Aclaris Therapeutics : Overview - November 2020

EMPOWERING PATIENTS THROUGH

KINOME INNOVATION

Company Overview

November 2020

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

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 Aclaris' development of its drug candidates, including the availability of data from its clinical trials and the timing of its regulatory submissions. 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, 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" section of the Investors page 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. This data involves 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.

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

2

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 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.

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

3

The Kinase Opportunity

Unlocking the Potential of the Kinome

Medically Important and Productive Target Class

Most Members of the Kinome Remain Unexplored

3

~36 Marketed Drugs1	518 Members
~$48B1,2	>90% of the Human Kinome
Annual Sales of Kinase Drugs	remains undrugged4

Creating New Medicines Targeting Previously Inaccessible Kinome Targets

1. Data on file.
2. Oprea TI, et al. Unexplored opportunities in the druggable human genome. Nature Rev Drug Discov. Poster Jan. 2017.
3. Manning G, et al. Science. 2002;298(5600):1912-1934.

4. Oprea TI, et al. Nat Rev Drug Discov. 2018;17(5):317-332.	** All trademarks are the property of their respective owners.	4
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

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
				PhD
	Chief Medical Officer		EVP, R&D (Head of		SVP, R&D
				VP, Chemistry
			Discovery)

• 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.

5

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

KINect™ Platform

Developing Kinase Drug Candidates Rapidly & Efficiently

TARGET SELECTION &	KINect Platform - LEAD GENERATION	ASSET GENERATION
VALIDATION

Explore	Select	Assess
500+	Cysteine	Target
Kinases	Kinases	Confidence
											Custom Kinase
								MODELING		and Immune
					ANALYSIS					Assays
			Proprietary
			Chemical
			Library
>300	w/Published	• Disease							DESIGN	SchrödingerTM
								Enabled
Cysteine	Crystal	• Genetics
	SYNTHESIS
• Safety				Drug Design
Kinases	Structures
• Distribution

Proprietary Portfolio

• MK2 Inhibitors
• JAK Inhibitors
• ITK Inhibitors

Strategic Partnerships

• Research
• Licensing
• Commercial

Proprietary Library:	Faster Path:	Multiple Approaches:
High affinity/selective	Decrease time to Lead	Design approach
drug scaffolds	Optimization by half	specific to each
	or more	kinase

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6

KINect™ Platform

Demonstrated Success in Reversible and Covalent MOA

MK2 Inhibitor

• Oral anti-TNF,anti-IL1, and anti-IL6
• Novel approach for a difficult to target kinase
• Broad potential in several immuno-inflammatory diseases

Tissue Restricted JAK and ITK	Covalent ITK Inhibitors
Inhibitors

• ATI-1777: Skin specific	• ITK/TXK/JAK3: Oral and
topical T cell kinase
(Soft) topical JAK1/3
inhibitors for autoimmune
• Oral Gut-restricted
diseases
reversible and irreversible
inhibitors
• Goal: comparable clinical
efficacy with improved
safety profile

Unique substrate-selective	Tailoring physico-chemical	Covalent inhibition for
drug design	and potency properties	difficult-to-target kinase

Small Molecule Therapeutics Targeting Multi-billion Dollar

Immunology and Inflammation Markets

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7

Pipeline

Program	Indication(s)	Preclinical	Phase 1	Phase 2	Phase 3
	Rheumatoid Arthritis
ATI-450 MK2
COVID-19*
Inhibitor Oral
	Cryopyrin-Associated
	Periodic Syndrome
	(CAPS)
ATI-1777 JAK1/JAK3	Atopic Dermatitis
Inhibitor Soft Topical	(moderate to severe)
ATI-2138	Psoriasis, Inflammatory
ITK/TXK/JAK3
Bowel Disease
Inhibitor Oral
JAK1/JAK3 Inhibitor	Inflammatory Bowel
Oral, gut-restricted	Disease
ITK/TXK/JAK3	Inflammatory Bowel
Inhibitor
Disease
Oral, gut-restricted

* This is an investigator-initiated trial sponsored by the University of Kansas Medical Center.

