Aclaris Therapeutics, Inc. · NASDAQ:ACRS
Aclaris Therapeutics — Investor Day (October 2025)
118 slides from Aclaris Therapeutics's investor day presentation, Oct 14, 2025
Slide 1: Patient Focused Innovation: 2025 R&D Day
Patient Focused Innovation Developing Therapeutic Franchises to Address Gaps in Important I&I Diseases 2025 R&D Day October 14, 2025
Slide 2: Forward-Looking Statements
2 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 “anticipate,” “believe,” “expect,” “int
Slide 3: Today's Agenda
Today’s Agenda 3 Patient Focused Innovation Roland Kolbeck, Ph.D. Chief Scientific Officer World Class Development Engine Zuzana Diamant, M.D, Ph.D., FERS SAB member; Pulmonologist & Clinical Pharmacologist, Department of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, Netherl
Slide 4: Aclaris Therapeutics
Aclaris Therapeutics Developing Therapeutic Franchises to Address Gaps in Important I&I Diseases Neal Walker, MD Chief Executive Officer Patient Focused Innovation
Slide 5: Aclaris Therapeutics: Innovation Driven, Patient Focused
Aclaris Therapeutics Innovation Driven Patient Focused Three clinical programs in 2025; four anticipated in 2026 2026 is an important year for Aclaris with four anticipated inflection points Validated targets; positioned in the oral and antibody space Bispecific and ITK oral programs could be potent
Slide 6: Aclaris: Positioned for Significant Growth Potential
Aclaris: Positioned for Significant Growth 6 Potential Best-in-Class Clinical Assets Continued Business Execution World Class Expertise/Capability • Bosakitug (ATI-045): Uniquely potent monoclonal antibody targeting TSLP • ATI-052: Bispecific antibody (BsAb) targeting both TSLP and IL-4Rα • ATI-2138
Slide 7: The Future Value of Drug Development
The Future Value of Drug Development Addressing Th1, Th2 and Th17-Mediated Disorders 7 Sources: Eczema stats: National Eczema Association (accessed 07/31/25); National Alopecia Areata Foundation (Accessed 07/31/25); Vitiligo Facts: Global Vitiligo Foundation (accessed 07/31/25); Precedence Research;
Slide 8: Opportunities in the I&I Space
Opportunities in the I&I Space Potential to Address Significant Gaps in Unsatisfied I&I Indications 8 Opportunities for Orals • Faster onset, durable, consistent effect • Broader efficacy across heterogenous populations • Optimize symptom control: anti-itch effect, FEV1 • Potential anti-fibrotic eff
Slide 9: Aclaris Today
Aclaris Today 9 Patient Focused Innovation • Unique State-of-the-Art R&D capabilities and World Class Scientists • Four potential Best-in-Class clinical stage assets in 2026 targeting validated and therapeutically-relevant immune targets highlighted by a potential Best-in-Class bispecific and oral I
Slide 10: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 10 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 11: World-Class Discovery Engine
World-Class Discovery Engine Leading Kinase and Antibody Innovation for the Treatment of Autoimmune & Inflammatory Diseases Roland Kolbeck, Ph.D. Chief Scientific Officer Patient Focused Innovation
Slide 12: What Makes Aclaris Stand Out
What Makes Aclaris Stand Out 12 • Oral compounds targeting previously inaccessible parts of the Kinome • Injectable potential best-in-class multi-specific antibodies designed to address unmet clinical need and raise the efficacy ceiling • World-class track record in drug discovery and development •
Slide 13: The Kinase Opportunity and KINect Technology Platform
The Kinase Opportunity 13 The Aclaris Solution KINect® Technology Platform Proprietary chemical library and integrated capabilities for interrogating 60% of the Kinome <10% of Kinome targeted by the 80+ FDA Approved Drugs 100s More to be Explored 500 Members 2% of the Human Genome Most Members of th
Slide 14: Proprietary Chemical Library Design Specific to Each Kinase
Proprietary Chemical Library Design Specific to Each Kinase Faster Path to High Quality Assets Proprietary Chemical Library Schrödinger Enabled Drug Design Custom Kinase and Immune Assays MODELING DESIGN SYNTHESIS ANALYSIS KINect Platform Rapid and Efficient Development of Kinase Drug Candidates 14
Slide 15: New Frontiers in Drug Discovery
New Frontiers in Drug Discovery Small Molecule Innovation Innovation Driven Patient Focused Molecular glues Small molecules that stabilize kinases in an inactive confirmation or set them up for degradation Covalent kinase inhibitors Small molecules inhibiting kinases by forming irreversible bonds wi
Slide 16: The Multi-Specific Antibody Opportunity
The Multi-Specific Antibody Opportunity 16 Multi-specific Antibodies are a Successful Class of Medicines for Cancers $12.6B Annual Sales of Multi-Specific Antibodies in 2024 Number of Multi-Specific Antibodies Approved Opportunity: Best-In-Class Multi-Specific Antibodies for Autoimmune and Inflammat
Slide 17: Developing Multi-Specific Antibodies for Autoimmune Diseases
• Superior target affinity, specificity, potency • Combinations of 2 or more clinically validated targets with non-overlapping biology • Combinations of clinically validated targets with novel biology • Synergistic target combinations: when one is not enough Format – Fit-for-purpose multi-specific f
Slide 18: Proven Track Record of Discovery and Development
