The investigators hypothesize that MK2 inhibition may improve efficacy of mFOLFIRINOX chemotherapy for patients with pancreatic ductal adenocarcinoma (PDAC).

Start Date31 Dec 2024

Sponsor / Collaborator

Washington University School of Medicine

[+2]

NCT06374459 / Not yet recruitingPhase 1/2IIT

A Phase Ib/II Trial of Zunsemetinib in Combination With Capecitabine in Patients With Hormone Receptor-Positive and HER2-Negative Metastatic Breast Cancer With Bone Metastasis

This is a phase Ib/II study evaluating the safety and efficacy of zunsemetinib (ATI-450) with capecitabine in patients with hormone receptor-positive and HER2-negative (HR+/HER2-) metastatic breast cancer (MBC).

Start Date31 Dec 2024

Sponsor / Collaborator

Washington University School of Medicine

[+2]

EUCTR2022-000847-62-PL / Not yet recruitingPhase 2

A Phase 2a, Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Zunsemetinib vs Placebo in Patients with Moderate-to-Severe Active Psoriatic Arthritis

Start Date17 Oct 2022

Sponsor / Collaborator

Aclaris Therapeutics, Inc.

100 Clinical Results associated with Zunsemetinib

100 Translational Medicine associated with Zunsemetinib

100 Patents (Medical) associated with Zunsemetinib

Literatures (Medical) associated with Zunsemetinib

01 Oct 2023·International journal of radiation oncology, biology, physics

Investigating the Role of MK2 in Head and Neck Squamous Cell Carcinoma Growth, Metastasis and STING Pathway Activation.

Article

Author: Yelder, T ; Lominska, C E ; Schmidt, A ; Gao, H ; Okwuone, D D D ; Spiess, C ; Millington, G ; Markiewicz, M A ; Berggren, K ; Wang, J ; Morgan, D ; Smith, H ; Gan, G N

PURPOSE/OBJECTIVE(S):

Our prior work demonstrated that inhibition of MAPKAPK2 (MK2) can enhance radiation (RT)-mediated in vivo head and neck squamous cell carcinoma (HNSCC) tumor control and survival in preclinical immune incompetent models. The cytosolic DNA sensor cyclic GMP-AMP synthetase (cGAS) and its downstream adaptor protein, stimulator of interferon genes (STING), are conserved proteins within the innate immune signaling pathways and are important for mediating host defense against microbial infection and can play a role in anti-cancer immunity. We hypothesized that loss of MK2 enhances radiation-induced cGAS-STING pathway activation leading to improved tumor control and survival.

MATERIALS/METHODS:

MK2 shRNA knockdown human (Tu167, CAL27) and MK2 Cas9/CRISPR knockout (KO) syngeneic murine (Ly2, MLM3) HNSCC cell lines were treated with 10 Gy irradiation. Micronuclei were quantitated by DAPI-immunofluorescence (IF). Protein changes in cGAS-STING were evaluated by immunoblot. Inflammatory cytokine production including Type I IFNβ1 were evaluated by RT-qPCR. Ly2 and MLM3 cells were orthotopically or flank engrafted into immune competent mice (Balb/c, C57Bl/6, respectively) for animal tumor control-survival studies. Tumor immune cell infiltrate was examined using FACS and immunohistochemistry. Selected drug studies using the MK2 inhibitor, ATI-450, were performed with RT.

RESULTS:

Loss of MK2 in HNSCC (Tu167, CAL27, Ly2, MLM3) treated with RT led to a significant increase in micronuclei formation compared to control cells. MK2-enhanced micronuclei generation following RT could be inhibited with the actin filament polymerization inhibitor, cytochalasin B. RT treatment of MK2 shRNA cells led to increased cGAS and phospho-STING levels compared to either treatment alone. IFNβ1 levels were significantly higher in HNSCC cell lines treated with RT and with MK2 inhibited by an MK2 inhibitor (ATI-450) or genetic reduction compared to either treatment alone. In-vivo implantation of MLM3 cells into C57Bl/6 comparing control vs MK2 KO tumors treated with ±8 Gy RT demonstrated improved mouse survival favoring RT+MK2 KO over RT, MK2 KO or parental (63, 58, 58.5, 35 days, respectively). FACS analysis of MLM3 WT v KO tumors 3 days post RT showed an overall increase in the number of CD3/CD8 T-cells infiltrating into the tumor in all groups except for parental tumors. Further analysis demonstrated that loss of MK2 reversed CD8 T-cell exhaustion and when combined with radiotherapy led to increased CD8 T-cell activation. Furthermore, activated CD4 and CD8 T cells were reduced in WT+RT cells compared to WT tumors whereas no reduction was seen in the KO or KO+RT.