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8

ATI-450: MK2 Inhibitor

(Investigational Drug Candidate)

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

9

ATI-450: Small Molecule, Oral MK2 Inhibitor

Blocks the Same Targets as Broadly Used Biologics

MK2* drives pro-inflammatory cytokine expression

• Inhibiting MK2 blocks TNFα, IL1 and IL61, the targets of the following biologics:
• • anti-TNFα: HUMIRA® (adalimumab), ENBREL® (etanercept), REMICADE® (infliximab)
  • anti-IL1: KINERET® (anakinra), ILARIS® (canakinumab), ARCALYST® (rilonacept)
  • anti-IL6: KEVZARA® (sarilumab), ACTEMRA® (tocilizumab)

ATI-450: Small molecule, oral MK2 inhibitor

• Potential alternative to injectable, anti-cytokine biologics and JAK inhibitors for immuno-inflammatory diseases

* MK2 = Mitogen-activated protein kinase-activated protein kinase 2	** All trademarks are the property of their respective owners.
1. Data on file.

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10

MK2-driven Cytokines are Central to Many Diseases*

TNFα, IL1, IL6 Are Mediators in Numerous Inflammatory Conditions

Rheumatoid arthritis/	Gout	Inflammatory Bowel	Ankylosing spondylitis
Juvenile idiopathic arthritis	Disease

Neutrophilic Dermatoses	COPD	CAPS	Cardiovascular/
(Hidradenitis Suppurativa)	Cerebrovascular Disease

*Singh RK, et al. Pharmacol Reports. 2017;69:746-756.

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11

Evolution in Understanding a Well-Known Inflammatory Pathway

The Path From p38α to MK2

The relationship of p38α to MK2 is key to overcoming barriers

for suppressing TNFα and other

pro-inflammatory cytokines

• Global p38α inhibitors have exhibited toxicity and/or lack of sustained efficacy in RA and IBD
• p38α phosphorylates over 60 substrates - yet MK2 drives the proinflammatory node of this pathway
• MK2 has been a high priority therapeutic target since 1999 but has proven very difficult to drug

INFLAMMATORY/STRESS STIMULI

p38α

Anti-		Pro-		Negative		Cellular
inflammatory		inflammatory		Feedback		Function

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

• 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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TNFα IL1β IL6 IL8

12

Novel Mechanism: Capturing MK2 in an Inactive State

				MK2
				(white)
p38α
(green)
						ATI-450
		binding
		pocket				(yellow)
					ATI-450 (yellow) docked in the
	Crystal structure of the
	p38α/MK2 complex		pocket

• In the nucleus, inactive MK2 and p38α dock in a high affinity complex that exhibits a binding pocket formed by juxtaposed walls of both proteins
• ATI-450binds to both walls of the pocket, stabilizing the complex and preventing MK2 activation

ATI-450 locks MK2 in a catalytically inactive state - a unique MOA

* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.	13
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ATI-450 Selectivity: Minimizing Off-Target Inhibition through High Affinity for the p38α/MK2 Complex

Human Kinome Selectivity1

	189	191	193	1	3	5	7	9
183185	120			11 13 15
								17 19
179181
177			100										21
175												23
173
														25
171
														27
169			80
													29
167
														31
165
														33
163			60
													35
161
159															37
157			40												39
155															41
153			20												43
151														45
149															47
147			0												49
145															51
143															53
141										p38β			55
139												57
137															59
135									p38α					61
133															63
131															65
129															67
127															69
125															71
123															73
121															75
119													79 77
117
115											83 81
113
111										85
109								89 87
107	103101 99 97 95 93 91
	105

• ATI-450(5µM) was tested vs 193 kinases
• >350-foldbinding selectivity on all kinases in this panel except p38α and p38β

MK2 Pathway Selectivity

ATI-450 is highly selective for the p38α/MK2

complex vs. other p38 substrates1

Assay

Fold Selective

p38α/MK21

p38α/ATF2700

p38α/PRAK750

ATI-450 binds to the p38α/MK2 complex with higher affinity than either p38 or MK2 alone*

Assay

Fold Selective

p38α/MK21

p38α/p38tide**51

MK2/HSP27>550

1. Wang C, et al. J Exp Med. 2018;215(5):1315-1325. * Data on file.

** Optimized p38 peptide substrate	14
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Animal Models Supporting the Development of ATI-450 in Immuno-Inflammatory Diseases