Proven Track Record of Discovery and Development 18 ITK is downstream of the T cell receptor and impacts T cell function and differentiation Covalent ITK/JAK3 Inhibitors (ATI-2138) JAK3 is necessary for signaling from γc cytokines like IL-2 Covalently modifying both targets interrupts these pathways
Slide 19: State of the Art R&D Capabilities
State of the Art R&D Capabilities Expertise in Small Molecules and Antibodies R&D 19 Biochemistry & Enzymology Bioanalytical Chemistry Immunology • Mechanistic Enzymology • Compound - Target Interaction • Enzyme Inhibitor Mechanisms • Direct Binding Kinetics • High Throughput Screening • Non-GLP Ana
Slide 20: World Class Discovery Engine Summary
World Class Discovery Engine Summary 20 • Oral compounds targeting previously inaccessible parts of the Kinome with proprietary KINect platform • Designing injectable multi-specific antibodies with superior target coverage and potency to raise the efficacy ceiling • Unique expertise in small and lar
Slide 21: Developing the Leading ITK Franchise
Developing the Leading ITK Franchise Innovation Through ITK Inhibition Joe Monahan, Ph.D. Special Scientific Advisor Founder, Confluence Discovery Technologies Patient Focused Innovation
Slide 22: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 22 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 23: T Cell Receptor Pathway and ITK
T Cell Receptor (TCR) Pathway Interleukin-2-inducible T-cell kinase (ITK) is a Key Kinase Involved in TCR Signaling Antigen-presenting cell T-cell Lck LAT Phosphorylation Zap-70 CD3 CD4 MHC Antigen SLP-76 ITK TCR δ ε ε γ α β Ca2+ ER Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Ca2+ Nucleus Cytoplasm Cytoplasm ζ ζ
Slide 24: 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 has a nonredundant role in the differentiation, proliferation and activation of TH2 and TH17 cells • ITK and the Tec kinase TXK are both required for Th1 function Selective b
Slide 25: Comparative Impact of ITK Inhibition
25 Th2 Th17 ILC2 Th1 IL4 IL5 IL13 IL31 IL17 IL21 IL22 IL5 IL13 IFNγ IL2 ITK Inhibitor ITK/TXK Inhibitor αIL-4R αIL-13 αIL-17 αIL-31R JAK1 JAK3 STAT6 Inhibitor Comparative Impact of ITK Inhibition Broad Applicability in Inflammatory/Allergic Pathways
Slide 26: ITK is Therapeutically Relevant But Historically Difficult to Drug
ITK is Therapeutically Relevant But Historically Difficult to Drug 2002 2003 2004 2005 2006 2007 2008 2012 2013 2014 2015 2016 2017 2018 Reversible ATP Competitive Inhibitors Discontinued for Weak Cellular Potency, Poor ADME Compounds targeting the ATP site of ITK have been pursued since the early 2
Slide 27: Issues with ATP Competitive ITK Inhibitors
Issues with ATP Competitive ITK Inhibitors 27 • Generally large, lipophilic molecules with poor physicochemical properties • Poor pharmacokinetic properties in most series • Reactive metabolites with gene tox issues • Variable selectivity against kinome • Ambiguous mechanisms of action in cells • La
Slide 28: Covalent ITK Inhibition Overcoming Biochemical Efficiency Issues
• Design guided by modeling and proprietary crystal structures • Crystal structure to confirm covalent binding characteristics – Designed to interact with the ATP site and covalently modifies CYS442 in ITK • Maximize reversible affinity and minimize electrophile reactivity • Approach overcomes issue
Slide 29: ATI-2138: First Generation ITK/JAK3 Inhibitor
ATI-2138: A First Generation Novel ITK/JAK3 Inhibitor for T Cell-Mediated Diseases Potent and Selective Investigational Drug Candidate with Strong Tolerability Profile Patient Focused Innovation
Slide 30: ATI-2138 Oral Covalent ITK & JAK3 Inhibitor
TCR APC T Cell Proliferation Differentiation Activation γc cytokines JAK3 pSTAT5 ATI-2138 T Cell NK Cell ATI-2138 Oral Small Molecule Covalent ITK & JAK3 Inhibitor for I&I Disease • Investigational oral compound which interrupts T cell receptor (TCR) signaling by inhibiting ITK and JAK3 signaling of
Slide 31: Why this Molecule is Unique
Why this Molecule is Unique 31 Regulation of T cell development and function both upstream (ITK) and downstream (JAK3) High potency for inhibiting both ITK and JAK3 Inhibiting both pathways may provide a more potent and complete anti-inflammatory response As both targets are restricted in expression
Slide 32: ATI-2138 Anti-inflammatory Activity in Mouse Models
ATI-2138 Anti-inflammatory Activity in Mouse Models IBD Mouse T Cell Transfer Vitiligo Score 3 0 6 9 12 15 18 Rheumatoid Arthritis Mouse CIA Model 32 Mean ±SE Clinical Arthritis Score (Scored 0-5) Naïve/Chow Vehicle Chow Enbrel (10 mg/kg) ATI-2138 (100 ppm) ATI-2138 (300 ppm) ATI-2138 (1000 ppm) 21
Slide 33: ATI-2138 Unique Dual Pharmacology vs Ritlecitinib
ATI-2138 Unique Dual Pharmacology and Best-in-Class JAK3 Inhibitor Potential ITK: HWB αCD3 Stimulated IFNγ Release JAK3: HWB IL2 Stimulated IFNγ Release 0.1 1 10 100 1000 10000 0 20 40 60 80 100 120 140 nM IFNg Production (% Stim) ATI-2138 Ritlecitinib 0.1 1 10 100 1000 10000 0 20 40 60 80 100 120 n
Slide 34: ATI-2138 and CPI-818 (Soquelitinib)
ATI-2138 and CPI-818 (Soquelitinib) Best-in-Class ITK Inhibitor Potential • ATI-2138 is 15-38x more potent than CPI-818 in inhibiting the ITK enzyme activity • ATI-2138 is significantly more potent than CPI-818 in blocking the Th2 derived cytokines, IL-4, IL-5 and IL-13 (30-100x) ITK, IC50, nM Kinac