CONCLUSION:

HNSCC tumor MK2 inhibition enhances RT-mediated micronuclei formation and subsequent cGAS-STING-IFNβ1 levels. Loss of HNSCC MK2 leads to increased CD4-CD8 T-cell infiltration into the tumor and this effect is enhanced following RT. Targeting tumor MK2 may facilitate improved tumor control.

01 Feb 2023·ACR open rheumatology

Selective Inhibition of the MK2 Pathway: Data From a Phase IIa Randomized Clinical Trial in Rheumatoid Arthritis

Article

Author: Kivitz, Alan ; Burt, David ; Bangs, Madison C. ; Singhal, Atul ; Hope, Heidi Rath ; Monahan, Joseph B. ; Gordon, David ; Huff, Emma E.

Objective:

The study objective was to evaluate the safety, tolerability, pharmacodynamics, and preliminary efficacy of ATI‐450 with methotrexate in patients with rheumatoid arthritis (RA).

Methods:

A parallel‐assignment, placebo‐controlled, investigator‐blinded/patient‐blinded multicenter study evaluated patients with moderate‐to‐severe RA aged 18 to 70 years. Eligible patients were randomized (1:1) to ATI‐450 50‐mg oral tablets twice daily or placebo with a stable weekly dose of methotrexate for 12 weeks. The primary objective was to assess ATI‐450 safety and tolerability. The secondary objectives were to assess the median percentage change from baseline high‐sensitivity C‐reactive protein (hs‐CRP) levels, the mean change from baseline in Disease Activity Score in 28 joints based on CRP level (DAS28‐CRP) and Rheumatoid Arthritis Magnetic Resonance Imaging Score hand‐wrist assessments of synovitis or bone erosion at week 12, and the proportion of patients with American College of Rheumatology 20/50/70 (ACR 20/50/70) and with DAS28‐CRP scores of less than 2.6. The exploratory outcomes were change from baseline in endogenous and ex vivo–stimulated cytokine levels.

Results:

ATI‐450 was well tolerated with no severe adverse events reported. ATI‐450 reduced median hs‐CRP levels by 42% or more at all posttreatment timepoints. In the ATI‐450 group, a mean (median) decrease in DAS28‐CRP score of 2.0 (2.1) was observed at week 12; proportions of patients with an ACR 20/50/70 response in the per‐protocol population were 60%, 33%, and 20%, respectively, at week 12. Endogenous plasma levels of key inflammatory cytokines (tumor necrosis factor α, macrophage inflammatory protein 1β, interleukin 6, interleukin 8) were reduced across the 12 treatment weeks.

Conclusion:

This is the first clinical study demonstrating that selective mitogen‐activated protein kinase (MAPK)–activated protein kinase 2 (MK2) pathway blockade leads to a sustained antiinflammatory effect. This suggests that targeting the MK2 pathway mitigates the tachyphylaxis observed with p38 MAPK inhibitors in RA and supports further exploration.

01 Dec 2021·Science translational medicineQ1 · MEDICINE

The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress.

Q1 · MEDICINE

Article

Author: Wei, Qing ; Ruzinova, Marianna B ; Monahan, Joseph B ; Grierson, Patrick M ; Herndon, John ; Zhang, Daoxiang ; Lim, Kian-Huat ; Dodhiawala, Paarth B ; Chen, Timothy Hung-Po ; Li, Lin ; Cheng, Yi ; Khawar, Iftikhar Ali