Therapeutic Area		Animal Model	Reference
	Mouse Collagen-Induced Arthritis Model
	• Reduction in clinical arthritis score
	• Protection of joint histology	Data on file
Rheumatoid Arthritis/	Rat streptococcal cell wall arthritis model
Psoriatic Arthritis	• Protection against bone deterioration	Wang C, et al. J Exp Med.
	•	Protection against lethality	2018;215(5):1315-1325.
	Inhibition of cellular IL1β mRNA stability &
	translation
	Adoptive transfer mouse model of colitis	Strasser S, et al.
Inflammatory Bowel	• Endoscopy scores show disease control
Integrative Biology.
Disease	•	Decreased inflammatory infiltrate
2019;11(7):301-314.
	• Protected structural integrity of mucosa
Cryopyrin-Associated	Murine NOMID (severe form of CAPS)	Wang C, et al. J Exp Med.
Periodic Syndrome	transgenic model
2018;215(5):1315-1325.
(CAPS)	Human CAPS PBMC* IL1β modulation

• PBMC = Peripheral blood mononuclear cells

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15

MK2 - Potential Effect in Rheumatoid Arthritis

ATI-450 regulates cells and cytokines involved in RA

Normal Joint	RA Joint	Cells

Monocyte/Macrophage

Osteoclast

Epithelial Cells

RA Synovial Fibroblast

Chondrocytes

Cytokines

TNFα, IL1β, IL1α

IL6, IL8, IL18, RANKL

ATI-450: for bold items above data on file and Wang

C, et al. J Exp Med. 2018;215 (5):1315-1325.

Strand V, et al. Nat Rev Drug Discov. 2007;6(Jan 2007):75-92.

MK2 is a key regulator of pathogenic signals in chronic immuno-inflammatory diseases

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16

In Vivo Preclinical Data of MK2 Pathway Inhibitor ATI-450

Joint Protection in Rat Arthritis Model1	Blockade of Gut Inflammatory Infiltrate in Murine Adoptive
Normal	Vehicle	450 (5 mpk)		Transfer Ulcerative Colitis Model2
			Normal	Inflamed	Inflamed + ATI-450

	2.8						Cytokine Modulation in Orphan
				vehicle		Autoinflammatory Disease (CAPS)1
	2.6
ml-										IL1β
2.4
VolumePaw	2.2		Oral dosing initiated			(pg)	70		(bone marrow fluid)
1.4						30
	2							60
	1.8					ATI-450		50				ATI-450
	1.6						40				PLACEBO
	1.2							20
							10
	1
							0
	0.8	Vehicle	CDD450 - 10 MPK	CDD450 - 5 MPK	CDD110 - 1.5 MPK		-	+	-	+
						ATI-450
		0	5	10	15	20
				Normal	NOMID
			Study Day

1. Wang C, et al. J Exp Med. 2018;215(5):1315-1325.

2. Strasser S, et al. Integrative Biology. 2019;11(7):301-314.	17
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Mouse Model: ATI-450 Inhibits RANKL-stimulated Macrophage Differentiation into Osteoclasts (Osteoclastogenesis)

Bone marrow-derived macrophages (BMDM) from NOMID mice

• In CAPS, osteoclastogenesis gives

rise to low bone mass

(osteopenia)Macrophages

• (a) When bone marrow
derived macrophages	RANKL
(BMDM) from NOMID	stimulation
mice are stimulated with
RANKL (RANK ligand),
they differentiate into	Osteoclasts
osteoclasts
• (b) ATI-450 blocks this
macrophage
differentiation

NOMID BMDM	NOMID BMDM
Plus ATI-450

(a)(b)

* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.	18
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Mouse Model: ATI-450 is Efficacious in Murine Collagen-Induced Arthritis (mCIA)

Day

1

18

21

35

DBA/1 Mice (12/group)

Dosing begins:

DBA/1 Mice

Terminate Study

Immunized with

•

Vehicle

boosted with

•

Joint Histopathology

bovine collagen/CFA

•

ENBREL: 10mg/kg QD

bovine collagen/CFA

•

Clinical Arthritis Score

•

ATI-450 chow 1000ppm

monitored daily day 21-35

Clinical Arthritis Score

ENBREL

ATI-450

Joint Histology Score

Meaned ATI-450 Histology Scores

16

	14			0%
Score
12
Joint	10
8
SE
6							64%		ATI-450
±
Mean	4
										86%
	2
	100%
	0
		Naïve	Vehicle	Enbrel (10mg/kg) ATI-450 (1000ppm)

ATI-450 demonstrated broad efficacy in the gold standard mCIA model

* Data on file.