Slide 35: ATI-2138 SAD/MAD Studies Summary
35 Safety Pharmacokinetics Pharmacodynamics • ATI-2138 was generally well tolerated at all doses tested in the trial • No serious adverse events were reported • ATI-2138 was rapidly absorbed • Multiple doses ranging from 10 to 80 mg daily over two weeks in healthy volunteers showed linear PK and dos
Slide 36: Phase 2a Trial in Atopic Dermatitis
Phase 2a Trial in Atopic Dermatitis • Twelve-week, open-label study with ATI-2138 (10mg BID) in moderate to severe AD patients • Favorable safety profile • Efficacy observed across multiple measures comparable to drugs approved for AD • Exposure similar to or slightly higher than predicted from MAD
Slide 37: Phase 2a Efficacy Results
PP-NRS: % of Pts with ≥4 Point Improvement in Worst Itch over Prior 24 Hours Phase 2a Trial in Atopic Dermatitis After four weeks of treatment • BSA decreased by 63.9% • EASI scores dropped by 77.3% • PP-NRS decreased by 44.7% • These changes were statistically significant and sustained through stud
Slide 38: ATI-2138 Mechanistically Unique and PD Supports Efficacy
ATI-2138 is Mechanistically Unique and PD Supports Observed Clinical Efficacy 38 Understanding PK/PD • ITK Assay – αCD3/aCD28 ex vivo stim mRNA (IL-2 and IFNγ) production • ITK Target Occupancy • JAK3 Assay – IL-15 ex vivo stim IFNg protein production • Immunophenotyping Relating PD to Efficacy • Pu
Slide 39: Marked and Sustained ITK Inhibition Observed
Phase 2a Trial in Atopic Dermatitis Marked and Sustained ITK Inhibition Observed 39 Functional inhibition and target occupancy retained across the dosing interval; >90% inhibition IFNγ mRNA and near complete target occupancy observed 1 hour post dose Data collected on 8 of 10 per protocol patients
Slide 40: Gene Set Variation Analysis and Tape Strip Proteomics
Gene Set Variation Analysis (GSVA) Tape Strip Proteomics Data Immune Genes (Extended) Th17 Th2 IgFCH vs Baseline IgFCH vs Baseline Week 4 Week 8 Week 12 Black stars: significance vs baseline Red stars: significance between change in lesional vs. change in non-lesional Th1 Week 4 Week 8 Week 12 Week
Slide 41: Correlation Between Clinical Scores and Gene Expression
Correlation B/W Change in Clinical Scores & in Key Gene Expression Decreases in inflammatory and fibrosis-related markers positively and strongly correlated with improvements in clinical scores CXCL12 TSLP CCL21 R=0.71 p=0.029 R=0.8 p=0.009 R=0.67 p=0.05 GENERAL INFLAMMATION Th2 Th17 SPON1 LUM ELN F
Slide 42: ITK Pathway Mediated Anti-Inflammatory Activity
Phase 2a Trial in Atopic Dermatitis ITK Pathway Mediated Anti-Inflammatory Activity in Skin and Plasma • ATI-2138 significantly downregulated multiple immune pathways in skin and plasma • Strong downregulation of key ITK dependent pathway markers such as: – Th2 (e.g., CCL17, CCL24, IL13, TSLP) – Th1
Slide 43: Next Generation ITK Inhibitors
Next Generation ITK Inhibitors Novel ITK and ITK/TXK Selective Inhibitors Designed to Limit JAK Inhibitory Activity Patient Focused Innovation
Slide 44: Aclaris ITK Inhibitor Program Status Summary
Aclaris ITK Inhibitor Program Status Summary 1 Next Generation Inhibitors st Generation Inhibitors Phase 2a AD study met primary and secondary key endpoints Well tolerated at all doses Validated ITK MOA and corroborates our work on next-generation ITK selective compounds Translatable JAK3 Selectivit
Slide 45: Designing ITK Potency and JAK3 Selectivity
JAK3 Kinase Domain Exploit collapse in G-loop to increase ITK selectivity ITK Kinase Domain Strong interaction with gatekeeper Phe435 increases ITK Potency Phe435 JAK3 G-loop ITK G-loop CYS442 ACRS-2 modeled into ITK kinase domain 3QGY and JAK3 kinase domain 5TOZ SP covalent dock Next Generation ITK
Slide 46: Efficiency and Selectivity in Enzyme-Based Assays
• Next Generation compounds have decreased efficiency against JAK3 and variable efficiency against TXK • Aclaris compounds are significantly more efficient inactivators of ITK as compared to CPI-818 46 Efficiency and Selectivity in Enzyme-Based Assays Aclaris Next Generation Compounds CPI-818
Slide 47: Potency, Occupancy and Selectivity in Human Primary Cells
Human PBMC Cell Data Human Whole Blood Data Compound Target ITK Occupancy (OC90) aCD3 stim IL-2 (IC50) ITK/JAK3 (IC50 Ratio) HWB ITK IC50 CD3/CD28 stim IL-2 mRNA ATI-2138 ITK/TXK/JAK3 1st Generation 17 nM 10 nM 0.1x 17 nM ACRS-1 ITK/TXK 7 nM 7 nM 79x 51 nM ACRS-2 69 nM 34 nM 95x 33 nM ACRS-3 ITK 16
Slide 48: Correlation Between Occupancy and Functional Inhibition
Correlation B/W Occupancy & Functional Inhibition in PBMC 48 Good correlation between functional ITK inhibition and target occupancy Demonstrates potency and occupancy superiority for the ACRS ITK inhibitors vs competitors
Slide 49: Differential Inhibitor Impact on Th1 and Th2 Cell Function
Differential Inhibitor Impact Th1 and Th2 Cell Function • Impact of inhibitors on canonical cytokines from human differentiated Th1 and Th2 cells • ACRS 1 and ACRS 2 block Th1 and Th2 responses through dual inhibition of ITK and TXK • ACRS 3 blocks Th2 responses and spares Th1 through selective inhi
Slide 50: Why is Potency Important with Covalent Drugs?
