Aclaris Therapeutics : ATI-450-RA-201 Phase 2a Preliminary Topline Data Presentation

EMPOWERING PATIENTS THROUGH

KINOME INNOVATION

ATI-450-RA-201

ATI-450-PKPD-102

January 2021

Preliminary Topline Analyses

© Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0544 01/21)

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," "potential," "will," and similar expressions, and are based on Aclaris' current beliefs and expectations. These forward-looking statements include expectations regarding ATI-450 as a potential treatment for rheumatoid arthritis and the clinical development of ATI-450, including the further development at higher doses. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ materially include uncertainties inherent in the conduct of clinical trials, risks and uncertainties associated with preliminary trial results varying from final results, Aclaris' reliance on third parties over which it may not always have full control, the uncertainty regarding the COVID-19pandemic including its impact on the timing of Aclaris' regulatory and research and development activities, and other risks and uncertainties that are described in the Risk Factors section of

Aclaris' Annual Report on Form 10-K for the year ended December 31, 2019, Aclaris' Quarterly Report on Form 10-Q for the quarter

ended September 30, 2020 and other filings Aclaris makes with the U.S. Securities and Exchange Commission from time to time. These documents are available under the "SEC Filings" page of the "Investors" section of Aclaris' website at http://www.aclaristx.com. Any forward-looking statements speak only as of the date of this presentation and are based on information available to Aclaris as of the date of this presentation, and Aclaris assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise

This presentation also contains estimates and other statistical data made by independent parties and by us relating to market size and other data about our industry. These data involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such estimates. In addition, projections, assumptions and estimates of our future performance and the future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.

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Biotechnology Company Focused on the Kinome:

People + Platform + Pipeline

LEADERSHIP

Founded and Led by Physicians and Scientists

• World class ex-Pfizer (kinase) and ex-GSK (immunology) leadership
• Kinome experts skilled at developing kinase targeted medicines

KINectTM

PLATFORM

Proprietary Kinase

Discovery Engine

• Versatile platform
• Fully integrated discovery and development team
• Advancing small molecule drug candidates designed to parallel or exceed efficacy of high-value biologics

INNOVATIVE PIPELINE

(investigational drug candidates)

ATI-450 - MK2i

• Oral anti-TNFα,anti-IL1, anti- IL6

ATI-1777 - Topical "Soft"

JAK1/3i

• Tissue specific therapy for the potential treatment of moderate-to-severe atopic dermatitis (AD)

ATI-2138 - ITK/TXK/JAK3i

• Oral dual inhibitor of T-cell and cytokine receptors

Development of Small Molecule Therapeutics for Immuno-inflammatory Diseases

* All trademarks are the property of their respective owners.	3
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Experienced R&D Leadership Team

Proven Track Record in Immunology and Inflammation

• Former SVP, R&D at GSK.
• Led discovery and development teams in Immuno-Inflammation and Dermatology leading to multiple successful NDAs, including NUCALA® &
  BENLYSTA®

• Former Executive Director,	• Former VP Research &
Pfizer Inflammation Research	Global Head, Pfizer
and Leader of Global Kinase	Inflammation,
Technology Team	co-leader of Pfizer Licensing
• >95 publications and patents	Team
(>30 total on kinases)	• Delivered 8 clinical
	candidates, 6 INDs and 1
	NDA in inflammation and
	cancer

• Former Research Fellow and Director, Pfizer Chemistry
• >100 publications and patents (15 total on kinases)
• Project Lead for PFE JAK Program

	David Gordon		Joseph Monahan,		Walter Smith		Jon Jacobsen,
		PhD		Scientific & BD		PhD
	Chief Medical Officer
		Chief Scientific Officer		Consultant		VP, Chemistry

• Immunologist/drug discovery leader at pharma (Pfizer & biotech)
• Validated JAK 1/3 as target for transplant/RA/psoriasis, leading to approval of
  XELJANZ®

• Former research project leader at Pfizer. Director of Chemistry at Mnemosyne, Luc, Cadent.
• Inventor of 6 clinical candidates and author of 40 peer reviewed publications and patents

• Former Exec. Director, Pfizer. Site Head for Medicinal & Structural Chemistry.
• >100 patents.
• Co-inventorof multiple drug candidates

Paul Changelian,		David R Anderson,		Gary DeCrescenzo
	PhD Sr. Director,
PhD
	Discovery, Early		SVP, Pharm R&D
VP, Biology
	Development

* All trademarks are the property of their respective owners.	4
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Strategic Focus

Leverage Kinome Target Discovery to Address Unmet Needs

Advance the process of identifying and targeting key kinome-based enzymes involved in chronic inflammation and autoimmune disease.

Model, elaborate and assess compounds through a unique combination of our proprietary chemical library of kinase inhibitors, our expertise in structure-baseddrug design, and our custom kinase assays.