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19

Mouse Model: ATI-450 Increases Regulatory T (Treg) Cells in mCIA

Day 1	18 21	35

DBA/1 Mice (12/group)		Dosing begins:
Immunized with		•	Vehicle
bovine collagen/CFA		•	ENBREL: 10mg/kg QD
		•	ATI-450 chow 1000ppm

• • The effect of ATI-450 treatment on T cell subsets was evaluated in the mCIA model
  • A highly significant increase in Treg cells within the CD4+ population was observed with mice treated with ATI-450
  • Treg cells are known to be involved in the maintenance of the immune response and have been shown to prevent autoimmune disease1
• Data on file.

1. Dominguez-Villar M, et al. Nat. Immunol. 2018;19:665-673.

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

DBA/1 Mice		Terminate Study
boosted with		• Draining lymph nodes
bovine collagen/CFA		analyzed by FACS

Murine CIA and Tregs

20

CD4+)	18
of	16
(%	14
Foxp3+	12
	10
								p < 0.0001
	8

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e

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v

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e

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r

0

i

b

a

i

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N

n

1

e

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(

V

0

5

4

-

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T

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20

Mouse Model: LPS-Induced TNFα Production

ATI-450 demonstrated durable response (no tachyphylaxis)

• CDD-111and ATI-450

	administered to mice in feed		180
	starting day 1 and continuing		160	CDD111	% Control Response
	through day 28		140	ATI-450
			120
• At the time point indicated,	TNFα	100
	mice were LPS challenged	80
	and blood TNFα levels		60
	determined		40
			20
•	Global investigational p38		0
	inhibitor CDD-111 lost			0.5	2	3	4
	inhibition over time				Weeks on Drug

* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.	21
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Ex Vivo Preclinical Data: ATI-450 Inhibits IL1β Expression in PBMCs from a Patient with CAPS

• PBMCs were isolated from patients with CAPS and healthy controls.
• In patients with CAPS (Muckle Wells Syndrome), IL1β expression is triggered by exposure to low temperatures.
• PBMCs from patients with CAPS spontaneously produced high amounts of IL1β at 32°C but not at 37°C.

ATI-450 blocks temperature stress induced IL1β production

* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.	22
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ATI-450 Clinical Development

Phase 1 Single and Multiple Ascending Doses

• Safety, PK, Tolerability
• PD (inhibition of TNFα, IL1β, IL6, IL8 & Hsp27)

		Phase 2a Clinical Trials
	Rheumatoid Arthritis		CAPS
	TNFα driven disease		IL1β driven disease
• 12 wks: ATI-450 vs placebo
• 12 wks: open-label
•	Assess CRP dynamics
•	IL1 biologic withdrawal
•	Clinical disease activity
•	Maintenance of remission
•	MRI: wrist synovitis
•	Safety and tolerability

• Safety and tolerability

				Demonstrate proof of concept
	Autoinflammatory					Inflammatory Bowel
	Diseases					Disease
	Psoriatic Arthritis				Hidradenitis Suppurativa
		Psoriasis				Gout

Rheumatoid Arthritis

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23

ATI-450-PKPD-101

Trial Design and Demographics

Three-Part Study (77 Subjects)

Part A: single ascending			Part B:: multiple			Part C: methotrexate
	dose (SAD) plus food			ascending dose (MAD)			(MTX) drug-drug
	effect (n=32)			(n=30)			interaction (DDI) (n=15)
•	4 cohorts: 10mg, 30mg,		•	3 cohorts: 10mg, 30mg,		•	1 cohort: MTX day 1
	50mg, 100mg (100mg			50mg all BID for 7 days			and 8. ATI-450 on days
	repeated with high fat		•	10 subjects per cohort			2-9
	meal)			(8 active, 2 placebo)		•	All dosed with active
•	8 subjects per cohort (6
	active, 2 placebo).
	Single dose after
	overnight fast

Demographics: (All dose groups, all parts):

• Age: Mean 34 years
• Gender: 44 female/33 male
• Race: White-40,Black-32,Other-5

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24

ATI-450-PKPD-101

Safety: ATI-450 Generally Well-Tolerated

Most Common Adverse Events (≥2 subjects in the trial)

SAD/MAD cohorts (blinded)