Combination chemotherapies remain the cornerstone treatment for pancreatic ductal adenocarcinoma (PDAC), but de novo and acquired resistance is common. In this study, we aimed to identify and characterize resistance mechanisms to a FIRINOX chemotherapy regimen (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) because it is the most aggressive regimen currently used clinically for patients with PDAC. Using an unbiased reverse-phase protein array, we detected phospho-activation of heat shock protein 27 (Hsp27) as the most up-regulated event after FIRINOX treatment in PDAC cells. Silencing HSP27 by RNA interference or by a small-molecule inhibitor enhanced apoptosis caused by FIRINOX in vitro. Mechanistically, FIRINOX up-regulated tumor necrosis factor–α (TNFα), causing autocrine phosphorylation and activation of transforming growth factor–β–activated kinase 1 (TAK1), MAPK activated protein kinase 2 (MAPKAPK2 or MK2), and, ultimately, Hsp27. Targeting MK2, the kinase that directly phosphorylates Hsp27, abrogated Hsp27 activation, sensitized PDAC cells to apoptosis, and suppressed SN-38–induced protective autophagy in vitro, in part by blocking phospho-activation of Beclin1. In an autochthonous PDAC mouse model, the MK2 inhibitor ATI-450 decreased PDAC development and progression. When combined with FIRINOX, ATI-450 eliminated most PDAC foci and marked prolonged mouse survival without causing additional toxicity. Last, we found that high phospho-MK2 expression in tumors was associated with poorer survival of patients with PDAC. Our study identified MK2 as a mediator of genotoxic stress–induced activation of prosurvival pathways and provides preclinical support for combining an MK2 inhibitor with FIRINOX-based chemotherapies to treat PDAC.

News (Medical) associated with Zunsemetinib

06 Nov 2024

·www.globenewswire.com

Aclaris Therapeutics Reports Third Quarter 2024 Financial Results and Provides a Corporate Update

