8-K
Aclaris Therapeutics, Inc. (ACRS)
8-K
2020-05-27
For: 2020-05-27
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April 08, 2026
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d) of
The Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): May 27, 2020
Aclaris Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
| | | | | |
|---|---|---|---|---|
| Delaware | | 001-37581 | | 46-0571712 |
| (State or other jurisdiction of incorporation) | | (Commission File Number) | | (IRS Employer<br>Identification No.) |
640 Lee Road, Suite 200
Wayne, PA 19087
(Address of principal executive offices, including zip code)
(484) 324-7933
(Registrant’s telephone number, including area code)
N/A
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
[ ] Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
[ ] Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
[ ] Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
[ ] Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
| Title of Each Class: | Trading Symbol(s) | Name of Each Exchange on which Registered |
|---|---|---|
| Common Stock, $0.00001 par value | ACRS | The Nasdaq Stock Market, LLC |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company þ
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. þ
Item 7.01 Regulation FD Disclosure.
On May 27, 2020, Aclaris Therapeutics, Inc. (the “Company”) updated its company overview presentation, a copy of which is furnished as Exhibit 99.1 to this Current Report on Form 8-K.
In accordance with General Instruction B.2. of Form 8-K, the information in this Item 7.01 and Exhibit 99.1 hereto shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liability of that section, nor shall it be deemed incorporated by reference in any of the Company’s filings under the Securities Act of 1933, as amended, or the Exchange Act, whether made before or after the date hereof, regardless of any incorporation language in such a filing, except as expressly set forth by specific reference in such a filing.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
| | | |
|---|---|---|
| Exhibit | | **** |
| Number | | Exhibit Description |
| 99.1 | | Company Presentation. |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| **** | | |
|---|---|---|
| | | ACLARIS THERAPEUTICS, INC. |
| | | |
| | By: | /s/ Frank Ruffo |
| Date: May 27, 2020 | | Frank Ruffo<br>Chief Financial Officer |
Exhibit 99.1
| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Company Overview<br>May 2020<br>EMPOWERING PATIENTS THROUGH<br>KINOME INNOVATION |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Any statements contained in this presentation that do not describe historical facts may constitute forward-looking statements as<br>that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as<br>"believe,” "expect," "may,“ "plan," "potential," "will," and similar expressions, and are based on Aclaris' current beliefs and<br>expectations. These forward-looking statements include expectations regarding Aclaris’ development of its drug candidates,<br>including the timing for initiation and completion of clinical trials, the availability of data from these trials and the timing of its<br>regulatory submissions related to these trials. These statements involve risks and uncertainties that could cause actual results to<br>differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ<br>materially include uncertainties inherent in the conduct of clinical trials, Aclaris' reliance on third parties over which it may not<br>always have full control, the uncertainty regarding the COVID-19 pandemic including its impact on the timing of Aclaris’<br>regulatory and research and development activities, and other risks and uncertainties that are described in the Risk Factors<br>section of Aclaris’ Annual Report on Form 10-K for the year ended December 31, 2019, Aclaris’ Quarterly Report on Form 10-Q<br>for the quarter ended March 31, 2020 and other filings Aclaris makes with the U.S. Securities and Exchange Commission from<br>time to time. These documents are available under the “SEC filings" section of the Investors page of Aclaris' website at<br>http://www.aclaristx.com. Any forward-looking statements speak