	ATI-450	Placebo
Preferred Term	n (%)	n (%)
	(n=48)	(n=14)
Dizziness	6 (12.5)	0
Headache	10	(20.8)	2 (14.3)
Upper respiratory tract	3	(6.3)	1 (7.1)
infection
Constipation	3	(6.3)	1 (7.1)
Nausea	2	(4.2)	1 (7.1)
Abdominal pain	2	(4.2)	0
Vomiting		0	2 (14.3)

DDI cohort (unblinded ATI-450 + MTX)

	ATI-450
Preferred Term	n (%)
	(n=15)
Dizziness	7 (46.7)
Headache	1 (6.7)
Upper respiratory tract	1 (6.7)
infection
Constipation	0
Nausea	0
Abdominal pain	0
Vomiting	0

• No serious adverse events or adverse events that led to discontinuation of study medication
• All adverse events were mild in severity and did not interfere with everyday activities
• A trend of a decrease in absolute neutrophil count was observed; no correlation with clinical sequelae o This effect is consistent with the pharmacodynamic profile of certain anti-TNF therapies1

1. Dillingh M, et al. Front. Immunol. 2016;7(508):1-9.

* Data on file.25 © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

ATI-450-PKPD-101

MAD Pharmacokinetics: Dose Proportional PK

Mean (SD) plasma concentration-time profiles of ATI-450: Day 7

t½ = 9-12 hours

* Data on file

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26

ATI-450-PKPD-101: Day 7 MAD PD Marker Time Dependence

Target Biomarker pHSP27 and Cytokines TNFα and IL1β

Day

	1	2	3	4	5	6	7
	ATI-450 BID
	Blood for
	ex vivo assay	predose							4 hr 12 hr
	pHSP27				TNFα			IL1β

• ATI-450dosed orally BID for 7 days in healthy subjects at doses of 10mg, 30mg and 50mg
• Day 1 (predose) is from blood taken on day 1 just prior to the first dose of ATI-450
• Samples ex vivo stimulated with LPS
• Data expressed as mean +/- SEM

* Data on file

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27

ATI-450-PKPD-101: Day 7 MAD PD Biomarker Time Dependence Cytokines IL8 and IL6

Day

1	2	3	4	5	6	7

ATI-450 BID

Blood for	predose	4 hr 12 hr
ex vivo assay

• ATI-450dosed orally BID for 7 days in healthy subjects at doses of 10mg, 30mg and 50mg
• Day 1 (pre-dose) is from blood taken on day 1 just prior to the first dose of ATI-450
• Samples ex vivo stimulated with LPS
• Data expressed as mean +/- SEM

* Data on file

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28

ATI-450-PKPD-101

Multiples of Cytokine IC80 Across Dosing Interval

The MAD 50mg BID cohort achieved systemic drug concentrations in excess of IC80

for pHSP27, TNFα, IL1β and IL8 at Cmax (3.5-6.0X) and Ctrough (1.4-2.4X).

Biomarker	*IC80	**Ctrough	**Cmax
	ng/ml	Multiple of IC80	Multiple of IC80
pHSP27	36.7	2.4x	6.0x
TNFα	62.6	1.4x	3.5x
IL1β	40.8	2.2x	5.4x
IL6	747.8	0.1x	0.3x
IL8	38.8	2.3x	5.6x

*IC80 values generated with all SAD/MAD exposure data using the Emax model in WinNonlin ** 50 mg BID MAD Cohort

50 mg BID Ctrough = 87.9 ng/ml

50 mg BID Cmax = 215 ng/ml

* Data on file.

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

29

In Vitro Model:

ATI-450Inhibited IL1b-Stimulated Cytokines in Human Whole Blood

IL1β-Stimulated HWB

Cytokine	IC80 (ng/ml)
TNFα	31 +6
IL6	41 +20
IL8	40 +12

• ATI-450was added to freshly isolated human whole blood for 1 hour and stimulated with IL1β (10 ng/ml) for 5 hours
• Cytokines were measured by Meso Scale Discovery technology.

* Data on file.
HWB = Human Whole Blood	30
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

ATI-450 Inhibited Additional CRS-Related Proteins in HWB

Ex Vivo LPS-Stimulated HWB from SAD/MAD Study

ATI-450 Modulation of LPS-stimulated Cytokine/Chemokine

Production (% Predose)

Analyte Production (% Predose)

125
																							SAD: 100mg (1 hr)
100							Predose												MAD: 50mg BID, Day 7 (4 hr)
75
50
25
0

GMCSF	IL2	MIP1a	IFNg
	Analyte: Cytokine or Chemokine

Marked Inhibition of CRS Cytokines by ATI-450 in Phase 1 Trial

*Data on file.