Validate newly created drug candidates through pathophysiologically-

relevant custom assays that effectively translate to human diseases.

Leverage research and commercial partnerships to accelerate the clinical evaluation and potential impact of discovery platforms.

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ATI-450: Investigational Small Molecule, Oral MK2 Inhibitor

Designed to Block the Targets of Broadly-Used Biologics

• MK2* drives pro-

inflammatory cytokine

Inhibiting MK2 blocks TNFα, IL1α/β and IL61, the targets of commercially successful biologics

	expression
•	By inhibiting multiple
	cytokines, ATI-450 may be a
	potential treatment for
	multiple diseases
•	Potential alternative to
	injectable, anti-cytokine
	biologics and JAK inhibitors

Rheumatoid arthritis

Juvenile Idiopathic

Arthritis

Ankylosing spondylitis

CAPS

Psoriatic Arthritis

Psoriasis

Neutrophilic Dermatoses (Hidradenitis Suppurativa)

Inflammatory Bowel

Disease

for immuno-inflammatory

diseases

Gout

Cancer

Global immunology market valued at >$77B in 20182

* MK2 = Mitogen-activated protein kinase-activated protein kinase 2
1.	Data on file.
2.	Fortune Business Insights. Accessed January 18, 2021.https://www.fortunebusinessinsights.com/industry-reports/immunology-market-100657.	6
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Evolution in Understanding a Well-Known Inflammatory Pathway

The Path From p38α to MK2

We believe MK2 is the optimal

drug target in the p38 pathway toINFLAMMATION/STRESS maximize anti-inflammatory

efficacy and minimize toxicity

• • Global p38α inhibitors have exhibited toxicity and/or lack of sustained efficacy in RA and IBD
  • • Inability to dose escalate due to safety
    • Signaling network reprogramming
    • Downregulation of anti-inflammatory cytokines
  • MK2 drives the proinflammatory node of this pathway while p38α phosphorylates over 60 substrates
  • MK2 has been a high priority therapeutic target since 1999 but has proven very difficult to drug
• Wang C, et al. J Exp Med. 2018;215(5):1315-1325.
• Cheung P, et al. EMBO J. 2003;22(21):5793-5805.
• Muniyappa H, et al. Cell Signal. 2008;20(4):675-683.
• Ma W, et al. J Biol Chem. 2001;276(17):13664-13674.

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p38α

Anti-		Pro-		Negative		Cellular
inflammatory		inflammatory		Feedback		Function

e.g., CREB,	MK2	e.g., TAB1,
C/EBPβ, SP1	CREB

TNFα IL1β IL6 IL8

7

p38 Inhibitors: Tachyphylaxis in RA Clinical Trials

Transient CRP Reduction

Pamapimod + MTX vs. Placebo + MTX1	SCIO-469 vs. Placebo2

304: VX-702 + MTX vs. Placebo + MTX3

Transient CRP reduction in multiple trials

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1.	Alten RE, et al. Ann Rheum Dis. 2010;69(2):364-367.	8
2.	Genovese MC, et al. J Rheumatol. 2011;38(5):846-854.
3.	Damjanov N, et al. Arthritis Rheum. 2009;60(5):1232-1241.

Overview

• ATI-450development program consists of:
• • Rheumatoid Arthritis
  • CAPS
  • COVID-19
  • MAD cohort extension (80mg BID, 120mg BID)
• Today's update:
• • Progress on RA-201: summary of topline data
  • MAD cohort extension (80mg and 120mg BID)

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ATI-450-RA-201

Preliminary Topline Data Analysis

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Trial Design

• Diagnosis of adult-onset RA (ACR/EULAR classification criteria)
• DAS28-CRP≥3.2 defined as moderate to high disease activity
• Moderately to severely active RA defined by at least 4/28 tender and 4/28 swollen joints
• hsCRP ≥5 mg/L at screening
• Definitive intra-articular synovitis or osteitis defined as a score of 1 or greater on a Hand-Wrist MRI (using RAMRIS)
• Stable MTX dose (defined as 7.5 mg to 25 mg weekly) for at least 4 weeks prior to the screening visit

			RANDOMIZATION (3:1)
	ARM 1					ARM 2
ATI-450, 50 mg BID + MTX					Placebo, BID + MTX

12 weeks

Primary Objective: Safety

N-25

(to get 15

completers)

Secondary Objectives

• % change from baseline in hsCRP
• Mean change from baseline in DAS28-CRP
• Proportion of patients with DAS28-CRP below 2.6
• Mean change in RAMRIS assessments of synovitis or osteitis
• Proportion of patients with ACR 20/50/70