– First Patient Dosed in ATI-2138 Phase 2a Trial in Atopic Dermatitis As Previously Announced;Top-line Data Anticipated in First Half of 2025 – WAYNE, Pa., Nov. 06, 2024 (GLOBE NEWSWIRE) -- Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, today announced its financial results for the third quarter of 2024 and provided a corporate update. "The third quarter of 2024 marked an important milestone for Aclaris with the dosing of our first patient in the Phase 2a trial of ATI-2138 for moderate to severe atopic dermatitis," said Dr. Neal Walker, Interim President & CEO and Chair of the Board of Directors of Aclaris. "This milestone, combined with our robust financial position, underscores our commitment to executing a capital-efficient development strategy." Research and Development Highlights: ITK Inhibitor Programs ATI-2138, an investigational oral covalent ITK/JAK3 inhibitor Atopic Dermatitis (ATI-2138-AD-201): This Phase 2a open-label trial to investigate the safety, tolerability, pharmacokinetics, efficacy, and pharmacodynamics of ATI-2138 in patients with moderate to severe atopic dermatitis (AD) is ongoing. Aclaris continues to expect top-line data in the first half of 2025. ITK Selective Compound Aclaris is progressing a second generation ITK selective inhibitor to development candidate selection for autoimmune indications. Lepzacitinib (ATI-1777), an investigational topical “soft” JAK 1/3 inhibitor In January 2024, Aclaris reported positive top-line results from its Phase 2b trial of lepzacitinib in AD.Aclaris is currently seeking a global development and commercialization partner for this program (excluding Greater China). As previously announced, in 2022 Aclaris granted Pediatrix Therapeutics exclusive rights to develop and commercialize lepzacitinib in Greater China. Zunsemetinib (ATI-450), an investigational oral small molecule MK2 inhibitor Aclaris plans to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib as a potential treatment for pancreatic cancer and metastatic breast cancer. Aclaris expects these trials to be primarily funded by grants awarded to Washington University. Financial Highlights: Liquidity and Capital Resources As of September 30, 2024, Aclaris had aggregate cash, cash equivalents and marketable securities of $173.4 million compared to $181.9 million as of December 31, 2023. Aclaris anticipates that its cash, cash equivalents and marketable securities as of September 30, 2024 will be sufficient to fund its operations into 2028, without giving effect to any potential business development transactions, financing activities or the outcome of its strategic review. Financial Results Third Quarter 2024 Net loss was $7.6 million for the third quarter of 2024 compared to $29.3 million for the third quarter of 2023.Total revenue was $4.3 million for the third quarter of 2024 compared to $9.3 million for the third quarter of 2023. The decrease was primarily driven by higher milestones earned during the prior year period compared to the current year period.Research and development (R&D) expenses were $6.0 million for the quarter ended September 30, 2024 compared to $23.9 million for the prior year period. The $17.9 million decrease was primarily the result of: Zunsemetinib development expenses associated with clinical trials in 2023, and drug candidate manufacturing costs;Costs associated with lepzacitinib preclinical development activities and a Phase 2b clinical trial for AD which was completed in January 2024;ATI-2138 development expenses, including costs associated with a Phase 1 multiple ascending dose (MAD) trial which was completed in September 2023 and other preclinical activities, which were partially offset by clinical development expenses associated with a Phase 2a clinical trial which commenced in August 2024; andLower compensation-related expenses due to a decrease in headcount and higher forfeiture credits. General and administrative (G&A) expenses were $5.7 million for the quarter ended September 30, 2024 compared to $7.1 million for the corresponding prior year period. The decrease was primarily due to a reduction in compensation-related expenses due to lower headcount and higher forfeiture credits.Licensing expenses were $1.8 million for the quarter ended September 30, 2024 compared to $7.3 million for the corresponding prior year period. The decrease was primarily due to higher milestones earned during the prior year period compared to the current year period.Revaluation of contingent consideration resulted in a $0.8 million loss for the quarter ended September 30, 2024 compared to a loss of $1.7 million for the prior year period. Year-to-date 2024 Net loss was $35.5 million for the nine months ended September 30, 2024 compared to $87.0 million for the nine months ended September 30, 2023.Total revenue was $9.5 million for the nine months ended September 30, 2024 compared to $13.7 million for the nine months ended September 30, 2023. The decrease was primarily driven by higher milestones earned during the prior year period compared to the current year period.R&D expenses were $24.6 million for the nine months ended September 30, 2024 compared to $71.7 million for the corresponding prior year period. The $47.1 million decrease was primarily the result of: Zunsemetinib development expenses associated with clinical trials in 2023, and drug candidate manufacturing costs;Costs associated with lepzacitinib preclinical development activities and