Aclaris Therapeutics, Inc. · NASDAQ:ACRS
Aclaris Therapeutics — Technical Presentation (July 2025)
28 slides from Aclaris Therapeutics's technical presentation, Jul 29, 2025
Slide 1: ATI-2138 Phase 2a Top-Line Results
ATI-2138 Phase 2a Top-Line Results July 29, 2025
Slide 2: Disclaimer and Cautionary Note Regarding Forward-Looking Statements
2 Disclaimer and Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release 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 b
Slide 3: ATI-2138 Oral Small Molecule Covalent ITK & JAK3 Inhibitor for I&I Disease
3 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 common γ chain cytokines in lymphocytes (including IL-2 & IL-15) • Highly potent for both ITK and JAK3
Slide 4: ATI-2138 Covalently Inhibits ITK and JAK3
4 ATI-2138 Covalently Inhibits ITK and JAK3 • Design guided by modeling and proprietary crystal structures • Designed to interact with the ATP site and covalently modifies CYS442 in ITK and CYS909 in JAK3 • Other oral drugs have successfully targeted this positional cysteine – Ritlecitinib (JAK3), I
Slide 5: ATI-2138 Unique Dual Pharmacology and Best-in-Class JAK3 Inhibitor Potential
5 ATI-2138 Unique Dual Pharmacology and Best-in-Class JAK3 Inhibitor Potential • ATI-2138 is 44.4x more potent than ritlecitinib for inhibiting anti-CD3 induced IFNγ production (ITK) and 5.4x more potent for inhibiting JAK3 dependent IL-2 induced IFNγ production in human whole blood • At the FDA rec
Slide 6: ATI-2138 and CPI-818 (Soquelitinib) Potency Comparison
6 ATI-2138 and CPI-818 (Soquelitinib) Potency Comparison • 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, IL4, IL-5 and IL-13 (~100x) ITK, IC50, nM Kinact/Ki (uM-1s-1) ATI-2
Slide 7: ATI-2138 Anti-inflammatory Activity in Mouse Models of IBD and Vitiligo
7 ATI-2138 Anti-inflammatory Activity in Mouse Models of IBD and Vitiligo ATI-2138 has demonstrated robust anti-inflammatory activity in mouse models of disease
Slide 8: ATI-2138: SAD/MAD Study Summary
8 • Dose-dependent inhibition of both ITK and JAK3 exploratory PD biomarkers was observed. • 50% to 90% inhibition of the ITK and JAK3 functional markers observed. ATI-2138: SAD/MAD Study Summary • ATI-2138 was generally well tolerated at all doses tested in the trial. • No serious adverse events we
Slide 9: ATI-2138 Phase 2a Trial Design in Atopic Dermatitis
9 ATI-2138 Phase 2a Trial Design in Atopic Dermatitis Single-Arm, Open-Label Trial Screening ~30 days Follow-up 2 weeks ATI-2138 (10mg BID) Treatment Period: 12 Weeks Week 12 Efficacy endpoint analysis 14 enrolled patients Moderate-to-Severe Atopic Dermatitis PRIMARY OBJECTIVE • Safety SECONDARY/EXP
Slide 10: Phase 2a: Patient Demographics
10 Phase 2a: Patient Demographics Age Sex M0,F1 Race Baseline EASI 56 F White 16.5 34 M Mixed-multiple 33.5 50 M Black or African American 17.6 28 F Black or African American,White 16.8 20 M Not Reported 19.2 19 F White 28.1 22 F Asian 23.7 56 M Black or African American 16.8 44 F Black or African A
Slide 11: Primary Endpoint (Safety): Strong Tolerability Profile of ATI-2138
11 Phase 2a Results: Primary Endpoint (Safety) Primary Endpoint Analysis Confirms Strong Tolerability Profile of ATI-2138 • ATI-2138 was very well tolerated in the 12 patients in the safety population – No severe adverse events (SAEs) or treatment-emergent adverse events (TEAEs) – No discontinuation
Slide 12: Secondary Endpoints (EASI) % Reduction from Baseline
12 Phase 2a Results: Secondary Endpoints (EASI) % Reduction from Baseline in Eczema Area and Severity Score (EASI) Over Time, Per Protocol (N=10) Mean improvement in EASI score 12 weeks 61% Median improvement in EASI score 12 weeks 77% EASI = Eczema Area and Severity Score: Measures the extent and s
Slide 13: Secondary Endpoints (EASI) Absolute Mean Reduction by Patient
13 Phase 2a Results: Secondary Endpoints (EASI) Absolute Mean Reduction Over Time by Patient, Per Protocol EASI = Eczema Area and Severity Score: Measures the extent and severity of lesional skin associated with atopic dermatitis across different body regions Outlier (in red) • Statistical molecular
Slide 14: EASI Score Excluding Outlier
14 Phase 2a Results: EASI Score Excluding Outlier % Reduction from Baseline in Eczema Area and Severity Score (EASI) Over Time Mean improvement in EASI score 12 weeks 77% Median improvement in EASI score 12 weeks 82% EASI = Eczema Area and Severity Score: Measures the extent and severity of lesional
Slide 15: Secondary Endpoints (PP-NRS) Itch Improvement