31

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

ATI-1777 (Topical "Soft" JAK Inhibitor)

(Investigational Drug Candidate)

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

32

Atopic Dermatitis Opportunity

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin condition1

• The prevalence rate for AD (US) is 10-12% in children and 0.9% in adults2
• Market projected to be $8-12 billion at peak (moderate to severe AD)3
• Systemic and topical JAK inhibition has demonstrated promising results in AD clinical trials4

Approach

• Comparable efficacy to other topical
  JAKs but "soft" drug to minimize the potential for systemic immunosuppression
• JAK1/3 selective to minimize JAK2 inhibition toxicity
• Deliver in a patient-friendly formulation
• Patients with moderate to severe AD

ATI-1777: Status

• Investigational Compound
• IND allowed
• First-in-humanPhase 2a trial in patients with moderate or severe AD underway

1. https://emedicine.medscape.com/article/1049085-overview. Last accessed 5-26-20.
2. https://emedicine.medscape.com/article/1049085-overview#a8. Last accessed 5-26-20.
3. Auster M, et al. Something Big Is Getting Bigger [research note]. Credit Suisse Equity Research; 2019.

4 Shreberk-Hassidim R, et al. J Am Acad Dermatol. 2017;Apr;76(4):745-753.	33
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

Porcine Model:

ATI-1777 Blocks IL15 Induced CCL8 mRNA in Skin

Apply	Intra-dermal	Harvest 6 mm
formulation to	Injection of	biopsy,
back of pig,	porcine IL15,	prepare RNA,
wait 1 hr	wait 3 hr	measure CCL8
		by qPCR

• Single application of 2% ATI-1777 development formulation significantly inhibits IL15 (JAK1/3) induced gene induction (CCL8).

* Data on file	34
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

Minipig Model:

ATI-1777Non-clinical Safety Program TK Data

Tolerability/Toxicokinetic with 7-day dermal administration (non-GLP)

• No adverse effects noted (10% body surface area, QD)
• Bleeds at 0.5, 1, 2, 4, 8, 12, and 24 hours post-application: Days 1 and 6
• All plasma samples were below limit of quantification (<0.50 ng/mL) - well below cellular IC50

MINIPIG1

HUMAN2,3

1. Data on file.
2. Chen X, et al. Clin Pharmacol Drug Dev. 2013;3(1):34-42.

3. Punwani N, et al. Br J Dermatol. 2015;173:989-997.	35
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

ATI-2138 (ITK/TXK/JAK3 Inhibitor)

(Investigational Drug Candidate)

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

36

ATI-2138: Covalent ITK/TXK/JAK3 (ITJ) Inhibitor

1. • ATI-2138covalently blocks ITK/TXK/JAK31
   • • Potential for synergistic efficacy
     • • ITK/TXK required for T-cell receptor (TCR) signaling
       • JAK3 required for γc cytokines (IL-2/4/7/9/15/21)
     • PD effects persist after plasma clearance
   • ATI-2138is selective for T-cell signaling2,3
   • • Drugs like cyclosporine (CsA) inhibit calcineurin which is widely expressed
     • ATI-2138targets unique kinases expressed only in immune cells
   • ATI-2138may potentially treat T-cell mediated autoimmune diseases4,5
2. Data on file.
3. Graham RM. Cleve Clin J Med. 1994;61(4):308-313.
4. Siliciano JD, et al. Proc Natl Acad Sci U S A. 1992;89(23):11194-11198.
5. Robinson MF, et al. [published online ahead of print, 2020 May 18]. Arthritis Rheumatol. 2020.
6. Russell SM, et al. Science. 1995;270(5237):797-800.