only as of the date of this presentation and are based on<br>information available to Aclaris as of the date of this presentation, and Aclaris assumes no obligation to, and does not intend to,<br>update any forward-looking statements, whether as a result of new information, future events or otherwise<br>This presentation also contains estimates and other statistical data made by independent parties and by us relating to market<br>size and other data about our industry. This data involves a number of assumptions and limitations, and you are cautioned not to<br>give undue weight to such estimates. In addition, projections, assumptions and estimates of our future performance and the<br>future performance of the markets in which we operate are necessarily subject to a high degree of uncertainty and risk.<br>Cautionary Note Regarding Forward-Looking Statements<br>2 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>LEADERSHIP<br>• Physician/Scientist founded<br>and led<br>• World class ex-Pfizer<br>kinase and ex-GSK<br>immunology leadership<br>• Kinome experts skilled at<br>developing kinase targeted<br>medicines<br>Strategy: Biotechnology company focused on developing small<br>molecule therapeutics for immuno-inflammatory diseases<br>KINectTM PLATFORM<br>Proprietary<br>Discovery Engine<br>• Versatile platform<br>• Fully integrated discovery<br>and development team<br>• Positioning small<br>molecule drug candidates<br>to parallel or exceed<br>efficacy of high value<br>biologics<br>INNOVATIVE<br>PORTFOLIO<br>INNOVATIVE PIPELINE<br>(investigational drug candidates)<br>ATI-450 – MK2i<br>• Oral anti-TNFα, anti-IL1, anti-<br>IL6<br>ATI-1777-Topical Soft-JAK1/3i<br>• Tissue specific therapy for the<br>potential treatment of<br>moderate-to-severe atopic<br>dermatitis (AD)<br>ATI-2138 - ITK/TXK/JAK3i<br>• Oral dual inhibitor of T-cell and<br>cytokine receptors<br>3 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>R&D Leadership Team<br>Experienced team with deep scientific and operational experience<br>Former VP Research & Global<br>Head, Pfizer Inflammation,<br>co-leader of Pfizer Licensing<br>Team<br>Delivered 8 clinical candidates,<br>6 INDs and 1 NDA in inflammation<br>and cancer<br>Walter Smith<br>SVP, R&D<br>Jon Jacobsen, PhD<br>VP, Chemistry<br>Former Research Fellow and<br>Director, Pfizer Chemistry<br>>100 publications and patents<br>(15 total on kinases)<br>Project Lead for PFE JAK<br>Program<br>Paul Changelian, PhD<br>VP, Biology<br>Immunologist/drug<br>discovery leader at pharma<br>(Pfizer & biotech)<br>Validated JAK 1/3 as target<br>for transplant/RA/psoriasis,<br>leading to approval of<br>XELJANZ®<br>David R Anderson, PhD<br>Sr. Director, Discovery, Early<br>Development<br>Former research project leader at<br>Pfizer. Director of Chemistry at<br>Mnemosyne, Luc, Cadent.<br>Inventor of 6 clinical candidates<br>and author of 40 peer reviewed<br>publications and patents<br>Gary DeCrescenzo<br>SVP, Pharm R&D<br>Former Exec. Director, Pfizer.<br>Site Head for Medicinal &<br>Structural Chemistry.<br>>100 patents.<br>Co-inventor of multiple drug<br>candidates<br>David Gordon<br>Chief Medical Officer<br>Former SVP, R&D at GSK.<br>Led discovery and development<br>teams in Immuno-Inflammation<br>and Dermatology leading to<br>multiple successful NDAs,<br>including NUCALA® &<br>BENLYSTA®<br>* All trademarks are the property of their respective owners.<br>Former Executive Director, Pfizer<br>Inflammation Research and<br>Leader of Global Kinase<br>Technology Team<br>>95 publications and patents<br>(>30 total on kinases)<br>Joseph Monahan, PhD<br>Exec. VP R&D<br>(Head of Discovery)<br>4 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Pipeline<br>Program Indication(s) Preclinical Phase 1 Phase 2 Phase 3<br>ATI-450 MK2<br>Inhibitor Oral<br>Rheumatoid Arthritis<br>Additional Immuno-<br>inflammatory Indication<br>ATI-1777 JAK1/JAK3<br>Inhibitor Soft Topical<br>Atopic Dermatitis<br>(moderate-to-severe)<br>ATI-2138<br>ITK/TXK/JAK3<br>Inhibitor Oral<br>Psoriasis, Inflammatory<br>Bowel Disease<br>JAK1/JAK3 Inhibitor<br>Oral, gut-restricted<br>Inflammatory Bowel<br>Disease<br>ITK/TXK/JAK3<br>Inhibitor<br>Oral, gut-restricted<br>Inflammatory Bowel<br>Disease<br>5 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>The Kinase Opportunity<br>Creating New Medicines Targeting Previously Inaccessible Kinome Targets<br>Science<br>2003<br>~36 Marketed Drugs<br>~$48B*<br>Annual Sales of Kinase Drugs<br>Medically Important and Productive Target Class Most Members of the Kinome Remain Unexplored<br>518 Members<br>>90% of the Human Kinome<br>remains undrugged<br>These drugs target less then 5% of the kinome<br>* Bologa C, et al. Unexplored opportunities in the druggable human genome. Nat Rev Drug Discov. 