Why is Potency Important with Covalent Drugs? 50 • Enzyme inactivation efficiency drives drug potency • Higher potency results in lower and less frequent dosing • Lower and less frequent dosing decreases drug burden • Lower drug burden increases selectivity and supports a superior safety profile • C
Slide 51: Next Gen ITK Inhibitors Demonstrate JAK3 Selectivity in Vivo
Next Gen ITK Inhibitors Demonstrate JAK3 Selectivity in Vivo Veh ACRS-2, 10mpk ACRS-2, 30mpk ACRS-2, 100mpk ATI-2138, 45mpk 0 2 4 6 8 10 NK, % of CD45+ ✱✱✱✱ ACRS-1 ACRS-2 ACRS-3 Veh ACRS-1, 10mpk ACRS-1, 30mpk ACRS-1, 100mpk ATI-2138, 45mpk 0 2 4 6 8 NK, % of CD45+ ✱✱✱ ✱✱✱✱ Vehicle ACRS-1 - 10MPK AC
Slide 52: Half-Life Comparison of Compounds
Half-Life Comparison of Compounds Elimination Half-Lives in Mice Aclaris Next Generation compounds demonstrate a significant increase in half-lives in mice as compared to ritlecitinib and CPI-818 More amenable to once-per-day dosing ritlecitinib CPI 818 ACRS 1 ACRS 2 ACRS 3 52
Slide 53: Profiling of Next Generation Compounds
Profiling of Next Generation Compounds ACRS-1 ACRS-2 ACRS-3 Patent applications have been filed on Next Generation compounds Biochemical IC50 and kinact/Ki (ITK, TXK, BTK, and JAK3) hPBMC Cell-Based Assays (Functional and Occupancy) ITK and JAK3 ITK Cell Cytotox IC50 HWB Translatable Functional Biom
Slide 54: Aclaris ITK Inhibitor Program Summary
Aclaris ITK Inhibitor Program Summary • Successfully generated a portfolio of covalent ITK inhibitors with differentiated pharmacological properties and selectivity profiles • These inhibitors expected to differentially modulate T cell biology across a broad range of disease indications and have bes
Slide 55: Next Generation ITK Inhibitor Program Indications
Aclaris Next Generation ITK Inhibitor Program Potentially beneficial in Th1, Th2, and Th17-driven diseases 55 • IBD • Psoriasis • Chronic GvHD • SO Transplant Rejection • Vitiligo • Alopecia • Celiac disease • Eosinophilic esophagitis • Prurigo nodularis • Others IL-4R: Dupixent® (dupilumab) IL-31R:
Slide 56: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 56 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 57: The Science of Antibody Development
The Science of Antibody Development Validating TSLP as an Effective Therapeutic Target Hugh Davis, Ph.D. President and Chief Operating Officer Patient Focused Innovation
Slide 58: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 58 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 59: Targeting Thymic Stromal Lymphopoietin (TSLP)
• Pleiotropic and broad activity – Master regulator of type 2 (Th2) immune responses at the barrier surfaces of skin and the respiratory/ gastrointestinal tract – Drives eosinophilic and neutrophilic inflammation and acts on a wide variety of adaptive, innate, and structural cells – Broad activity:
Slide 60: Driving High Efficacy in Dermatological Disease
Driving High Efficacy in Dermatological Disease High Potency Therapeutics are Key to Effectiveness • Abs must engage ligands at the site of action • Key variables related to efficacy – TSLP concentration at site of lesion – Antibody concentration at site of lesion • Concentration of mAb in general c
Slide 61: Bosakitug (ATI-045): Highly Differentiated Anti-TSLP Antibody
Bosakitug (ATI-045): Highly Differentiated Anti-TSLP Antibody Backbone Best-in-Class Potential Patient Focused Innovation
Slide 62: Bosakitug Key Properties
Bosakitug Key Properties • Very high affinity to TSLP • Extremely low dissociation rate from TSLP* leading to long residence time and enhanced neutralization activity • Very high potency • Unique binding characteristics to TSLP • ~23-day half-life that can potentially support an extended dosing inte
Slide 63: Lower Dissociation Rate = Longer Residence Time
Dissociation of TSLP from mAbs (TR-FRET) 0 1000 2000 3000 4000 0.0 0.5 1.0 Time (min) Fractional Response (yi/yo) ATI-045 ATI-052 GSK-5784283 V1 (hu3-13)* GSK-5784283 V2 (hu179-33)* Solrikitug/MK-8226** Tezepelumab** bosakitug Residence Time (hours) 416 402 14.3 8.11 22.1 3.59 20.7 ATI-052 ATI-045 T
Slide 64: Greater Potency Than Other TSLP/TSLPR Antibodies
70X 6X 5X 9X 2X 3X 1X Tezepelumab* hu3-13 (GSK1)** UPB-101* MK-8226* hu179-33 (GSK2)** ATI-052 ATI-045 IC50 (X∆) vs bosakitug bosakitug 0.1ng/ml TSLP TSLP Stimulated CCL17 Production from hPBMC 0.00001 0.0001 0.001 0.01 0.1 1 10 100 1000 0 20 40 60 80 100 120 140 Antibody (nM) UPB-101 (Verekitug ant
