Aclaris Therapeutics, Inc. · NASDAQ:ACRS
Aclaris Therapeutics — Investor Day (December 2021)
78 slides from Aclaris Therapeutics's investor day presentation, Dec 7, 2021
Slide 1: Aclaris Therapeutics Virtual R&D Day: The Productivity of the Platform
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0589 06/21) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Aclaris Therapeutics Virtual R&D Day The Productivity of the Pl
Slide 2: Cautionary Note Regarding Forward-Looking Statements
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as that term is defin
Slide 3: Agenda & Presenters
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Introduction ✓ Portfolio Overview • MK2 Inhibitor Program ✓ Clinical Update on Zunsemetinib (ATI-450), an Investigational MK2 Inhibitor ✓ Role of
Slide 4: Portfolio Overview
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 4 Portfolio Overview
Slide 5: Biopharmaceutical Company Focused on the Kinome: People + Platform + Pipeline
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) LEADERSHIP Founded and Led by Physicians and Scientists • World class ex-Pfizer (kinase) and ex-GSK (immunology) leadership • Kinome experts skille
Slide 6: Drug Development Pipeline
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Drug Development Pipeline Drug Candidate / Program Target Route of Administration Indication Development Phase Immuno-Inflammatory Diseases Zunseme
Slide 7: MK2 Inhibitor Program: Clinical Update on Zunsemetinib (ATI-450)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 7 MK2 Inhibitor Program: ▪ Clinical Update on Zunsemetinib (ATI-450), an Investigational MK2 Inhibitor
Slide 8: Zunsemetinib (ATI-450) Clinical Studies (1)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) ATI-450-RA-202: Adult methotrexate inadequate responders Zunsemetinib (ATI-450) Clinical Studies (1) 8 Moderate to Severe Rheumatoid Arthritis Plac
Slide 9: Zunsemetinib (ATI-450) Clinical Studies (2)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) ATI-450-PsA-202: Adults with moderate to severe Psoriatic Arthritis Zunsemetinib (ATI-450) Clinical Studies (2) 9 Moderate to Severe Psoriatic Arth
Slide 10: KINect Drug Discovery Platform
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 10 KINect® Drug Discovery Platform
Slide 11: KINect Platform: Developing Kinase Drug Candidates Rapidly & Efficiently
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) KINect® Platform Developing Kinase Drug Candidates Rapidly & Efficiently Proprietary Portfolio • MK2 Inhibitors • JAK Inhibitors • ITK Inhibitors S
Slide 12: MK2 Inhibitor Program: Role of MK2 in IL-17 Biology
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 12 MK2 Inhibitor Program: ▪ Role of MK2 in IL-17 Biology
Slide 13: Zunsemetinib Inhibited Proinflammatory Cytokine Production in Human Whole Blood
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 13 TLR4: LPS-Stimulated HWB % Control (LPS - Stim) TLR7/8: R848-Stimulated HWB % Control (R848 - Stim) ATI-450 (mM) 100ng/ml LPS ATI-450 0 1hr 4hr
Slide 14: Does Zunsemetinib Have a Role in IL-17 Biology?
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Understand the role of zunsemetinib in TH17 biology ✓Preclinical cellular studies executed to understand the role of MK2 and zunsemetinib in IL-1
Slide 15: Impact of Zunsemetinib on IL-17 Production in Preclinical Human Cellular Studies
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Impact of Zunsemetinib on IL-17 Production in Preclinical Human Cellular Studies 15 • hPBMC treated with antiCD3/28 for 72 hr • Intracellular IL-17
Slide 16: IL-17 Signal Transduction: Is MK2 Involved?
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) IL-17 Signal Transduction: Is MK2 Involved? 16 MK2 Adapted from Amatya N, et al. Trends Immunol. 2017 May;38(5):310-322.