2018.<br>** All trademarks are the property of their respective owners. 6 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Market Overview of Select Inflammatory Indications<br>* Auster M, et al. Something Big Is Getting Bigger [research note]. New York, NY: Credit Suisse Equity Research; 2019.<br>1 Estimates of total sales per indication from EvaluatePharma.<br>2 CS projections: based on US branded pricing.<br>3 Assumed peak treatable population with biologics/novel agents in the US: RA 350-400k / Psoriasis 300-350k / Ulcerative Colitis 225-275k / Crohn’s 225-275k /<br>Atopic Dermatitis 150-200k.<br>RA Psoriasis Ulcerative<br>Colitis<br>Crohn’s<br>Disease Atopic Dermatitis<br>(moderate -<br>severe)<br>(moderate -<br>severe)<br>(moderate -<br>severe)<br>(moderate -<br>severe)<br>(moderate -<br>severe)<br>2018E WW Sales1 ~$25B ~$15B ~$5B ~$11B ~$1B<br>Estimated Peak Market (WW)2 ~$25-30B ~$20-25B ~$8-12B ~$15B ~$8-12B<br>Prevalent US Moderate/Severe Population3 ~1,000K+ ~1,000-1,300K ~400-500K ~350-450K ~300-700K<br>Opportunity for New Treatments<br>Orals, Improved<br>risk/benefit, novel<br>mechanism<br>Oral, novel<br>mechanism,<br>improved safety<br>Gut-restricted<br>(improved<br>safety)<br>Gut-restricted<br>(Improved<br>safety)<br>Improved<br>risk/benefit, topical<br>in moderate to<br>severe<br>7 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>KINect Platform<br>Developing Kinase Drug Candidates Rapidly & Efficiently<br>Proprietary Portfolio<br>• MK2 Inhibitor<br>• JAK Inhibitors<br>• ITK Inhibitors<br>Strategic Partner(s)<br>• Project 1<br>• Project 2<br>• Project 3<br>ASSET GENERATION KINect Platform – LEAD GENERATION TARGET SELECTION &<br>VALIDATION<br>>300<br>Cysteine<br>Kinases<br>500+<br>Kinases<br>Select<br>Cysteine<br>Kinases<br>w/Published<br>Crystal<br>Structures<br>Assess<br>Target<br>Confidence<br>• Disease<br>• Genetics<br>• Safety<br>• Distribution<br>• Proprietary Library: High affinity/selective drug scaffolds<br>• Faster Path: Decrease time to Lead Optimization by half or more<br>• Multiple Approaches: Design approach specific to each kinase<br>Proprietary<br>Chemical<br>Library<br>SchrödingerTM<br>Enabled<br>Drug Design<br>Custom<br>Kinase and<br>Immune<br>Assays<br>MODELING<br>DESIGN<br>SYNTHESIS<br>ANALYSIS<br>8 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>KINect™ Platform Demonstrated Success<br>Reversible and Covalent<br>• Oral anti-TNF, anti-IL1, and<br>anti-IL6<br>• Novel approach for a<br>difficult to target kinase<br>• ATI-450 Phase 1 clinical<br>trial data available<br>• ITK T cell kinase<br>inhibitors for autoimmune<br>diseases<br>• Oral and topical covalent<br>drug candidates<br>developed<br>• ATI-2138 (Oral): IND<br>enabling work<br>• Potential approaches to<br>achieve efficacy with<br>improved safety<br>• Skin specific: Soft, topical<br>drug for the potential<br>treatment of moderate-to-<br>severe AD<br>• Gut-restricted inhibitor: for<br>the potential treatment for<br>inflammatory bowel<br>disease<br>Covalent ITK Inhibitors MK2 Inhibitor Tissue Restricted JAK and ITK<br>Inhibitors<br>Unique Substrate Selective<br>Drug Design<br>Covalent Inhibition: for<br>difficult to target kinase<br>Tailoring physico-chemical<br>and potency properties<br>9 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-450: MK2 Inhibitor<br>(Investigational Drug Candidate)<br>10 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>MK2 Inhibitor: Oral Small Molecule Inhibitor of TNFα, IL1, and IL6<br>• MK2* drives pro-inflammatory cytokine expression<br>• The effects of inhibiting MK2 mirror the effects of anti-inflammatory<br>biologics1<br>✓ anti-TNFα: HUMIRA® (adalimumab), ENBREL® (etanercept),<br>REMICADE® (infliximab)<br>✓ anti-IL1: KINERET® (anakinra), ILARIS® (canakinumab), ARCALYST®<br>(rilonacept)<br>✓ anti-IL6: KEVZARA® (sarilumab), ACTEMRA® (tocilizumab)<br>• ATI-450: Small molecule MK2 inhibitor<br>✓ Potential alternative to injectable, anti-cytokine biologics and JAK<br>inhibitors for immuno-inflammatory diseases<br>** All trademarks are the property of their respective owners.