a Phase 2b clinical trial for AD which was completed in January 2024;ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial which was completed in September 2023 and other preclinical activities, which were partially offset by clinical development expenses associated with a Phase 2a clinical trial which commenced in August 2024; andLower compensation-related expenses due to a decrease in headcount and higher forfeiture credits. G&A expenses were $17.2 million for the nine months ended September 30, 2024 compared to $24.2 million for the prior year period. The decrease was primarily due to a reduction in compensation-related expenses due to lower headcount and higher forfeiture credits and the recognition of bad debt expense recorded in the prior year period from Aclaris’ determination that collection of amounts due from EPI Health are uncertain as a result of their filing for Chapter 11 bankruptcy protection.Licensing expenses were $4.1 million for the nine months ended September 30, 2024 compared to $9.0 million for the prior year period. The decrease was primarily due to higher milestones earned during the prior year period compared to the current year period.Revaluation of contingent consideration resulted in a $3.8 million loss for the nine months ended September 30, 2024 compared to a gain of $0.6 million for the corresponding prior year period. About Aclaris Therapeutics, Inc. Aclaris Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates to address the needs of patients with immuno-inflammatory diseases who lack satisfactory treatment options. The company has a multi-stage portfolio of drug candidates powered by a robust R&D engine exploring protein kinase regulation. For additional information, please visit www.aclaristx.com. Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release 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 “anticipate,” “believe,” “expect,” “intend,” “may,” “plan,” “potential,” “will,” and similar expressions, and are based on Aclaris’ current beliefs and expectations. These forward-looking statements include expectations regarding its plans for its development programs, including its plans to seek a development and commercialization partner for lepzacitinib, the clinical development of ATI-2138, including the timing of top-line data, its plan to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib, the sufficiency of its cash, cash equivalents and marketable securities to fund its operations into 2028, as well as its strategic review. 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, Aclaris’ ability to enter into strategic partnerships on commercially reasonable terms, the uncertainty regarding the macroeconomic environment 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, 2023, and other filings Aclaris makes with the U.S. Securities and Exchange Commission from time to time. These documents are available under the “SEC Filings” page of the “Investors” section of Aclaris’ website at www.aclaristx.com. Any forward-looking statements speak only as of the date of this press release and are based on information available to Aclaris as of the date of this release, 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. Aclaris Therapeutics, Inc.Condensed Consolidated Statements of Operations(unaudited, in thousands, except share and per share data) Three Months Ended Nine Months Ended September 30, September 30, 2024 2023 2024 2023Revenues: Contract research $645 $705 $1,926 $2,469 Licensing 3,701 8,577 7,583 11,210 Total revenue 4,346 9,282 9,509 13,679 Costs and expenses: Cost of revenue (1) 654 848 2,087 2,698 Research and development (1) 5,956 23,876 24,560 71,738 General and administrative (1) 5,653 7,091 17,249 24,198 Licensing 1,754 7,344 4,070 8,955 Revaluation of contingent consideration 800 1,700 3,800 (600)Total costs and expenses 14,817 40,859 51,766 106,989 Loss from operations (10,471) (31,577) (42,257) (93,310)Other income: Interest income 1,991 2,316 5,850 6,320 Non-cash royalty income 894 — 894 — Total other income 2,885 2,316 6,744 6,320 Net loss $(7,586) $(29,261) $(35,513) $(86,990)Net loss per share, basic and diluted $(0.11) $(0.41) $(0.50) $(1.25)Weighted average common shares outstanding, basic and diluted 71,381,731 70,807,934 71,249,813 69,452,495 (1) Amounts include stock-based compensation expense as follows: Cost of revenue $232 $347 $707 $1,119 Research and development 1,124 3,072 2,192 9,168 General and administrative 1,648 2,529 5,097 8,989 Total stock-based compensation expense $3,004 $5,948 $7,996 $19,276 Aclaris Therapeutics, Inc.Selected Consolidated Balance Sheet Data(unaudited, in thousands, except share data) September 30, 2024 December 31, 2023Cash, cash equivalents and marketable securities $173,436 $181,877 Total assets $182,394 $197,405 Total current liabilities $18,816 $30,952 Total liabilities $52,243 $40,226 Total stockholders’ equity $130,151 $157,179 Common stock outstanding 71,417,513 70,894,889 Aclaris Therapeutics, Inc.Selected Consolidated Cash Flow Data(unaudited, in thousands) Nine Months Ended Nine Months Ended September 30, 2024 September 30, 2023Net loss $(35,513) $(86,990)Depreciation and amortization 664 635 Stock-based compensation expense 7,996 19,276 Revaluation of contingent consideration 3,800 (600)Changes in operating assets and liabilities 11,916 (3,885)Net cash used in operating activities $(11,137) $(71,564) Aclaris Therapeutics Contact: investors@aclaristx.com