Slide 17: Zunsemetinib Inhibited IL-17 Activation of the MK2 Pathway
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Zunsemetinib Inhibited IL-17 Activation of the MK2 Pathway in Preclinical Human Cellular Studies 17 hDF cells: pHSP27 • Stimulation of hRASF (not s
Slide 18: Zunsemetinib Inhibited IL-17 Induced IL-8 in a Cell Dependent Manner
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Zunsemetinib Inhibited IL-17 Induced IL-8 in a Cell Dependent Manner in Preclinical Human Cellular Studies 18 hRASF cells: IL-8 hPBMC: IL-8 • IL-17
Slide 19: ATI-2231: an MK2 Inhibitor for Oncology
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 19 MK2 Inhibitor Program: ▪ ATI-2231: an MK2 Inhibitor for Oncology (Investigational Drug Candidate)
Slide 20: ATI-2231: a Novel MK2 Inhibitor
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Designed for decreased metabolism and clearance • Preclinical biochemical/biological potency comparable to zunsemetinib • Planned IND submission
Slide 21: ATI-2231: Potential for Differentiated PK Relative to Zunsemetinib
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • ATI-2231 showed lower clearance and higher AUC in rats compared to zunsemetinib (ATI-450) • Potential for differential dosing levels and interval
Slide 22: ATI-2231: MK2 Inhibition and Target Selectivity
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) ATI-2231: MK2 Inhibition and Target Selectivity Assay ATI-2231 (IC50, nM) Zunsemetinib (IC50, nM) p38/MK2 4.9 (1.3*) 15.6 (1.5*) * Geometric standa
Slide 23: ATI-2231: Cytokine Inhibition from Human Whole Blood
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) ATI-2231: Cytokine Inhibition from Human Whole Blood Stimuli IC50 (nM) from Stimulated Human Whole Blood (HWB) TNFa IL-1b IL-6 IL-8 HWB + LPS 19 +/
Slide 24: ATI-2231: Activity in Murine Collagen-Induced Arthritis
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) ATI-2231: Activity in Murine Collagen-Induced Arthritis 24 • Left: Clinical Arthritis Score: collagen injections on days 1 and 21, dosing begins on
Slide 25: MK2: Distinct Mechanisms in MBC vs. PDAC
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) MK2: Distinct Mechanisms in Metastatic Breast Cancer (MBC) vs. Pancreatic Ductal Adenocarcinoma (PDAC) Blocking Tumor Cell Survival (MBC) vs. Ampli
Slide 26: Metastatic Breast Cancer: A Role for the MK2 Pathway in the Tumor Microenvironment
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 26 Metastatic Breast Cancer: A Role for the MK2 Pathway in the Tumor Microenvironment Sheila Stewart and Cynthia Ma, Washington University School o
Slide 27: Stromal Cells Promote Tumorigenesis
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Stromal Cells Promote Tumorigenesis 27 Stromal (non-tumor) cells • tumor cell proliferation • migration • invasion • angiogenesis • immunosuppressi
Slide 28: The MK2 Pathway is Activated in the Stroma of Primary Breast and Metastatic Bone Lesions
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) The MK2 Pathway is Activated in the Stroma of Both Primary Breast and Metastatic Bone Lesions 28 • Immunohistochemistry reveals phospho-MK2 in prim
Slide 29: Modeling Bone and Visceral Metastasis in the Mouse
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 29 Modeling Bone and Visceral Metastasis in the Mouse • 70% of all metastatic breast cancer patients harbor bone metastasis1 • Patients with bone m
Slide 30: Zunsemetinib Reduced Breast Cancer Bone and Visceral Metastases in Mouse Model
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Zunsemetinib Reduced Breast Cancer Bone and Visceral Metastases in Mouse Model of Disease Vehicle Zunsemetinib Murali B, et al. Cancer Res. 2018 Oc
Slide 31: Zunsemetinib Reduced Breast Cancer Metastases and Preserved Bone
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 31 Zunsemetinib Reduced Breast Cancer Metastases and Preserved Bone Murine Intra-cardiac Tumor Cell Injection Model Zunsemetinib preserved bone qua
Slide 32: Comparison of Zunsemetinib and ATI-2231 in Mouse MBC Model
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Comparison of Zunsemetinib and ATI-2231 in Mouse MBC Model Intra-cardiac injection of Bo-1 PyMT MBC Cells 32 Whole Body Tumor Burden Left: ATI-2231
Slide 33: Proposed Study: Phase 1/2 Trial of ATI-2231 in Metastatic Breast Cancer
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 33 Proposed Study: A Phase 1/2 trial of ATI-2231 in combination with paclitaxel or capecitabine in patients with hormone receptor positive and HER2
Slide 34: The First Trial of ATI-2231 in Metastatic Breast Cancer
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) The First Trial of ATI-2231 in Metastatic Breast Cancer 34 Plan: • Investigator initiated study - DoD grant awarded to investigator • Phase 1/2 tri
Slide 35: Inhibiting MK2 Blocked Tumor Growth in Models of PDAC