Slide 65: Bosakitug: High affinity, long residence time, high potency
65 Bosakitug High affinity, long residence time, high potency Best-in-Class Potential Greater Potency Requires Lower Concentration to Exhibit the Same Effect
Slide 66: Tezepelumab vs Bosakitug
Tezepelumab vs Bosakitug Relationship of Potency and Exposure to Extent of TSLP Inhibition • The highest dose of Tezepelumab may not cover the IC99 for TSLP at the site of action based on in vitro potency • Bosakitug is expected to cover multiples over the concentration needed for 99% inhibition of
Slide 67: Uniquely Binds Both the N- and C-Terminus of TSLP
MKCLGQSKKEEVSFRKIFILQLVGLVLT28YDFTNCDFEKIKAAYLSTISKDLITYMSGTKSTEFNNTVSCSNRPHCLTEI QSLTFNPTAGCASLAKEMFAMKTKAALAIWCPGYSETQINATQAMKKRRKRKVTTNKCLEQVSQLQGLWRRFNRPLLKQQ159 Signal peptide TSLP binding AA to TSLPR TSLP Hot spot(R149/150/153L156) to TSLPR Projected Bosakitug(ATI-045)binding site Tezepelumab
Slide 68: Bosakitug Potential Best-in-Class Anti-TSLP Antibody
Bosakitug Potential Best-in-Class Anti-TSLP Antibody 68 • Key properties support best-in-class potential – Greater potency than other TSLP/TSLPR antibodies – High affinity anti-TSLP mAb with long, natural half-life of 23 days – Unique binding mechanism, providing very low dissociation from TSLP – Ve
Slide 69: ATI-052: Anti-TSLP x IL-4Rα Bispecific
ATI-052: Anti-TSLP x IL-4Rα First Generation Bispecific Antibody Program Patient Focused Innovation Highly Potent and Bioactive Investigational Product Candidate
Slide 70: Advantages of Multispecific Antibodies
Advantages of Multispecific Antibodies Superior therapeutic window: Enhanced efficacy with favorable safety profile Increased efficacy ceiling via multi-target engagement Reduced therapy resistance Extended dosing regimens drive simplified treatment protocols 70 Access to a projected BsAb global mar
Slide 71: ATI-052: Key Asset Highlights
ATI-052: Key Asset Highlights Potential Best-in-Class Bispecific Anti-TSLP/IL-4Rα mAb ATI-052 YTE mutation Anti-TSLP Fab Anti-IL4Rα scFv CH2 CH3 CH2 CH3 71 • Bispecific utilizing same antibody binding regions of Bosakitug combined with anti-IL-4Rα, inhibiting TSLP upstream and immune cells downstrea
Slide 72: ATI-052 Bispecific Binding Attributes
72 ATI-052 Bispecific Binding Attributes Clinical Opportunity Multispecific Binding Potential Clinical Efficacy Simultaneous Binding of TSLP and IL-4Rα High affinity to both ligands simultaneously: ATI-052 binds two molecules of TSLP and sIL4Rα Effective Binding of TSLP and IL-4Rα ATI-052 binds both
Slide 73: Concurrent Binding of TSLP and sIL4Rα to ATI-052
Concurrent Binding of TSLP and sIL4Rα to ATI-052 High Affinity to Both TSLP and IL-4Rα 73 a ATI-052 Binds Both Targets Effectively High affinity of either ligand is not altered by the binding of the other Comparison of Affinity for sIL-4Rα Binding to ATI-052 or ATI-052:TSLP Complex Comparison of Aff
Slide 74: Simultaneous Binding of TSLP and IL-4Rα
Concurrent Binding of TSLP and sIL4Rα to ATI-052 Simultaneous Binding of TSLP and IL-4Rα 74 a High Affinity to Both Ligands Simultaneously: ATI-052 binds two molecules of TSLP and sIL4Rα TSLP:ATI-052 sIL-4Rα:ATI-052 Binding Sequence Stoichiometry* Stoichiometry* ATI-052 capture / sIL-4Rα dose-respon
Slide 75: Comparison of ATI-052 vs Dupilumab + Tezepelumab
Comparison of ATI-052 vs Dupilumab + Tezepelumab ATI-052 Demonstrates Greater Potency than the mAb Combination ATI-052 is Significantly More Potent than the Combination of Dupilumab and Tezepelumab mAb Concentration [nM] Antibody IC50 (nM) ATI-052 0.016 Dupilumab + Tezepelumab 0.069 Fold change 4.3
Slide 76: Impact of ATI-052 on IL-4 and IL-13 Receptor Activation
Impact of ATI-052 on IL-4 and IL-13 Receptor Activation • IL-4 and IL-13 both bind to a receptor complex composed of the IL-4Rα and IL-13Rα1 • IL-4 also signals through the IL-4Rα and common gamma-chain (γc) • Upon binding, the receptor complex activates the receptor-associated kinases (JAK1 and Tyk
Slide 77: IL-4 vs IL-13 Driven Chemokine Activation
IL-4 Stimulation N=3 Donors IL-13 Stimulation N=4 Donors Stim Concentration [ng/mL] 0.01 0.1 1 10 100 CCL17 [pg/mL] 0 500 1000 1500 2000 IL-4 Appears to be a More Dominant and Consistent Driver of Downstream Chemokine Activation Compared to IL-13 Comparison of CCL17 Levels Induced by IL-4 or IL-13 •
