris Aclaris Therapeutics, Therapeutics, Inc. Inc. All All rights rights reserved reserved (XX)
Slide 2: Cautionary Note Regarding Forward-Looking Statements
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 wo
Slide 3: ATI-2138: A First Generation Novel ITK/JAK3 Inhibitor for T Cell-Mediated Diseases
ATI-2138: A First Generation Novel ITK/JAK3 Inhibitor for T Cell-Mediated Diseases (Investigational Drug Candidate) 3 © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2024 Aclaris Therapeutics, Inc. All rights reserved
Slide 4: ATI-2138 is a Combined Covalent ITK & JAK3 Inhibitor for Autoimmune Disease
ATI-2138 is a Combined Covalent IL-2-Inducible Tyrosine Kinase (ITK) & JAK3 Inhibitor for Autoimmune Disease 1 2 ATI-2138 • ATI-2138 is an investigational oral compound which interrupts T cell receptor (TCR) signaling by inhibiting ITK and JAK3 signaling of common γ chain cytokines in lymphocytes (i
Slide 5: ATI-2138 Covalently Inhibits ITK and JAK3
ATI-2138 Covalently Inhibits ITK and JAK3 ATI-2138 was designed to interact with the ATP site and covalently modifies CYS442 in ITK and CYS909 in JAK3 ATI-2138 CYS442 • Design guided by modeling and proprietary • Other oral drugs have successfully targeted these crystal structures cysteines in kinas
Slide 6: ATI-2138: Potential for Meaningful Differentiation
ATI-2138: Potential for Meaningful Differentiation ATI-2138, by modulating both TCR signaling (via ITK blockade) and cytokine signaling (via JAK3 blockade), is a T cell focused modulator and potentially ideal for treating autoimmune diseases with high unmet medical need Cell IC50, nM ITK JAK3 JAK1/2
Slide 7: ATI-2138 Differentiation from Ritlecitinib
ATI-2138 Differentiation from Ritlecitinib Dual ITK and JAK3 Inhibitors ITK: HWB aCD3 Stimulated IFNg Release JAK3: HWB IL2 Stimulated IFNg Release ATI-2138 ATI-2138 Ritlecitinib Ritlecitinib 44.4x 5.4x • ATI-2138 is 44.4x more potent than ritlecitinib for inhibiting αCD3 induced IFNγ production (IT
Slide 8: ITK Modulates T Cell Differentiation and Activation
ITK Modulates T Cell Differentiation and Activation Skews T Helper Cell Differentiation Towards Th2 and Th17 Phenotypes ITK/TXK • ITK has a nonredundant role in the TH1 differentiation and activation of TH2 and TH17 cells • Knockdown or inhibition of ITK in mice TH2 ITK and humans results in skewing
Slide 9: ATI-2138 Dose-Dependently Inhibited Adjuvant Induced Arthritis in Rats
ATI-2138 Dose-Dependently Inhibited Adjuvant Induced Arthritis (AIA) in Rats Ankle Diameter Swelling and Histology • Semi-therapeutic model with PO dosing beginning on day 6 after FCA injection (Bolder BioPath)1,2 • No significant difference between 5 mg/kg BID, 15 mg/kg BID and 30 mg/kg QD 1 Study
Slide 10: ATI-2138 Dose-Dependently Inhibited Inflammation in Mouse T Cell Transfer IBD Model
ATI-2138 Dose-Dependently Inhibited Inflammation in the Mouse T Cell Transfer Model of Inflammatory Bowel Disease Proximal Colon Distal Colon Ileum ATI-2138 dose-dependently Greater effect than anti-IL12 ATI-2138 inhibited colitis in decreased inflammation in (P40) that significantly the mouse T cel
Slide 11: ATI-2138 SAD and MAD Studies Complete: Data Summary
ATI-2138 Single (SAD) and Multiple Ascending Dose (MAD) Studies Complete: Data Summary Safety Pharmacokinetics Pharmacodynamics • ATI-2138 was generally well • ATI-2138 was rapidly • Dose-dependent inhibition of tolerated at all doses tested in absorbed. both ITK and JAK3 the trial. • Multiple doses
Slide 12: Pharmacokinetic Analysis from MAD Study