<br>* MK2 = Mitogen-activated protein kinase-activated protein kinase 2<br>1 Data on file.<br>11 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>MK2-driven Cytokines are Central to Many Diseases<br>TNFα,<br>IL1β, IL6<br>Psoriasis / psoriatic arthritis<br>Gout<br>Inflammatory bowel disease<br>Rheumatoid arthritis /<br>Juvenile idiopathic arthritis<br>Ankylosing spondylitis<br>Asthma / COPD<br>Cardiovascular /<br>cerebrovascular disease<br>Cancer<br>Singh RK, et al. Pharmacol Reports. 2017;69:746-756. 12 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Evolution in Understanding of a Well-Known Path<br>The Path From p38α to MK2<br>INFLAMMATORY/STRESS STIMULI<br>p38α<br>Anti-<br>inflammatory<br>Negative<br>Feedback<br>TNFa IL1b IL6 IL8<br>MK2<br>Cellular<br>Function<br>Pro-<br>inflammatory<br>p38α was initially targeted for<br>suppressing TNFα and other pro-<br>inflammatory cytokines<br>• Global p38α inhibitors have<br>exhibited toxicity and/or lack of<br>sustained efficacy in RA and IBD<br>• p38α phosphorylates over 60<br>substrates - yet MK2 drives the<br>proinflammatory node of this<br>pathway<br>• MK2 has been a high priority<br>therapeutic target since 1999 but<br>has proven very difficult to drug e.g. CREB,<br>C/EBPb, SP1<br>e.g. TAB1,<br>CREB<br>* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.<br>* Cheung P, et al. EMBO J. 2003;22(21):5793-5805.<br>* Muniyappa H, et al. Cell Signal. 2008;20(4):675–683.<br>* Ma W, et al. J Biol Chem. 2001;276(17):13664-13674.<br>13 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Novel mechanism: Capturing MK2 in an Inactive State<br>Crystal structure of the p38α/MK2 complex ATI-450 (yellow) docked in the pocket<br>• In the nucleus, inactive MK2 and p38α dock in a high affinity complex that<br>exhibits a binding pocket formed by juxtaposed walls of both proteins<br>• ATI-450 binds to both walls of the pocket, stabilizing the complex and<br>preventing MK2 activation<br>binding<br>pocket<br>p38α<br>(green)<br>MK2<br>(white)<br>ATI-450<br>(yellow)<br>ATI-450 locks MK2 in a catalytically inactive state – a unique MOA<br>* Wang C, et al. J Exp Med. 2018;215(5):1315-1325. 14 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• ATI-450 (5µM) was tested vs 193 kinases<br>• >350-fold binding selectivity on all kinases<br>in this panel except p38α and p38β<br>ATI-450 Selectivity<br>Assay Fold Selective<br>p38α/MK2 1<br>p38α/p38tide* 51<br>MK2/HSP27 >550<br>Human Kinome Selectivity1 MK2 Pathway Selectivity<br>* Optimized p38 peptide substrate<br>** Data on file.<br>1 Wang C, et al. J Exp Med. 2018;215(5):1315-1325.<br>ATI-450 is highly selective for the<br>p38/MK2 complex vs. other p38<br>substrates1<br>Assay Fold Selective<br>p38α/MK2 1<br>p38α/ATF2 700<br>p38α/PRAK 750<br>ATI-450 binds to the p38α/MK2 complex<br>with higher affinity than either p38 or<br>MK2 alone**<br>0<br>20<br>40<br>60<br>80<br>100<br>120 1 3 5 7 9 11 13 15 1719 21<br>23<br>25<br>27<br>29<br>31<br>33<br>35<br>37<br>39<br>41<br>43<br>45<br>47<br>49<br>51<br>53<br>55<br>57<br>59<br>61<br>63<br>65<br>67<br>69<br>71<br>73<br>75<br>77 79 81 83 85 87 89 91 93 95 97 99 101<br>p38α<br>p38β<br>103 105 107 109 111 113 115 117<br>119<br>121<br>123<br>125<br>127<br>131<br>129<br>133<br>135<br>137<br>139<br>141<br>143<br>145<br>147<br>151<br>149<br>153<br>155<br>157<br>159<br>161<br>163<br>165<br>167<br>171<br>169<br>173<br>175 177<br>179 181 183185189 191 193<br>15 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Animal Models Supporting the Development of ATI-450 in<br>Immuno-Inflammatory Diseases<br>Therapeutic Area Animal Model Reference<br>Rheumatoid<br>Arthritis / Psoriatic<br>Arthritis<br>Rat streptococcal cell wall arthritis model<br>• Protection against bone deterioration<br>• Protection against lethality<br>Inhibition of cellular IL1β mRNA stability &<br>translation<br>Wang C, et al. J Exp Med.