Slide 78: Comparison to Marketed Biologics Inhibiting IL-4/IL-13
Comparison to Marketed Biologics that Inhibit IL-4 +/- IL-13 Signaling 78 Adapted from Lylvyn and Gooderham; Pharmaceutics 2023, 15(2), 568 Markovic and Savvides; Front. Immunol., Vol 11 - 2020 Dupilumab Anti-IL4Rα Lebrikizumab Anti-IL13 Tralokinumab Anti-IL13 TSLP IL-4 IL-13 ATI-052 Anti-TSLP and A
Slide 79: Comparison of IL-4/IL-13 Monoclonal Antibodies
Comparison of IL-4/IL-13 Monoclonal Antibodies IL-4-induced CCL17 release IL-13-induced CCL17 release TSLP-induced CCL17 release IL-4+IL-13-induced CCL17 release Antibody concentration [nM] 0.00001 0.0001 0.001 0.01 0.1 1 10 100 CCL17 (% stim) 0 20 40 60 80 100 120 140 160 Antibody concentration [nM
Slide 80: ATI-052 Summary
ATI-052 Summary • Bispecific antibodies are engineered to have two distinct binding domains that can efficiently bind to two targets simultaneously – ATI-052 has two distinct binding domains that independently bind both TSLP and IL-4Rα with high affinity, efficiency and completeness • YTE mutation i
Slide 81: Developing Next-Generation Bispecific Antibodies
Developing Next-Generation Bispecific Antibodies Patient Focused Innovation
Slide 82: Next Generation Bispecific Antibodies: Optimal Synergies with TSLP
Next Generation Bispecific Antibodies Designing Optimal Synergies with TSLP for I&I Diseases 82 a Critical role of epithelium-derived cytokines in dermatological and respiratory / airway I&I disorders guides design of potent and selective bispecific antibodies Modified from Divekar et al., 2015
Slide 83: Opportunities for Aclaris Next Generation BsAbs
83 0 Pruritis (Itch) Alarmin Combinations Eosinophil-Driven Diseases • TSLP combinations with itch mediators may have a positive impact on itch and QoL in AD and other dermatological diseases • Could impact initiation of allergic response and associated downstream inflammation and enhance anti-viral
Slide 84: Next Generation Bispecific Antibodies Progressing Toward IND
Next Generation Bispecific Antibodies Progressing Toward IND Multispecific Ab development Progressing Toward IND Multispecific approach enables synergistic target binding and addresses shortcomings of multi-drug administration Additional bispecific and trispecific modalities under initial considerat
Slide 85: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 85 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 86: Efficient Clinical Trial Execution and Milestones
Efficient Clinical Trial Execution and Milestones Derisking Small and Large Molecule Assets with Time- and Cost-Efficient Clinical Evaluation Jesse Hall, MD Chief Medical Officer Patient Focused Innovation
Slide 87: Broad Clinical and Preclinical I&I Pipeline
ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 87 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical Development
Slide 88: Innovating in Immuno-Inflammatory Disorders
Aclaris Therapeutics Innovating in Immuno-Inflammatory Disorders Innovation Driven Patient Focused Leadership in I&I/immuno-dermatology Potential Best-in-Class molecules and “white space” Multiple shots on goal with a diversified pipeline Near term catalysts expected in next 6-12 months and beyond A
Slide 89: Broad Immunology Development Pipeline
Broad Immunology Development Pipeline 89 Preclinical Phase 1 Phase 2 Phase 3 Partner Bosakitug (ATI-045) TSLP mAb Subcutaneous Atopic Dermatitis (moderate-to-severe) Severe Asthma CTTQ (China)* Chronic Rhinosinusitis with Nasal Polyps CTTQ (China)* COPD CTTQ (China)* ATI-2138 ITK/JAK3 Inhibitor Oral
Slide 90: Clinical Focus in 2025
Clinical Focus in 2025 Fully integrated Biosion molecules and team members and have continued to build out our clinical capabilities 2025 clinical goals: • Program execution, financial discipline • Establishment of foundation for continued execution in 2026 and beyond Derisking of clinical programs:
Slide 91: Portfolio Execution: Strong Execution in 2025 Creates Packed 2026
Portfolio Execution Strong Execution in 2025 Creates Packed 2026 91 Target Engagement (ex-vivo assay in HV) Top line results from AD Phase 2 Initiation of Phase 2 in 2nd Indication 6-month tox dosing started 3Q25 Phase 1a LPI: complete dosing Preliminary PK results in house IND filed and cleared Pha