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Key Demographics

Parameter	Placebo (n=3)	ATI-450 (n=16)
	Median (Min - Max)	Median (Min - Max)
Age (years)	53 (50 - 63)	59.5 (32 - 65)
Gender	(F) 3/3 (100%)	(F) 11/16 (68.75%)
(M) 0/0 (0%)	(M) 5/16 (31.25%)
Weight (kg)	105.4 (82.2 - 109.2)	88.15 (52.7 - 141.5)
Duration of Disease	1.6 (0.3 - 20.6)	6.45 (0.3 - 33.4)
hsCRP (mg/L)	21.3 (12.6 - 31.2)	11.7 (2.6 - 29.5)
DAS-28	5.3 (5.3 - 6.7)	5.65 (3.9 - 7.4)
	Mean (SD): 5.77 (0.808)	Mean (SD): 5.71 (0.937)

• 19 subjects randomized (16 ATI-450, 3 PBO)
• Broad range of disease duration 0.3 - 33.4 years
• • High hsCRP despite long history and multiple treatment options
• 2 Withdrawals
• • Placebo: subject required prohibited meds for musculoskeletal pain
  • ATI-450:subject evaluated for palpitations and elevated CPK - no cardiac event

* Data on file	12

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DAS28-CRP

Mean Change From Baseline

Numbers on lines = no. of subjects at each timepoint

* Data on file	13

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Swollen Joint Count

Median Percent Change From Baseline

Numbers on lines = no. of subjects at each timepoint

* Data on file	14

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Tender Joint Count

Median Percent Change From Baseline

Numbers on lines = no. of subjects at each timepoint

* Data on file	15

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Subjective Physician & Patient VAS Scores

Median Percent Change

percentage

				Patient: Disease			Patient: Arthritic Pain
				Activity
30										30
									10
10
-10										-10		1 28	56 84	Visit	day
	1 7 14 28	42 56 84	Visit day	percentage		percentage
	-30
-30
		ATI-450			placebo				ATI-450			placebo

Physician: Disease

Activity

	50
	30
	10
	-10
	1	28	56	84
percentage	-30
-90
	-50
	-70							Visit day
				ATI-450		placebo

Patient: HAQ-DI

30

10

-10	1 28 56 84 Visit day

-30

ATI-450 placebo

* Data on file

HAQ-DI= Health Assessment Questionnaire-DisabilityIndex16 © Copyright 2021 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0544 01/21)

ACR20/50/70: Responder Analysis over time

* Data on file	17

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DAS28-CRP: Responder Analysis over time

DAS-28 Responders

Percentage response

45

40

35

30

25

20

15

10

5

0

1	7	14	28	42	56	84
		DAS28<2.6		DAS28<=3.2			DAS28<2.6		DAS28<=3.2

ATI-450	placebo
* Data on file	18

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hsCRP (mg/L)

Median Percent Change From Baseline

Numbers on lines = no. of subjects at each timepoint

* Data on file	19

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RA Patients Treated with ATI-450 for 12 Weeks

Ex Vivo LPS-Stimulated Cytokines Day 1 vs Day 84

Hypothesis: p38 transient efficacy (tachyphylaxis) may be associated with feedback loops and

pathway reprogramming. Selectively targeting MK2 inhibition circumvents these issues

through selective downstream pathway blockade.

Durable Dependence on MK2 for Cytokine Production

Interim Data N=11 Active, 2 Pbo
* Data on file as of December 10, 2020.	20
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Impact of ATI-450 on Endogenous Plasma Cytokine Levels in RA-201

TNFα, IL6, IL8 and MIP1β

• Cytokines with endogenous levels <0.5 pg/ml predose:IL1β, IL10, IL4 and GM-CSF

* Data on file

21

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Adverse Events: Subjects with at least one event

	ATI-450 50 mg BID (N = 16)	Placebo (N = 3)
Preferred Term	Mild	Moderate	Mild	Moderate
	n(%)	n(%)	n(%)	n(%)
Blood cholesterol increased	1(6.25)	0
Blood creatine phosphokinase increased	0	1(6.25)
Constipation	1(6.25)	0
Dental caries			1(33.33)	0
Ear infection	1(6.25)	0
Electrocardiogram abnormal	1(6.25)	0
Essential hypertension	0	1(6.25)
Hyperlipidaemia	0	1(6.25)
Hypokalaemia	0	1(6.25)
Ligament sprain	1(6.25)	0
Low density lipoprotein increased	1(6.25)	0
Mouth ulceration	1(6.25)	0
Muscle strain			0	1(33.33)
Palpitations	1(6.25)	0
Rash erythematous	1(6.25)	0
Sinusitis	0	1(6.25)
Skin abrasion	1(6.25)	0
Urinary tract infection	0	2(12.5)
Ventricular extrasystoles	1(6.25)	0
White blood cell count increased	1(6.25)	0

• No Serious Adverse Events (SAE)
• No Severe Adverse Events
• ATI-450:one subject withdrew - evaluated for palpitations and elevated CPK - no cardiac event