<br>2018;215(5):1315-1325.<br>Inflammatory<br>Bowel Disease<br>Adoptive transfer mouse model of colitis<br>• Endoscopy scores show disease control<br>• Decreased inflammatory infiltrate<br>• Protected structural integrity of mucosa<br>Strasser S, et al.<br>Integrative Biology.<br>2019;11(7):301-314.<br>Cryopyrin-<br>Associated<br>Periodic<br>Syndromes<br>(CAPS)<br>Murine NOMID (severe form of CAPS)<br>transgenic model<br>Human CAPS PBMC* IL1β modulation<br>Wang C, et al. J Exp Med.<br>2018;215(5):1315-1325.<br>* PBMC = Peripheral blood mononuclear cells<br>16 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>MK2 – Potential Effect in Rheumatoid Arthritis<br>ATI-450 regulates cells and cytokines involved in RA<br>MK2 is a key regulator of pathogenic signals in chronic immuno-inflammatory diseases<br>Cells<br>Monocyte/Macrophage<br>Osteoclast<br>Epithelial Cells<br>RA Synovial Fibroblast<br>Chondrocytes<br>Cytokines<br>TNFα, IL1β, IL1a<br>IL6, IL8, IL18, RANKL<br>Normal Joint RA Joint<br>Strand V, et al. Nat Rev Drug Discov. 2007;6(Jan 2007):75-92.<br>ATI-450: for bold items above data on file and Wang<br>C, et al. J Exp Med. 2018;215 (5):1315-1325.<br>17 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>In vivo Preclinical Data of MK2 Pathway Inhibitor ATI-450<br>Normal Vehicle 450 (5 mpk)<br>Joint Protection in Rat Arthritis Model1<br>Cytokine Modulation in Orphan<br>Autoinflammatory Disease (CAPS)1<br>Normal Inflamed Inflamed + ATI-450<br>Blockade of Gut Inflammatory Infiltrate in Murine Adoptive<br>Transfer Ulcerative Colitis Model2<br>1 Wang C, et al. J Exp Med. 2018;215(5):1315-1325.<br>2 Strasser S, et al. Integrative Biology. 2019;11(7):301-314.<br>0.8<br>1<br>1.2<br>1.4<br>1.6<br>1.8<br>2<br>2.2<br>2.4<br>2.6<br>2.8<br>0 5 10 15 20<br>Paw Volume<br>-<br>ml<br>Study Day<br>Vehicle CDD450 - 10 MPK CDD450 - 5 MPK CDD110 - 1.5 MPK<br>Oral dosing initiated<br>vehicle<br>ATI-450<br>IL1β<br>(bone marrow fluid)<br>CDD-450 - + - +<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>70<br>(<br>p<br>g<br>)<br>(<br>n<br>g<br>/<br>m<br>l<br>)<br>0<br>0.5<br>1.0<br>1.5<br>2.0<br>2.5<br>3.0<br>Normal NOMID<br>CDD-450 - + - +<br>Normal NOMID<br>IL6<br>(serum)<br>(<br>p<br>g<br>)<br>0<br>10<br>20<br>30<br>40<br>50<br>60<br>70<br>CDD-450 - + - +<br>Normal NOMID<br>IL18<br>(bone marrow fluid)<br>ATI-450<br>ATI-450<br>ATI-450<br>ATI-450<br>PLACEBO<br>18 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• In CAPS,<br>osteoclastogenesis gives<br>rise to low bone mass<br>(osteopenia)<br>•(a) When bone marrow<br>derived macrophages<br>(BMDM) from NOMID<br>mice are stimulated with<br>RANKL (RANK ligand),<br>they differentiate into<br>osteoclasts<br>•(b) ATI-450 blocks this<br>macrophage differentiation<br>Mouse Model: ATI-450 Inhibits RANKL-induced<br>Osteoclastogenesis<br>ATI-450 inhibits RANKL-stimulated<br>macrophage differentiation into<br>osteoclasts from NOMID mice<br>* Wang C, et al. J Exp Med. 2018;215(5):1315-1325.<br>RANKL<br>stimulation<br>Macrophages<br>Osteoclasts<br>NOMID BMDM<br>NOMID BMDM<br>Plus ATI-450<br>(a) (b)<br>Bone marrow derived macrophages (BMDM) from NOMID mice<br>19 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Mouse Model: LPS-Induced TNFa Production<br>ATI-450 demonstrated durable response (no tachyphylaxis)<br>• CDD-111 and ATI-450 administered to mice in<br>feed starting day 1 and continuing through day<br>28<br>• At the time point indicated, mice were LPS<br>challenged and blood TNFa levels determined<br>0<br>20<br>40<br>60<br>80<br>100<br>120<br>140<br>160<br>180<br>0.5 2 3 4<br>CDD111<br>CDD450 ATI-450<br>% Control Response<br>Weeks on Drug<br>• Global investigational<br>p38 inhibitor CDD-111<br>lost inhibition over<br>time<br>• MK2 inhibitor ATI-<br>450 (investigational<br>compound)<br>demonstrated<br>durable response<br>(no tachyphylaxis)<br>TNF<br>-<br>α<br>CDD-111<br>* Wang C, et al. J Exp Med. 2018;215(5):1315-1325. 20 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Ex vivo Preclinical Data: ATI-450 Inhibits IL1β Expression in<br>PBMCs from a Patient with CAPS<br>• Peripheral blood mononuclear cells<br>(PBMCs) were isolated from patients<br>with CAPS and healthy controls.