Slide 92: ATI-052: Anti-TSLP x IL-4Rα Bispecific Antibody Program
ATI-052: Anti-TSLP x IL-4Rα Bispecific Antibody Program Highly Potent and Bioactive Investigational Product Candidate
Slide 93: ATI-052: Key Asset Highlights
ATI-052: Key Asset Highlights Potential Best-in-Class Bispecific Anti-TSLP/IL-4R mAb ATI-052 YTE mutation Anti-TSLP Fab Anti-IL4Rα scFv CH2 CH3 CH2 CH3 93 • Same antibody binding regions of ATI-045 + IL-4Rα – Retains dissociation kinetics, residence time, and potency advantages • Half-life enhanced:
Slide 94: Placebo Controlled Phase 1a/1b Program Ongoing
Placebo Controlled Phase 1a/1b Program Ongoing 94 Cohort 1: SC, N=8 D1-113 Screening Randomization 3:1 Cohort 3: SC, N=8 D1-113 Cohort 4: SC, N=8 D1-113 Cohort 2: SC, N=8 D1-113 Part A Single Ascending Dose (SAD) in Healthy Volunteers Part B Multiple Ascending Dose (MAD) in Healthy Volunteers Screen
Slide 95: ATI-052 Anticipated Key Learnings and Milestones
95 Key Learnings Expected in 2025 Expected Milestones • Initial PK • Safety and Tolerability • TMDD role • Indications of prolonged exposure • Complete SAD/MAD assessment YE 2025 • SAD/MAD results 1Q 2026 • Initiate Phase 1b POC trial in asthma 1H 2026 • Initiate Phase 1b POC trial in AD 1H 2026 • P
Slide 96: Expected Asthma Phase 1b POC Study Design
96 Placebo (single dose) ATI-052 (single dose) Screening/ Washout Follow-up Randomization 3:1 Active to Placebo Day 28 Efficacy Assessment Primary Endpoint To evaluate the safety and tolerability of ATI-052 compared to placebo in patients with moderate-to-severe asthma Next Steps with ATI-052 Expect
Slide 97: Expected Atopic Dermatitis Phase 1b POC Study Design
97 Screening/ Washout Randomization 3:1 Active to Placebo Primary Endpoint To evaluate the safety and tolerability of ATI-052 compared to placebo in patients with moderate-to-severe atopic dermatitis Next Steps with ATI-052 Expected Atopic Dermatitis (AD) Phase 1b POC Study Design 12 Patients Modera
Slide 98: Bosakitug (ATI-045) Anti-TSLP Monoclonal Antibody Program
Bosakitug (ATI-045) Anti-TSLP Monoclonal Antibody Program Differentiated Investigational Product Candidate with Best-in-Class Potential
Slide 99: Phase 2a POC Monotherapy Trial
Clinical Translation Phase 2a (US-Based) POC Monotherapy Trial 99 Bosakitug 300 mg QW Bosakitug 300 mg Q2W Screening/ Washout up to 30 days 12 Week Follow-up Week 26 (2 weeks after last dose) Primary endpoint analysis Enrolled: 22 subjects (17 completed treatment) at 7 US-based sites Primary Objecti
Slide 100: Bosakitug Exposure and Efficacy Time Profile
Bosakitug Exposure and Efficacy Time Profile Demonstrated Sustained Clinical Response After the Last Dose 0 4 8 12 16 20 24 28 32 0.01 0.1 1 10 100 0 20 40 60 80 100 Time (Week) Concentration (μg/mL) Percent Change from Baseline of EASI Score (%) Last Dose Simulated Mean Conc. Observed Conc. Observe
Slide 101: Bosakitug Demonstrated Improvement in Efficacy Measures
Phase 2a (US-Based) POC Monotherapy Trial Bosakitug Demonstrated Improvement in Efficacy Measures 101 EASI 75 % @ Week 26 EASI 90 % @ Week 26 EASI 100 % @ Week 26 IGA 0/1 @ Week 26 94% 65% 24% 88% % of Patients Achieving Clinical Endpoint 0 10 20 30 40 50 60 70 80 90 100 0 4 8 12 16 20 24 28 32 36 E
Slide 102: Phase 2 Monotherapy Trial Ongoing
Phase 2 Monotherapy Trial Ongoing Dosing Proceeding to Plan 102 Placebo Week 0 & 2 Bosakitug Week 0 & 2 Placebo Q2W, Week 4 through Week 22 Bosakitug 300 mg Q2W, Week 4 through Week 22 Screening/ Washout up to 30 days 12 Week Follow-up Randomization 2:1 Active to Placebo Week 24 (2 weeks after last
Slide 103: Derisking High Placebo Rates in Atopic Dermatitis
Derisking High Placebo Rates in Atopic Dermatitis Defining a New Industry Standard in Eligibility Review Enrolling Patients That Meet Strict Eligibility Criteria Three step process provides robust patient screening prior to randomization Step 1 Standardized Lesion and BSA Photography Step 2 Review b
Slide 104: Next Steps with Bosakitug
Next Steps with Bosakitug Competitively Positioned as Potential Best-in-Class TSLP mAb • Preclinical and clinical data generated to date reinforce the enhanced potency of bosakitug and support further development in dermatological conditions – Two-arm placebo-controlled Phase 2 trial of bosakitug in