* Data on file	22

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ATI-450-PKPD-102

Preliminary Topline Data Analysis

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ATI-450-PKPD-102

Evaluation of Safety, PK and PD of Higher Doses

Background:

• ATI-450-PKPD-101:Phase 1 SAD/MAD trial in male and female healthy volunteers
  o No SAEs or AEs that led to discontinuation

1. All AEs were mild in severity and did not interfere with everyday activities o Trend of decrease in ANC observed; no correlation with clinical sequelae

1. Linear (dose-andtime-independent) PK after multiple-dosing with terminal

t1/2 of ~9-12 hours; steady state by day 2

• 1. No meaningful impact on systemic exposure in the fed state o MTX PK was similar with or without ATI-450 exposure
• ATI-450-PKPD-102:Phase 1 MAD trial in male and female healthy volunteers o Same design to MAD portion of PKPD-101
• 
  o 2 cohorts: 80mg, 120mg BID for 6.5 days o 10 subjects per cohort (8 active, 2 placebo)

* Data on file	24

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ATI-450-PKPD-101 & ATI-450-PKPD-102

Day 7 Steady State

• t½ 9-14 hours
• 80mg cohort dose proportional with previous cohorts
• No significant increased exposure in 120mg cohort

* Data on file	25

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ATI-450-PKPD-101 & ATI-450-PKPD-102

Ex vivo LPS stimulated pHSP27 and TNFα Day7 Peak and Trough

Day 7 Peak and Trough

Dose Response Day 7 Peak

pHSP27

TNFα

	(*) = All placebo samples (all time points)
* Data on file	26

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ATI-450-PKPD-101 & ATI-450-PKPD-102

Ex vivo LPS stimulated IL1β and IL8 Day7 Peak and Trough

Day 7 Peak and Trough

Dose Response Day 7 Peak

IL1β

IL8

	(*) = All placebo samples (all time points)
* Data on file	27

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ATI-450-PKPD-101 & ATI-450-PKPD-102

Ex vivo LPS stimulated IL6 Day7 Peak and Trough

Day 7 Peak and Trough

Dose Response Day 7 Peak

IL6

(*) = All placebo samples (all time points)

* Data on file	28

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Phase 1 MAD Extension

Differential Modulation of Ex Vivo LPS-Stimulated IL10 vs. TNFα and IL1β by ATI-450 Day 7 (4 hr)

(*) = All placebo samples (all time points)

The anti-inflammatory cytokine, IL10, was only modulated approximately 30% at doses of ATI-450 that generated near maximal inhibition of proinflammatory cytokines (TNFα and IL1β)

* Data on file	29

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ATI-450 Phase 1 MAD Extension: 80mg and 120mg

Ex Vivo IL1β Stimulation of HWB Day 7 (4 hr)

(*) = All placebo samples (all time points)

ATI-450 potently inhibited ex vivo IL1β-induced proinflammatory cytokines, TNFα, IL6 and IL8

* Data on file	30
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ATI-450-PKPD-102

Adverse Events

	Cohort 1	Cohort 1	Cohort 2	Cohort 2
	80mg BID	Pbo	120mg BID	Pbo	Severity
	N=8	N=2	N=8	N=2
Total subjects with at	4 (50%)		8 (100%)	1 (50%)
least 1 AE
Headache#	2 (25%)		7 (88%)	1 (50%)	Mild
Dizziness+	2 (25%)		6 (75%)		Mild
Dry Skin*	1 (13%)		5 (63%)		Mild
Constipation	1 (13%)				Mild
Nausea			2 (25%)		Mild
Parasthesia			2 (25%)		Mild
Abdominal Pain			1 (13%)		Mild
Diarrhea			1 (13%)		Mild
Pharyngitis			1 (13%)		Mild

• No SAEs
• No withdrawal for AEs
• No significant ECG, Laboratory findings

# only 1st or 2nd day

• 7 cases resolved on drug * After stopping drug

* Data on file	31

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Topline Analyses Summary

• Main objectives of POC trial were achieved

• Potent and durable clinical activity with 50mg BID

1. Rapid reduction in median percentage of tender and swollen joint count, which persisted

1. DAS28-CRPreduction persisted

• • 1. ACR20/50/70 observed in 60%/33%/20% of treatment arm o hsCRP reduction maintained
  • ATI-450was generally well tolerated
• Positive Phase 1 trial (80 and 120mg BID)
• • No dose limiting toxicity in phase 1
  • Incremental inflammatory cytokine suppression
  • Pharmacokinetics data continue to support dosing flexibility (QD or BID)
  • Pharmacodynamic data provide rationale for evaluating activity at 80- 120mg BID
• Next steps
• • Planning for Phase 2b program initiated

* Data on file	32

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