<br>• In patients with CAPS (Muckle Wells<br>Syndrome; MWS), IL1β expression is<br>triggered by exposure to low<br>temperatures.<br>• PBMCs from patients with CAPS<br>spontaneously produced high<br>amounts of IL1β at 32°C but not at<br>37°C.<br>• ATI-450 blocks temperature stress<br>induced IL1β production.<br>* Wang C, et al. J Exp Med. 2018;215(5):1315-1325. 21 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-450 Clinical Development<br>Rheumatoid Arthritis Phase 2a Clinical Trial<br>• 12 wks: ATI-450 vs placebo<br>• Assess CRP dynamics<br>• Clinical Disease Activity/PD Biomarkers<br>• MRI: wrist synovitis<br>• Safety and tolerability<br>Demonstrate proof of<br>concept data<br>Rheumatoid Arthritis<br>Psoriasis<br>Psoriatic Arthritis Hidradenitis Suppurativa<br>Inflammatory Bowel Disease<br>Gout<br>Autoinflammatory<br>Diseases<br>Phase 1 Single and Multiple Ascending Doses<br>• Safety, PK, Tolerability<br>• PD (inhibition of TNFα, IL1b, IL6, IL8 & Hsp27)<br>22 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• Three-Part Study:<br>✓ Part A: single ascending dose (SAD) plus food effect (n=32)<br>• 4 cohorts: 10mg, 30mg, 50mg, 100mg (100mg repeated with high fat<br>meal)<br>• 8 subjects (6 active, 2 placebo). Single dose after overnight fast<br>✓ Part B: multiple ascending dose (MAD) (n=30)<br>• 3 cohorts: 10mg, 30mg, 50mg all BID for 7 days<br>• 10 subjects (8 active, 2 placebo)<br>✓ Part C: methotrexate (MTX) drug-drug interaction (DDI) (n=15)<br>• 1 cohort: MTX day 1 and 8. ATI-450 on days 2-9<br>• 15 subjects all dosed with active<br>• Demographics: (All dose groups, all parts)<br>✓ Age: Mean 34 years<br>✓ Gender: 44 female/33 male<br>✓ Race: White-40, Black-32, Other-5<br>ATI-450-PKPD-101<br>Trial Design and Demographics<br>23 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Most Common Adverse Events (≥2 subjects in the trial)<br>• No serious adverse events or adverse events that led to discontinuation of study medication<br>• All adverse events were mild in severity and did not interfere with everyday activities<br>• A trend of a decrease in absolute neutrophil count was observed<br>✓ No correlation with clinical sequelae<br>✓ This effect is consistent with the pharmacodynamic profile of certain anti-TNF therapies1<br>ATI-450-PKPD-101<br>Safety: ATI-450 Generally Well-Tolerated<br>Preferred Term<br>ATI-450<br>n (%)<br>(n=48)<br>Placebo<br>n (%)<br>(n=14)<br>Dizziness 6 (12.5) 0<br>Headache 10 (20.8) 2 (14.3)<br>Upper respiratory tract<br>infection 3 (6.3) 1 (7.1)<br>Constipation 3 (6.3) 1 (7.1)<br>Nausea 2 (4.2) 1 (7.1)<br>Abdominal pain 2 (4.2) 0<br>Vomiting 0 2 (14.3)<br>Preferred Term<br>ATI-450<br>n (%)<br>(n=15)<br>Dizziness 7 (46.7)<br>Headache 1 (6.7)<br>Upper respiratory tract<br>infection 1 (6.7)<br>Constipation 0<br>Nausea 0<br>Abdominal pain 0<br>Vomiting 0<br>SAD/MAD cohorts (blinded) DDI cohort (unblinded ATI-450 + MTX)<br>1 Dillingh M, et al. Front. Immunol. 2016;7(508):1-9.<br>* Data on file. 24 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-450-PKPD-101<br>MAD Pharmacokinetics: Dose Proportional PK<br>25<br>Mean (SD) plasma concentration-time profiles of ATI-450: Day 7<br>t½ = 9-12 hours<br>* Data on file |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-450-PKPD-101: Day 7 MAD PD Marker Time Dependence<br>Target Biomarker pHSP27 and Cytokines TNFa and IL1b<br>• ATI-450 dosed orally BID for 7 days in healthy subjects at doses of 10mg, 30mg and 50mg<br>• Day 1 (predose) is from blood taken on day 1 just prior to the first dose of ATI-450<br>• Samples ex vivo stimulated with LPS<br>• Data expressed as mean +/- SEM<br>TNFa IL1b pHSP27<br>Day<br>1 2 3 4 5 6 7<br>ATI-450 BID<br>Blood for ex-<br>vivo assay predose 4 hr 12 hr<br>26<br>* Data on file |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-450-PKPD-101: Day 7 MAD PD Biomarker Time Dependence<br>Cytokines IL6 and IL8<br>• ATI-450 dosed orally BID for 7 days in healthy subjects at doses of 10mg, 30mg and 50mg<br>• Day 1 (pre-dose) is from blood taken on day 1 just prior to the first dose of ATI-450<br>• Samples ex vivo stimulated with LPS<br>• Data expressed as mean +/- SEM<br>Day<br>1 2 3 4 5 6 7<br>predose 4 hr 12 hr<br>ATI-450 BID<br>Blood for ex-<br>vivo assay<br>27<br>* Data on file |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20) 28<br>*IC80 values generated with all SAD/MAD exposure data using the Emax model in WinNonlin<br>** 50 mg BID MAD Cohort<br>50 mg BID Ctrough = 87.9 ng/ml<br>50 mg BID Cmax = 215 ng/ml<br>The MAD 50mg BID cohort achieved systemic drug concentrations in excess of IC80 for pHSP27,<br>TNFa, IL1b and IL8 at Cmax (3.5-6.0X) and Ctrough (1.4-2.4X).