Phase 2Financial StatementLicense out/inPhase 1Clinical Result

07 Aug 2024

·www.globenewswire.com

Aclaris Therapeutics Reports Second Quarter 2024 Financial Results and Provides a Corporate Update

-Initiated Phase 2a Study Activities for ATI-2138 in Atopic Dermatitis--Strengthened Balance Sheet Through Sale of Future OLUMIANT® Royalties for Proceeds of up to $31.5 Million- WAYNE, Pa., Aug. 07, 2024 (GLOBE NEWSWIRE) -- Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, today announced its financial results for the second quarter of 2024 and provided a corporate update. "With study activities underway for our ATI-2138 Phase 2a trial in moderate to severe atopic dermatitis and the strengthening of our balance sheet through the completion of our royalty purchase agreement with OMERS, we're well-positioned to drive our strategic initiatives forward,” said Dr. Neal Walker, Interim President & CEO and Chair of the Board of Directors of Aclaris. “Our focus remains on leveraging our resources to maximize the potential of our innovative drug candidates, pursue available opportunities, and create long-term value for patients and shareholders alike." Research and Development Highlights: ITK Inhibitor Programs ATI-2138, an investigational oral covalent ITK/JAK3 inhibitor ATI-2138-AD-201: Aclaris is activating clinical sites and expects to enroll patients in the coming weeks in this Phase 2a open-label trial to investigate the safety, tolerability, pharmacokinetics, efficacy, and pharmacodynamics of ATI-2138 in subjects with moderate to severe atopic dermatitis (AD). ITK Selective Compound Aclaris is progressing to development candidate selection a second generation ITK selective inhibitor for autoimmune indications. Lepzacitinib (ATI-1777), an investigational topical “soft” JAK 1/3 inhibitor In January 2024, Aclaris reported positive top-line results from its Phase 2b trial of lepzacitinib in atopic dermatitis (AD).Aclaris is currently seeking a global development and commercialization partner for this program (excluding Greater China). As previously announced, in 2022 Aclaris granted Pediatrix Therapeutics exclusive rights to develop and commercialize lepzacitinib in Greater China. Zunsemetinib (ATI-450), an investigational oral small molecule MK2 inhibitor Aclaris plans to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib as a potential treatment for pancreatic cancer and metastatic breast cancer. Aclaris expects these trials to be primarily funded by grants awarded to Washington University. Financial Highlights: Liquidity and Capital Resources As of June 30, 2024, Aclaris had aggregate cash, cash equivalents and marketable securities of $149.9 million compared to $181.9 million as of December 31, 2023. In July 2024, Aclaris received an upfront payment of $26.5 million and is eligible to receive up to an additional $5.0 million upon the achievement of certain sales milestones in connection with the sale of OLUMIANT® royalties and milestones to OMERS Life Sciences. Aclaris anticipates that its cash, cash equivalents and marketable securities as of June 30, 2024 in combination with the $26.5 million from the sale of OLUMIANT® royalties and milestones will be sufficient to fund its operations into 2028, without giving effect to any potential new business development transactions, additional financing activities or the outcome of its strategic review. Financial Results Second Quarter 2024 Net loss was $11.0 million for the second quarter of 2024 compared to $29.6 million for the second quarter of 2023. Total revenue was $2.8 million for the second quarter of 2024 compared to $1.9 million for the second quarter of 2023. The increase was primarily driven by an increase in royalties under the Lilly license agreement during the three months ended June 30, 2024. Research and development (R&D) expenses were $8.8 million for the quarter ended June 30, 2024 compared to $25.3 million for the prior year period. The $16.5 million decrease was primarily the result of lower: Zunsemetinib development expenses associated with clinical activities for a Phase 2a trial for hidradenitis suppurativa which was completed in March 2023, a Phase 2b trial for rheumatoid arthritis which was completed in November 2023, a Phase 2b trial for psoriatic arthritis which was discontinued in December 2023, and drug candidate manufacturing costs;Costs associated with lepzacitinib preclinical development activities and a Phase 2b clinical trial for AD which was completed in January 2024;ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial which was completed in September 2023 and other preclinical activities; andCompensation-related expenses due to a decrease in headcount and higher forfeiture credits. General and administrative (G&A) expenses were $4.8 million for the quarter ended June 30, 2024 compared to $8.3 million for the prior year period. The decrease was primarily due to a reduction in compensation-related expenses due to lower headcount and higher forfeiture credits, along with the recognition of bad debt expense recorded in the prior year period from Aclaris’ determination that collection of amounts due from EPI Health are uncertain as a result of their filing for Chapter 11 bankruptcy protection. Licensing expenses were $1.3 million for the quarter ended June 30, 2024 compared to $0.6 million for the prior year period. The increase was due to an increase in royalties earned under the Lilly license agreement. Revaluation of contingent consideration resulted in a $0.2 million loss for the quarter ended June 30, 2024 compared to a gain of $1.5 million for the prior year period. Year-to-date 2024 Net loss was $27.9 million for the six months ended June 30, 2024 compared to $57.7 million for the six months ended June 30, 2023. Total revenue was $5.2 million for the six months ended June 30, 2024 compared to $4.4 million for the six months ended June 30, 2023. The increase was primarily driven by