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
- Data on file.
- Oprea TI, et al. Unexplored opportunities in the druggable human genome. Nature Rev Drug Discov. Poster Jan. 2017.
- 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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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.
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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. |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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.
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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.
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
TNFα IL1β IL6 IL8
12
Novel Mechanism: Capturing MK2 in an Inactive State
MK2 | |||||||
(white) | |||||||
p38α | |||||||
(green) | |||||||
ATI-450 | |||||||
binding | |||||||
(yellow) | |||||||
ATI-450 (yellow) docked in the | |||||||
Crystal structure of the | |||||||
p38α/MK2 complex | |||||||
- 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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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.
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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 | |||||||||||||||||
e | e | l | ) | ||||||||||||||
v | l | e | 0 | ||||||||||||||
c | r | 0 | |||||||||||||||
i | b | ||||||||||||||||
a | i | ||||||||||||||||
h | 0 | ||||||||||||||||
N | n | 1 | |||||||||||||||
e | E | ( | |||||||||||||||
V | 0 | ||||||||||||||||
5 | |||||||||||||||||
4 | |||||||||||||||||
- | |||||||||||||||||
I | |||||||||||||||||
T | |||||||||||||||||
A |
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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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 |
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20) | |
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
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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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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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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
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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.
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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
- https://emedicine.medscape.com/article/1049085-overview. Last accessed 5-26-20.
- https://emedicine.medscape.com/article/1049085-overview#a8. Last accessed 5-26-20.
- 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 |
- Data on file.
- 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
- 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
- Data on file.
- Graham RM. Cleve Clin J Med. 1994;61(4):308-313.
- Siliciano JD, et al. Proc Natl Acad Sci U S A. 1992;89(23):11194-11198.
- Robinson MF, et al. [published online ahead of print, 2020 May 18]. Arthritis Rheumatol. 2020.
- 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 | ||||||||||||||
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
42
EMPOWERING PATIENTS THROUGH
KINOME INNOVATION
THANK YOU
© Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0526 11/20)
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Aclaris Therapeutics Inc. published this content on 04 November 2020 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 04 November 2020 14:05:05 UTC