<br>Biomarker *IC80<br>ng/ml<br>**Ctrough<br>Multiple of IC80<br>**Cmax<br>Multiple of IC80<br>pHSP27 36.7 2.4x 6.0x<br>TNFa 62.6 1.4x 3.5x<br>IL1b 40.8 2.2x 5.4x<br>IL6 747.8 0.1x 0.3x<br>IL8 38.8 2.3x 5.6x<br>ATI-450-PKPD-101<br>Multiples of Cytokine IC80 Across Dosing Interval<br>* Data on file. |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>In Vitro Model: ATI-450 Inhibits IL1b-Stimulated Cytokines<br>in Human Whole Blood<br>29<br>IL1b-Stimulated HWB<br>ATI-450 was added to freshly isolated human whole blood<br>for 1 hr and stimulated with IL1b (10 ng/ml) for 5 hrs.<br>Cytokines were measured by Meso Scale Discovery<br>technology.<br>Cytokine IC80 (ng/ml)<br>TNFa 31 + 6<br>IL6 41 + 20<br>IL8 40 + 12<br>* Data on file. |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• Discovered a novel approach to drug the target<br>• Potential alternative for diseases treated by biologics and JAK<br>inhibitors<br>✓ Robust efficacy in a range of inflammation and mouse cancer models1,2<br>• Phase 1 SAD/MAD Data*<br>✓ Generally well-tolerated at all doses<br>✓ Dose response noted<br>✓ Potent target suppression: ATI-450 dosed at 50 mg BID drove plasma levels 1.4-<br>2.4x greater than those required to hit an IC80 for 4 key biomarkers<br>• Phase 2a clinical trial in Rheumatoid Arthritis underway<br>MK2 inhibitor ATI-450 Summary<br>1 Murali B, et al. Cancer Res. 2018;78(19):1-13.<br>2 Wang C, et al. J Exp Med. 2018;215(5):1315-1325.<br>* Data on file<br>30 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-1777 (Topical Soft-JAK Inhibitor)<br>(Investigational Drug Candidate)<br>31 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Atopic Dermatitis Opportunity<br>• Positioning:<br>• Comparable efficacy to other<br>topical JAKs but “soft” drug to<br>minimize the potential for systemic<br>immunosuppression<br>• JAK1/3 selective to minimize JAK2<br>inhibition toxicity<br>• Deliver in a patient-friendly<br>formulation<br>• Moderate to severe patients<br>Approach<br>• Plan to study in patients with<br>moderate-to-severe AD<br>• IND mid year<br>• Next key milestone: First In Human -<br>2H2020<br>Status<br>• Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin<br>condition1<br>✓ The prevalence rate for AD in the US is 10-12% in children and 0.9% in adults2<br>✓ Market projected to be $8-12 billion at peak (moderate-to-severe AD)3<br>✓ Systemic and topical JAK inhibition has demonstrated promising results in AD<br>clinical trials4<br>1 https://emedicine.medscape.com/article/1049085-overview. Last accessed 5-26-20.<br>2 https://emedicine.medscape.com/article/1049085-overview#a8. Last accessed 5-26-20.<br>3 Auster M, et al. Something Big Is Getting Bigger [research note]. Credit Suisse Equity Research; 2019.<br>4 Shreberk-Hassidim R, et al. J Am Acad Dermatol. 2017;Apr;76(4):745-753. 32 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• No adverse effects noted (10% body surface area, QD)<br>• Bleeds at 0.5, 1, 2, 4, 8, 12, and 24 hours post-application: Days 1 and 6<br>• All plasma samples were below limit of quantification (<0.50 ng/mL) – well<br>below cellular IC50<br>Minipig Model: ATI-1777 Nonclinical Safety Program TK Data<br>Tolerability/Toxicokinetic with 7-day dermal administration (non-GLP)<br>1 Data on file.<br>2 Chen X, et al. Clin Pharmacol Drug Dev. 2013;3(1):34–42.<br>3 Punwani N, et al. Br J Dermatol. 2015;173:989–997.<br>HUMAN2,3 MINIPIG1<br>33 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• Single application of 2% ATI-1777<br>development formulation<br>significantly inhibits IL15 (JAK1/3)<br>induced gene induction (CCL8).