an increase in royalties under the Lilly license agreement during the six months ended June 30, 2024. R&D expenses were $18.6 million for the six months ended June 30, 2024 compared to $47.9 million for the prior year period. The $29.3 million decrease was primarily the result of lower: Zunsemetinib development expenses associated with clinical activities for a Phase 2a trial for hidradenitis suppurativa which was completed in March 2023, a Phase 2b trial for rheumatoid arthritis which was completed in November 2023, a Phase 2b trial for psoriatic arthritis which was discontinued in December 2023, and drug candidate manufacturing costs;Costs associated with lepzacitinib preclinical development activities and a Phase 2b clinical trial for AD which was completed in January 2024;ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial which was completed in September 2023 and other preclinical activities; andCompensation-related expenses due to a decrease in headcount and higher forfeiture credits. G&A expenses were $11.6 million for the six months ended June 30, 2024 compared to $17.1 million for the prior year period. The decrease was primarily due to a reduction in compensation-related expenses due to lower headcount and higher forfeiture credits, a decrease in patent, legal and accounting related expenses, and the recognition of bad debt expense recorded in the prior year period from Aclaris’ determination that collection of amounts due from EPI Health are uncertain as a result of their filing for Chapter 11 bankruptcy protection. Licensing expenses were $2.3 million for the six months ended June 30, 2024 compared to $1.6 million for the prior year period. The increase was due to an increase in royalties earned under the Lilly license agreement. Revaluation of contingent consideration resulted in a $3.0 million loss for the six months ended June 30, 2024 compared to a gain of $2.3 million for the prior year period. OLUMIANT® is a registered trademark of Eli Lilly and Company. About Aclaris Therapeutics, Inc. Aclaris Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates to address the needs of patients with immuno-inflammatory diseases who lack satisfactory treatment options. The company has a multi-stage portfolio of drug candidates powered by a robust R&D engine exploring protein kinase regulation. For additional information, please visit www.aclaristx.com. Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release 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 “anticipate,” “believe,” “expect,” “intend,” “may,” “plan,” “potential,” “will,” and similar expressions, and are based on Aclaris’ current beliefs and expectations. These forward-looking statements include expectations regarding its plans for its development programs, including its plans to seek a development and commercialization partner for lepzacitinib, the clinical development of ATI-2138, its plan to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib, the sufficiency of its cash, cash equivalents and marketable securities to fund its operations into 2028, as well as its strategic plans and strategic review. 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, Aclaris’ ability to enter into strategic partnerships on commercially reasonable terms, the uncertainty regarding the macroeconomic environment 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, 2023, and other filings Aclaris makes with the U.S. Securities and Exchange Commission from time to time. These documents are available under the “SEC Filings” page of the “Investors” section of Aclaris’ website at www.aclaristx.com. Any forward-looking statements speak only as of the date of this press release and are based on information available to Aclaris as of the date of this release, 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. Aclaris Therapeutics, Inc.Condensed Consolidated Statements of Operations(unaudited, in thousands, except share and per share data) Three Months Ended Six Months Ended June 30, June 30, 2024 2023 2024 2023 Revenues: Contract research $625 $875 $1,281 $1,764 Licensing 2,141 994 3,882 2,633 Total revenue 2,766 1,869 5,163 4,397 Costs and expenses: Cost of revenue (1) 624 1,042 1,433 1,850 Research and development (1) 8,759 25,275 18,604 47,862 General and administrative (1) 4,752 8,317 11,596 17,107 Licensing 1,285 550 2,316 1,611 Revaluation of contingent consideration 200 (1,500) 3,000 (2,300)Total costs and expenses 15,620 33,684 36,949 66,130 Loss from operations (12,854) (31,815) (31,786) (61,733)Other income, net 1,868 2,246 3,859 4,004 Net loss $(10,986) $(29,569) $(27,927) $(57,729)Net loss per share, basic and diluted $(0.15) $(0.42) $(0.39) $(0.84)Weighted average common shares outstanding, basic and diluted 71,291,400 70,633,528 71,183,129 68,763,542 (1) Amounts include stock-based compensation expense as follows: Cost of revenue $223 $473 $475 $772 Research and development 1,097 3,494 1,068 6,096 General and administrative 1,583 2,555 3,449 6,460 Total stock-based compensation expense $2,903 $6,522 $4,992 $13,328 Aclaris Therapeutics, Inc.Selected Consolidated Balance Sheet Data(unaudited, in thousands, except share data) June 30, 2024 December 31, 2023 Cash, cash equivalents and marketable securities $149,871 $181,877 Total assets $161,071 $197,405 Total current liabilities $15,682 $30,952 Total liabilities $27,249 $40,226 Total stockholders' equity $133,822 $157,179 Common stock outstanding 71,332,825 70,894,889 Aclaris Therapeutics, Inc.Selected Consolidated Cash Flow Data(unaudited, in thousands) Six Months EndedJune 30, 2024 Six Months EndedJune 30, 2023 Net loss $(27,927) $(57,729)Depreciation and amortization 485 416 Stock-based compensation expense 4,992 13,328 Revaluation of contingent consideration 3,000 (2,300)Changes in operating assets and liabilities (13,687) (722)Net cash used in operating activities $(33,137) $(47,007) Aclaris Therapeutics Contact:investors@aclaristx.com