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 35 Inhibiting MK2 Blocked Tumor Growth in Models of PDAC Kian Lim Lab, Washington University School of Medicine
Slide 36: MK2 Inhibitor Pancreatic Cancer Update
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Standard of care for PDAC is switching from gemcitabine to FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, oxaliplatin) for preoperative, pos
Slide 37: MK2 Inhibitor Value Proposition
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Unmet Need: There is a significant unmet need in PDAC as FOLFIRINOX is the preferred regimen but not all patients respond and response time is li
Slide 38: MK2 Inhibition Rationale for Pancreatic Cancer
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Lim lab showed that chemotherapy induced stress in PDAC cells is driven by irinotecan and its active metabolite SN381 • SN38 activates MK2/HSP27
Slide 39: Autochthonous Mouse Model of Pancreatic Cancer (KPPC)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Autochthonous Mouse Model of Pancreatic Cancer (KPPC) Zunsemetinib (ATI-450) + Modified FOLFIRINOX Improved Activity 39 • Combination of zunsemetin
Slide 40: ATI-2138 (ITK/TXK/JAK3 Inhibitor)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 40 ATI-2138 (ITK/TXK/JAK3 (ITJ) Inhibitor) (Investigational Drug Candidate)
Slide 41: ATI-2138: Covalent ITJ Inhibitor
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • ATI-2138 covalently blocks ITJ1 ✓ Potential for synergistic efficacy • ITK/TXK required for T-cell receptor (TCR) signaling • JAK3 required for g
Slide 42: Mouse Model: ATI-2138 Showed Activity in mCIA
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Mouse Model: ATI-2138 Showed Activity in mCIA 42 Clinical Arthritis Score Joint Histology Score In the gold standard mCIA model, ATI-2138 demonstra
Slide 43: Mouse Model: ATI-2138 - T Cell Transfer Colitis
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Mouse Model: ATI-2138 - T Cell Transfer Colitis 43 0 47 28 CD4+CD45RBhigh naïve T cells IP injected to SCID mice Randomize/Dosing begins • Control
Slide 44: ATI-2138: Phase 1 Clinical Plan
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Placebo-controlled, randomized, observer-blind single ascending dose trial in healthy volunteers ✓ Study initiation expected December 2021 ✓ Endp
Slide 45: Oral Gut-Biased JAK Inhibitors for IBD: CDD-2603 and CDD-2676
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 45 Oral Gut-Biased JAK Inhibitors for Inflammatory Bowel Disease: CDD-2603 and CDD-2676 Development Candidates (Investigational Drug Candidates)
Slide 46: Drugs for Inflammatory Bowel Disease (IBD)
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Autoimmune diseases are most commonly treated with broadly immune suppressive drugs (e.g., steroids, JAK inhibitors, anti-TNFa biologics) with sy
Slide 47: JAK Inhibitors for IBD
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Xeljanz® (tofacitinib) approved for ulcerative colitis (UC)1, fails initial trials in Crohn’s disease (CD)2 ✓ 9/2021: Updated FDA Warnings for al
Slide 48: GB Candidate Identification Strategy
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 1. Design compounds with gut-biased potential o Potent against JAK kinases o Low-moderate permeability o Lipophilic with high rates of efflux o Mod
Slide 49: T Cell Adoptive Transfer (TCT) Mouse Model and Readouts
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) T Cell Adoptive Transfer (TCT) Mouse Model and Readouts Day 0 Day 21 Day 49 Disease development Dosing, body weight measurements Q2W • Day 0: Naïve
Slide 50: Intestinal Geography
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Intestinal Geography 101 50 • TCT model primarily thought of as UC model (colon damage), but damage also seen in the ileum – thus relevant to CD as
Slide 51: Evaluation of Systemic Effects in Mouse Model - Spleen
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Evaluation of Systemic Effects in Mouse Model - Spleen 51 CD25 CD4 Vehicle1 Tofacitinib1 • CD62Lhi (L-selectin) naïve T cells are transferred into
Slide 52: Evaluation of Systemic Effects in Mouse Model - Blood
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Evaluation of Systemic Effects in Mouse Model - Blood • At study end, after 4 weeks of dosing – blood is stimulated with IL-2 and IL-12 for 30 min
Slide 53: Compound Testing in Mouse Models
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Positive control: Tofacitinib dosing was optimized in the TCT model to be commensurate with its dosing clinically • Theravance drug candidate: TD
Slide 54: Xeljanz (tofacitinib), an FDA Approved JAK Inhibitor for UC
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 54 Xeljanz® (tofacitinib), an FDA Approved JAK Inhibitor for the Treatment of UC * All trademarks are the property of their respective owners.