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

APCs

TCR/CD3

ATI-2138

T cells

T

cell

	T
T	cell	TH
cell		Cells

37

ATI-2138 is a Potent Covalent Inhibitor

ATI-2138

Covalent bond between ITKcys and ATI-2138

Cellular Inhibition of JAK and ITK/TXK

Assay Description	ATI-2138	Assay
IC50 (nM)
ITK/TXK activity	7	Jurkat pPLCγ-1
JAK1/3 activity	20	PBMC pSTAT-5
Both ITK/TXK and JAK3	13	HWB αCD3/IL15
IFNγ
BTK activity	52	Ramos pPLCγ-2

Co-Crystal Structure of ATI-2138/ITK -	ATI-2138 potently inhibits
shows ATI-2138 covalent binding	ITK/TXK and JAK3 in cells and in
to ITK	whole blood

* Data on file	38
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

Rat Adjuvant Induced Arthritis (AIA) Model:

ATI-2138 Reduced Inflammation and Protected Bone

Weigh every other day

Measure ankle diameter

Day 0	Day 6	Day 12	Day 23
Male
Lewis Rat	Begin PO dosing
Inject with		Histology, BMD
adjuvant	of ATI-2138

Adjuvant

induced bony destruction of

Day 23 ankle diameter

	12
mm	11
Diameter,	9
	10
Ankle	8

7

				e					D				D					ID		ID
		c
			l					Q				Q					B			B
		i
	h						-			0
					0								5				5
e					1					3
V					-					8				8				1
			8								3						8
			3						3			1						3
		1						1			2					1
	2						2			I
-					-				-					2
I					I				T					-
			T										I
T													T
A				A						A			A

ATI-2138 bone mineral density in rat AIA study

	220
	200	****			****
)

2	****	****
(mg/cm
180
BMD	160
140

**** p <0.00001

120

				D					D					D					ID	ID
	H	Q					-Q					-Q				-B		-B
						0						0				5			5
E						1						3				-			-
				-						-
V					8						8					38				8
				3						3					1					13
			1						1					2
		2						2					-					2
	-						-						I
	I					I					T				-
T					T									I
											T
A					A						A				A

rat hindlimb

ATI-2138

Preservation of

Joint Material with

ATI-2138

ATI-2138 reduced inflammation and bone mineral density loss

* Data on file	39
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

Mouse Model: ATI-2138 is Efficacious in mCIA

Day

1

18

21

35

DBA/1 Mice (12/group)

Dosing begins:

DBA/1 Mice

Terminate Study

Immunized with

-Vehicle

boosted with

•

Joint Histopathology

bovine collagen/CFA

-ENBREL: 10mg/kg QD

bovine collagen/CFA

•

Clinical Arthritis Score

-ATI-2138 chow:

monitored daily day 21-35

100/300/10000ppm

Clinical Arthritis Score

ENBREL

Joint Histology Score

Meaned ATI-2138 Histology Scores

16
	0%
14

Score	12
Joint	10
8
±SE
6						64%
Mean	4														ATI-2138
										92%
	2
ATI-2138		100%												99%		100%
0
	Naïve	Vehicle	Enbrel	ATI-2138	ATI-2138	ATI-2138
							(10mg/kg)	(100ppm)	(300ppm)	(1000ppm)

In the gold standard mCIA model, ATI-2138 demonstrated efficacy superior to ENBREL

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

40

Empowering Patients Through Kinome Innovation

Executive Team

Proven track record of R&D and business development

Research and Development

Scientific leadership in immuno-inflammatory diseases

KINect™ Technology Platform

Proprietary discovery engine enables targeted design of novel drug candidates

IP

Intellectual Property

Global IP estate

Commitment to Patients

Focus on addressing the needs of patients with immuno-inflammatory diseases who lack satisfactory treatment options

Pipeline

Multiple therapeutic programs ranging from discovery to clinical development

Cash Position

$55.2 million as of September 30, 2020

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)

41

Key Milestones

Program/Milestone

2020

2021

1Q

2Q

3Q

4Q

1Q

2Q

3Q

4Q

ATI-450 (MK2 Inhibitor)

Phase 1 Data (SAD/MAD)

✓

Initiate Phase 2a Trial in Rheumatoid

✓

Arthritis

Phase 2a Data in Rheumatoid Arthritis

Initiate Phase 2a Trial in CAPS

✓

ATI-1777 (Topical "Soft" JAK Inhibitor)

Submit IND

✓

Initiate Phase 2a Trial in Moderate to

✓

Severe Atopic Dermatitis

ATI-2138 (ITK/TXK/JAK3 Inhibitor)

Submit IND

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42

EMPOWERING PATIENTS THROUGH

KINOME INNOVATION

THANK YOU

© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)