ATI-2138 Pharmacokinetic Analysis from MAD Study ATI-2138 had linear PK and achieved adequate exposure ATI-2138 PK Steady State PK Dose Proportionality • Day 15 plasma concentration curves demonstrated linear PK for ATI-2138 • Targeted ATI-2138 average exposure over the dosing interval was achieved
Slide 13: MAD Exploratory Pharmacodynamics
ATI-2138 MAD Exploratory Pharmacodynamics Dose Response Data (BID Cohorts) • Pharmacodynamic biomarkers - Ex-vivo stimulation of whole blood taken from subjects before and after administration of ATI-2138 – BID cohorts • Stimulation with anti-CD3 and anti-CD28 (readout IL-2 mRNA; T-cell activation),
Slide 14: High Potency of ATI-2138 Maintained in SAD/MAD Clinical Studies
High Potency of ATI-2138 for ITK and JAK3 Observed in Preclinical Studies Maintained in the SAD/MAD Clinical Studies ITK Dependent Response JAK3 Dependent Response ITK/JAK3 Response 200 200 200 a CD3 & a CD28 Stim IL2 mRNA a CD3 & IL15 Stim IFNg Protein IL15 Stim IFNg Protein (% Predose - All data)
Slide 15: Rationale for Dual Inhibition of ATI-2138 in Atopic Dermatitis
Rationale for Dual Inhibition of ITK and JAK3 ATI-2138 in Atopic Dermatitis • ITK Inhibition ✓ Atopic dermatitis (AD) is a Th2 cell driven disease and ITK inhibition blocks T cell differentiation/activation and production of IL-4 and IL-13 • Dupilumab (anti-IL4Ra) and tralokinumab (anti-IL-13) are e
Slide 16: Phase 2a Trial Design of ATI-2138 in Atopic Dermatitis
Phase 2a Trial Design of ATI-2138 in Atopic Dermatitis Eligibility Treatment Endpoints • Moderate to Severe • Open label design • Safety, PK Atopic Dermatitis • Total 12 weeks treatment • PD: RNA analysis, • EASI ≥ 16 • 10mg BID dosing proteomics, IHC to analyze • vIGA 3-4 specific pathway inhibitio
Slide 17: ATI-2138: Combined ITK & JAK3 Inhibitor for Autoimmune Disease
ATI-2138: Combined IL-2-Inducible Tyrosine Kinase (ITK) & JAK3 Inhibitor for Autoimmune Disease • ATI-2138 is an oral compound which interrupts T cell receptor (TCR) signaling by inhibiting ITK and JAK3 signaling of common g chain cytokines in lymphocytes (including IL-2 & IL-15) • ATI-2138 potently
Slide 18: Next Generation Selective ITK Inhibitor
Next Generation Selective ITK Inhibitor 18 © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2024 Aclaris Therapeutics, Inc. All rights reserved
Slide 19: ITK is an Interesting but Hard to Drug Target
ITK is an Interesting but Hard to Drug Target Reversible ATP competitive inhibitors discontinued for weak cellular potency, poor ADME 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 • Compounds targeting the ATP site of ITK have been pursued since the early 2000’
Slide 20: ITK Selective Covalent Inhibitor
ITK Selective Covalent Inhibitor Next Generation Follow-on to ATI-2138 • ATI-2138 is a dual pathway inhibitor of ITK and JAK3 mediated cytokine signaling pathways • Goal of next generation inhibitor is to minimize crossover onto JAK3 • Selective targeting of ITK (TH2 and TH17 inhibition) and/or ITK/
Slide 21: ITK Selective Inhibitor: Potential Indications
ITK Selective Inhibitor: Potential Indications Multiple potential indications supported by ITK genetic phenotypes RA, AD, cGVHD, solid organ transplant rejection, MS, IBD Lechner, K. S. et al. (2020) Role of the IL-2 Inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis. J. Mol. M
Slide 22: Empowering Patients Through Kinome Innovation
EMPOWERING PATIENTS THROUGH KINOME INNOVATION Overview of ITK Portfolio May 7, 2024 © Copyright © Copyright 2024 2020 Aclaris Aclaris Therapeutics, Therapeutics, Inc. Inc. All All rights rights reserved reserved (XX)