Slide 55: Tofacitinib Efficacy and PK in UC Phase 3 Clinical Trial
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Tofacitinib Efficacy and PK in UC Phase 3 Clinical Trial 55 • Left: Mucosal healing after 52 weeks (remission data looks similar) • Right: Average
Slide 56: Tofacitinib PK and Activity in TCT Mouse Model
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Tofacitinib PK and Activity in TCT Mouse Model 56 V e h i c l e T o f a - 1 8 0 V e h i c l e T o f a - 1 8 0 V e h i c l e T o f a - 1 8 0 0 1 2 3
Slide 57: Theravance TD-1473: Gut-Selective JAK Inhibitor
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 57 Theravance TD-1473: Gut-Selective JAK Inhibitor
Slide 58: TD-1473 Mouse PK
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) TD-1473 Mouse PK • Consistent with Theravance findings1, after oral dosing in mice, TD- 1473 achieved high concentrations in the ileum and colon, w
Slide 59: TD-1473 TCT Mouse Model Data - In Life and Ex Vivo
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Unlike tofacitinib, TD-1473 at all doses failed to prevent weight loss during TCT studies – a predictor of efficacy • Splenic CD4+ cells have sig
Slide 60: TD-1473 TCT Mouse Model Data - Histology
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) TD-1473 TCT Mouse Model Data - Histology 60 • Histological activity demonstrated in all tissues analyzed with tofacitinib • TD-1473 did not demonst
Slide 61: Theravance TD-1473: Learnings from Aclaris Preclinical Studies
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Consistent with Theravance findings1, TD-1473 primarily resides in the ileum > colon >> plasma2 • In life systemic activity measures (splenic CD4
Slide 62: CDD-2603: Aclaris JAK GB Development Candidate
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 62 CDD-2603: Aclaris JAK GB Development Candidate
Slide 63: CDD-2603: Mouse PK/Human PBMC Potency
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2603: A JAK GB Development Candidate Mouse PK/Human PBMC Potency At all time points in mouse after dose of 5 mg/kg PO, drug concentrations in t
Slide 64: CDD-2603 TCT Mouse Model: Body Weight Changes
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2603 TCT Mouse Model: Body Weight Changes 64 • In both TCT studies with CDD-2603, dosing begins on day 21, ends on day 49 • In life body weight
Slide 65: CDD-2603 TCT Mouse Model: Histological Activity
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2603 TCT Mouse Model: Histological Activity 65 In repeat TCT studies, CDD-2603 produced histological activity in all regions of the colon and i
Slide 66: CDD-2603 TCT Mouse Model: Minimal Systemic Effects
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2603 TCT Mouse Model: Minimal Systemic Effects 66 • Left: Tofacitinib induced a dose dependent decrease in the percentage of splenocytes that a
Slide 67: CDD-2676: Aclaris JAK GB Development Candidate
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 67 CDD-2676: Aclaris JAK GB Development Candidate
Slide 68: CDD-2676: Mouse PK/Human PBMC Potency
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2676: JAK GB Development Candidate Mouse PK/Human PBMC Potency 68 Plasma and intestinal PK of CDD-2676 in mice after 5 mg/kg PO dose show that
Slide 69: CDD-2676 TCT Mouse Model: Body Weight Changes
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2676 TCT Mouse Model: Body Weight Changes 69 • In both TCT studies with CDD-2676, dosing begins on day 21, ends on day 49 • In life body weight
Slide 70: CDD-2676 TCT Mouse Model: Histological Activity
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2676 TCT Mouse Model: Histological Activity 70 • In both TCT studies, CDD-2676 produced histological activity in the ileum down to 100 ppm (abo
Slide 71: CDD-2676 TCT Mouse Model: Minimal Systemic Effects
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) CDD-2676 TCT Mouse Model: Minimal Systemic Effects 71 • Left: Tofa induces a dose dependent decrease in the percentage of splenocytes that are CD62
Slide 72: CDD-2603 and CDD-2676: 7 Day Rat Toxicology
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Both GB development candidates have completed 7 day dose-range finding study in rats at doses of 30, 100 and 300 mpk; no adverse events • TK conf
Slide 73: Summation: Histological Activity vs. Systemic Activity in Mice
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Summation: Histological Activity vs. Systemic Activity in Mice 73 • Activity in IBD defined by histological improvement: Reduced sum scores = prote
Slide 74: Oral JAK GB Candidate - Summary and Plans
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Two JAK GB development candidates with histological activity in a murine IBD model comparable to tofacitinib have been identified • Within the sa
Slide 75: Closing Remarks and Q&A
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) 75 Closing Remarks and Q&A
Slide 76: R&D Day Key Takeaways
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) • Zunsemetinib ✓ Phase 2 programs are on track • Three phase 2 studies planned in RA, HS, and PsA ✓ Planning to add 2 programs ✓ Recent preclinical
Slide 77: Key Milestones
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) Key Milestones Program/Milestone 2021 2022 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q Zunsemetinib (ATI-450): MK2 Inhibitor Phase 2a Data in Moderate to Severe Rheuma
Slide 78: Presenters and Management Biographies
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0677 12/21) •Co-founded Aclaris in 2012 •Board-certified dermatologist •Serial entrepreneur with over 20 years of experience in the life sciences industry Neal