<br>Porcine Model: ATI-1777 Blocks IL15 Induced CCL8 mRNA<br>in Skin<br>Apply<br>formulation to<br>back of pig,<br>wait 1 hr<br>Intra-dermal<br>Injection of<br>porcine IL15,<br>wait 3 hr<br>Harvest 6 mm<br>biopsy,<br>prepare RNA,<br>measure CCL8<br>by qPCR<br>* Data on file 34 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-2138 (ITK/TXK/JAK3 Inhibitor)<br>(Investigational Drug Candidate)<br>35 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>• ATI-2138 covalently blocks ITK/TXK/JAK3*<br>✓ Potential for synergistic efficacy<br>• ITK/TXK required for T-cell receptor (TCR)<br>signaling<br>• JAK3 required for gc cytokines (IL-2/4/7/9/15/21)<br>✓ PD effects persist after plasma clearance<br>• ATI-2138 is selective for T-cell signaling<br>✓ Drugs like cyclosporine (CsA) inhibit calcineurin<br>which is widely expressed<br>✓ ATI-2138 targets unique kinases expressed only in<br>immune cells<br>✓ ATI-2138 may potentially treat any T-cell<br>mediated autoimmune disease<br>ATI-2138: Covalent ITK/TXK/JAK3 (ITJ) Inhibitor<br>TH<br>Cells<br>TCR/CD3<br>T<br>cell<br>T<br>cell<br>T cells<br>T<br>cell<br>ATI-2138<br>APCs<br>* Data on file 36 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-2138 is a Potent Covalent Inhibitor<br>ATI-2138 potently inhibits<br>ITK/TXK and JAK3 in cells and in<br>whole blood<br>Assay Description ATI-2138<br>IC50 (nM) Assay<br>ITK/TXK activity 7 Jurkat pPLCγ-1<br>JAK1/3 activity 20 PBMC pSTAT-5<br>Both ITK/TXK and JAK3 13 HWB<br>αCD3/IL15 IFNγ<br>BTK activity 52 Ramos pPLCγ-2<br>Cellular Inhibition of JAK and ITK/TXK<br>Co-Crystal Structure of ATI-2138/ITK -<br>shows ATI-2138 covalent binding to ITK<br>Covalent Bond between<br>ATI-2138 and ITK<br>ATI-2138<br>Covalent bond between<br>ITKcys and ATI-2138<br>* Data on file 37 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>ATI-2138 reduced inflammation and bone mineral density loss<br>Rat Adjuvant Induced Arthritis (AIA) Model:<br>ATI-2138 Reduced Inflammation and Protected Bone<br>VEH QD<br>ATI-2138-10-QD<br>ATI-2138-30-QD<br>ATI-2138-5-BID<br>ATI-2138-15-BID<br>120<br>140<br>160<br>180<br>200<br>220<br>ATI-2138 bone mineral<br>density in rat AIA study<br>B<br>M<br>D<br><br>(<br>m<br>g<br>/<br>c<br>m<br>2<br>)<br>****<br>****<br>****<br>****<br>**** p <0.00001<br>Adjuvant<br>induced bony<br>destruction of<br>rat hindlimb<br>Preservation of<br>Joint Material with<br>ATI-2138<br>* Data on file<br>ATI-2138<br>Vehicle<br>ATI-2138-10-QD<br>ATI-2138 30 QD<br>ATI-2138 5 BID<br>ATI-2138 15 BID<br>7<br>8<br>9<br>10<br>11<br>12<br>A<br>n<br>k<br>l<br>e<br><br>D<br>i<br>a<br>m<br>e<br>t<br>e<br>r<br>,<br><br>m<br>m<br>Day 23 ankle diameter<br>Measure ankle diameter<br>Weigh every other day<br>Male<br>Lewis Rat<br>Day 0<br>Inject with<br>adjuvant<br>Day 6<br>Begin PO dosing<br>of ATI-2138<br>Day 12 Day 23<br>Histology, BMD<br>38 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Biopharmaceutical Company<br>Cash Position<br>$79 million as of March 31, 2020<br>Commitment to Patients<br>Focus on addressing the needs of<br>patients with immuno-inflammatory<br>diseases who lack satisfactory treatment<br>options<br>Research and Development<br>Scientific leadership in immuno-inflammatory<br>diseases - innovative clinical and regulatory<br>strategies<br>Executive Team<br>Proven track record of R&D and<br>business development<br>Pipeline<br>Multiple therapeutic programs<br>ranging from discovery to Phase 3<br>Intellectual Property<br>Global IP estate<br>KINect™ Technology Platform<br>Proprietary discovery engine enables<br>targeted design of novel drug candidates<br>IP<br>39 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>Catalysts<br>Milestone 2020 2021<br>1Q 2Q 3Q 4Q 1Q 2Q<br>ATI-450 (MK2 Inhibitor)<br>Phase 1 Data (SAD/MAD) ✓<br>Initiate Phase 2a Trial in Rheumatoid Arthritis ✓<br>ATI-1777 (Topical Soft-JAK Inhibitor)<br>Submit IND<br>Initiate Phase 1/2 Trial<br>ATI-2138 (ITK/TXK/JAK3 Inhibitor)<br>Submit IND<br>Initiate Phase 1 Trial<br>40 |
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| © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (XX) © Copyright 2020 Aclaris Therapeutics, Inc. All rights reserved (PP--US-0480 05/20)<br>THANK YOU<br>EMPOWERING PATIENTS THROUGH<br>KINOME INNOVATION |
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