15 Phase 2a Results: Secondary Endpoints (PP-NRS) % of Patients with ≥4 Point Improvement in Worst Itch over Prior 24 Hours Note: Each other compound efficacy is the average percent improvement from multiple studies, at week 12 or 16 data from Phase 2 and Phase 3 published sources; head-to-head clin
Slide 16: Secondary Endpoint Pharmacodynamic Assessments
16 ITK Assay • CD3/CD28 ex vivo stim mRNA (IL2 and IFNγ) production ITK Target Occupancy JAK3 Assay • IL15 ex vivo stim IFN protein production Immunophenotyping Punch Biopsy Analysis • Immunohistochemistry • RNAseq Analysis (>16,000 genes) Tape Strip Analysis • RNAseq Analysis (>16,000 genes) • O
Slide 17: Ex vivo Stimulated ITK HWB Assays
17 Phase 2a Results: Ex vivo Stimulated ITK HWB Assays ITK-TCR Assay – IL2 mRNA ITK-TCR Assay – IFNγ mRNA • ~90% inhibition of both IL2 and IFN mRNA observed 1 hr post dose (~peak) across the 12 weeks of dosing • 40-60% inhibition of both IL2 and IFN mRNA observed at trough across the 12 weeks of
Slide 18: ITK Target Occupancy with ATI-2138
18 Phase 2a Results: ITK Target Occupancy with ATI-2138 • Utilized biotinylated ITK probe with MSD readout using patient PBMCs • Data collected on 7 of the 10 per protocol patients • Near complete ATI-2138 ITK target occupancy observed one hour post-dose (~peak) across the 12 weeks of dosing • Appro
Slide 19: ATI-2138-AD-201 JAK3 PD Data
19 ATI-2138-AD-201 JAK3 PD Data ATI2138 (ng/ml) 0.01 0.1 1 10 100 1000 IL15 Stim IFN Protein (% Predose - All data) 0 50 100 150 200 All PD from ATI-2138-MAD Trial All PD from ATI-2138-AD-201 Trial Exposure Response Overlay of Phase 2a (ATI-2138-AD-201) and MAD Studies • ~80% inhibition of JAK3-ind
Slide 20: Week Week Week Week Fol ow-up 2000 4000 6000 000 10000 Leukocytes (cells/uL) Visit
20 Week 1 Week 4 Week 8 Week 12 Fol ow-up 0 2000 4000 6000 8000 10000 Leukocytes (cells/uL) Visit Cells/μL Week 1 Week 4 Week 8 Week 12 Fol ow-up 0 500 1000 1500 2000 2500 T cells (cells/uL) Visit Cells/μL Week 1 Week 4 Week 8 Week 12 Fol ow-up 0 500 1000 1500 CD4+ T cells (cells/uL) Visit Cells/μL
Slide 21: Plasma O-Link Analysis Immune Subset Week 12 vs Baseline
21 Key Modulated Markers*: Th1: IL8, IL2RA, IL2 Th2: CCL13, CCL17, CCL24, IL4, IL33, IL7 Th17: CXCL1, PI3, TGB1 T cell activation: XCL1, IL1RL2 *significance observed at any timepoint • Evaluations at baseline, week 4, week 8 and week 12 Phase 2a Results: Plasma O-Link Analysis Immune Subset Week 12
Slide 22: Skin Tape Strip O-Link Analysis Immune Protein Subset
22 Key Modulated Pathway Markers*: Th1 CCL3, CXCL9, CXCL11, TNF, IL2RA Th2 IL13, TSLP Th17 IL17A, CXCL1, S100A12, TGFB1, IL6R T cell activation /Immune Signaling CCL19, IL17C, CCL8, CCL16, , CCL15, CCL23, TNFSF10 Fibrosis TNFRSF9 *significant in any comparison • Evaluations at baseline, week 4, week
Slide 23: Skin Biopsy RNAseq Immune Pathway Modulation Week 12 vs Baseline
23 • Downward directional trends observed with key pathways • Biopsy pathway modulation consistent with tape strip data Phase 2a Results: Skin Biopsy RNAseq Immune Pathway Modulation Week 12 vs Baseline Downward trends observed in mRNA markers associated with key immunologic pathways at week 12; dow
Slide 24: Skin Biopsy RNAseq Analysis TCR (ITK) and JAK3 Pathways
24 Phase 2a Results: Skin Biopsy RNAseq Analysis TCR (ITK) and JAK3 Pathways • Heat map describes impact on both (TCR) ITK and JAK3 pathways at week 12 • Similar to tape strip RNAseq data Reduction observed in mRNA markers consistent with the expected ITK and JAK3 dual pharmacology Biopsies from 5 P
Slide 25: Phase 2a Conclusions: Secondary Endpoint (PD Assessments)
25 Phase 2a Conclusions: Secondary Endpoint (PD Assessments) Results Support Conviction in Therapeutic Potential of ITK Inhibition • PD analyses clearly demonstrate modulation of the ITK and JAK3 pathways as evidenced by inhibition of ex vivo pathway specific stimulation of patient whole blood • Nea
Slide 26: Next Steps with ITK Franchise
26 Next Steps with ITK Franchise • Positive results from single-arm Phase 2a open-label trial of ATI-2138 in AD validate ITK franchise; provide conviction on two programs: – ATI-2138 • Aclaris intends to further develop ATI-2138 in alopecia areata • Also exploring other indications relevant to the m
Slide 27: Executing on Rich Clinical Catalyst Calendar
27 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 1a SAD/MA
Slide 28: ATI-2138 Phase 2a Top-Line Results
ATI-2138 Phase 2a Top-Line Results July 29, 2025
Aclaris Therapeutics — Technical Presentation (July 2025) on 6ix