Slide 105: ATI-2138: First-Generation ITK/JAK3 Inhibitor
ATI-2138: A First-Generation Novel ITK/JAK3 Inhibitor for T Cell-Mediated Diseases Potent and Selective Investigational Drug Candidate with Strong Tolerability Profile
Slide 106: ATI-2138 Positive Phase 2a Results
ATI-2138 Positive Phase 2a Results Inform Trials in Additional Indications 106 • Positive results from single arm OL Phase 2a trial in AD provide proof of concept: – PD results that validate ITK as a therapeutic target – Favorable tolerability profile of ATI-2138 – Clinically meaningful improvements
Slide 107: ATI-2138 Oral Covalent ITK & JAK3 Inhibitor
ATI-2138 Oral Small Molecule Covalent ITK & JAK3 Inhibitor for I&I Disease • Unique dual pharmacology; best-in-class potential • Potent compound that interrupts TCR signaling by inhibiting ITK and JAK3 signaling of common γ chain cytokines in lymphocytes • Highly selective for both ITK and JAK3 • Is
Slide 108: The Lichen Planus Opportunity
Next Clinical Steps with ATI-2138 The Lichen Planus Opportunity 108 An unaddressed chronic, inflammatory, immune-mediated disorder • Affects skin, mucous membrane, hair and nails; multiple clinical subtypes • Most common symptoms: severe itch, Wickham’s striae, sores, scales/plaques, hair loss, fati
Slide 109: ATI-2138 in Lichen Planus
109 ATI-2138 in Lichen Planus Dual Pharmacology Creates Ideal Mechanistic Fit • Chronic inflammatory skin disease • Aberrant activation of TH1/2/17 and cytotoxic CD8 T-cells • IFN mediated pathology in affected skin • Severe itch associated with IL31 up-regulation • Fibrosis common • Activity demons
Slide 110: Potential Lichen Planus Clinical Program
110 Potential Lichen Planus Clinical Program Next Steps • Complete trial design, market analysis, and TPP of Lichen planus • Finalize assessment of additional potential future targets – Other immunological disorder opportunities based on mechanism may include Hidradenitis suppurativa, Prurigo nodula
Slide 111: Opportunity in Alopecia
Opportunity in Alopecia Market is Rapidly Evolving but Opportunities Remain • Market and competitive landscape dynamics shape indication selection process • Strong mechanistic rationale: JAK3 inhibition shown to be effective in alopecia areata • Multiple types of alopecia exist, some of which are un
Slide 112: Continued Clinical Momentum in 2026
Continued Clinical Momentum in 2026 Four Expected Clinical Programs Bosakitug (ATI-045) Phase 2 in atopic dermatitis ongoing Top line results in 2H 2026 ATI-052 Top line SAD/MAD results in 1Q 2026 Top line Proof-of-Concept results in asthma and AD in 2H 2026 ATI-2138 Phase 2b initiation in second in
Slide 113: Results: Broad Clinical and Preclinical I&I Pipeline
Results: ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 113 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical De
Slide 114: Aclaris Therapeutics
Aclaris Therapeutics Developing Therapeutic Franchises to Address Gaps in Important I&I Diseases Neal Walker, MD Chief Executive Officer Patient Focused Innovation
Slide 115: Results: Broad Clinical and Preclinical I&I Pipeline
z Results: ITK Franchise Antibody Franchise Broad Clinical and Preclinical I&I Pipeline Potential Best-in-Class Inhibitors of Immunoinflammatory Cascade 115 First Generation Next Generation Monoclonal Antibodies Multispecific Antibodies ATI-2138 ITK/JAK3 Phase 2a Complete ITK Selectives Preclinical
Slide 116: 2025/2026: Executing on Rich Clinical Catalyst Calendar
2025/2026: Executing on Rich Clinical Catalyst Calendar 2025 ATI-052 IND Clearance by FDA Bosakitug (ATI-045) Initiation of Phase 2 Trial in Atopic Dermatitis ATI-052 Initiation of Phase 1a/1b Program ATI-2138 Atopic Dermatitis Phase 2a Top Line Data July 2025 ATI-052 Completion of dosing in Phase 1
Slide 117: Aclaris Today
Aclaris Today 117 • Unique State-of-the-Art R&D capabilities and World Class Scientists • Four potential Best-in-Class clinical stage assets in 2026 targeting validated and therapeutically-relevant immune targets highlighted by a potential Best-in-Class bispecific and oral ITK inhibitor • Rich calen
Slide 118: Patient Focused Innovation: 2025 R&D Day
Patient Focused Innovation Developing Therapeutic Franchises to Address Gaps in Important I&I Diseases 2025 R&D Day October 14, 2025