Phase 2License out/inFinancial StatementPhase 1Clinical Result

07 May 2024

·www.globenewswire.com

Aclaris Therapeutics Reports First Quarter 2024 Financial Results and Provides a Corporate Update

- Progressing ATI-2138 into Atopic Dermatitis -- Management to Host Conference Call at 5:00 PM ET Today - WAYNE, Pa., May 07, 2024 (GLOBE NEWSWIRE) -- Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, today announced its financial results for the first quarter of 2024 and provided a corporate update. “We are pleased to announce that following a review of the potential development pathways for ATI-2138, our investigational ITK/JAK3 compound with best-in-class potential, we have decided to progress ATI-2138 into a proof-of-concept Phase 2a trial in patients with moderate to severe atopic dermatitis,” stated Dr. Neal Walker, co-founder and Interim Chief Executive Officer & President of Aclaris. “Across all of our programs, we remain focused on executing a capital efficient strategy to advance novel immuno-inflammatory therapies.” Research and Development Highlights: ITK Inhibitor Programs ATI-2138, an investigational oral covalent ITK/JAK3 inhibitor Aclaris plans to progress ATI-2138 into a Phase 2a trial in subjects with moderate to severe atopic dermatitis.In September 2023, Aclaris reported positive results from its Phase 1 multiple ascending dose (MAD) trial of ATI-2138. ITK Selective Compound Aclaris is progressing to development candidate selection a second generation ITK selective inhibitor for autoimmune indications. Lepzacitinib (ATI-1777), an investigational topical “soft” JAK 1/3 inhibitor In January 2024, Aclaris reported positive top-line results from its Phase 2b trial in atopic dermatitis (AD).Aclaris is currently seeking a global development and commercialization partner for this program (excluding Greater China). As previously announced, in 2022 Aclaris granted Pediatrix Therapeutics exclusive rights to develop and commercialize lepzacitinib in Greater China. Zunsemetinib (ATI-450), an investigational oral small molecule MK2 inhibitor Aclaris plans to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib as a potential treatment for pancreatic cancer and metastatic breast cancer. Aclaris expects these trials to be primarily funded by grants awarded to Washington University. Financial Highlights: Liquidity and Capital Resources As of March 31, 2024, Aclaris had aggregate cash, cash equivalents and marketable securities of $161.4 million compared to $181.9 million as of December 31, 2023. A majority of cash expenditures in the first quarter of 2024 were related to payments associated with exit activities, including the wind down of discontinued R&D programs and the previously announced reduction in force. Aclaris anticipates payments associated with these activities to be substantially completed by the second quarter of 2024. As a result, Aclaris expects significantly lower quarterly cash expenditures in future quarters, without giving effect to any potential business development activities resulting from its ongoing strategic review of its business. Financial Results First Quarter 2024 Net loss was $16.9 million for the first quarter of 2024 compared to $28.2 million for the first quarter of 2023.Total revenue was $2.4 million for the first quarter of 2024 compared to $2.5 million for the first quarter of 2023. The decrease was primarily driven by lower contract research revenue during the three months ended March 31, 2024.Research and development (R&D) expenses were $9.8 million for the quarter ended March 31, 2024 compared to $22.6 million for the prior year period. The $12.8 million decrease was primarily the result of lower: Zunsemetinib development expenses associated with clinical activities for a Phase 2a trial for hidradenitis suppurativa, a Phase 2b trial for rheumatoid arthritis, and drug candidate manufacturing costs.Costs associated with lepzacitinib preclinical development activities and a Phase 2b clinical trial for AD.ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial and other preclinical activities.Compensation-related expenses due to a decrease in headcount and higher forfeiture credits. General and administrative (G&A) expenses were $6.8 million for the quarter ended March 31, 2024 compared to $8.8 million for the prior year period. The decrease was primarily due to a reduction in compensation-related expenses due to lower headcount and higher forfeiture credits.Licensing expenses were $1.0 million for the quarter ended March 31, 2024 compared to $1.1 million for the prior year period. The decrease was due to the achievement of a commercial milestone during the three months ended March 31, 2023, offset by an increase in royalties earned under the Lilly license agreement.Revaluation of contingent consideration resulted in a $2.8 million loss for the quarter ended March 31, 2024 compared to a gain of $0.8 million for the prior year period. Conference Call and Webcast As previously disclosed on April 30, 2024, management will host a conference call and webcast, with an accompanying slide presentation, at 5:00 PM ET today to provide a corporate update. To access the live webcast of the call and the accompanying slide presentation, please visit the “Events” page of the “Investors” section of Aclaris’ website, www.aclaristx.com. The webcast will be archived for at least 30 days on the Aclaris website. About Aclaris Therapeutics, Inc. Aclaris Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing a pipeline of novel drug candidates to address the needs of patients with immuno-inflammatory diseases who lack satisfactory treatment options. The company has a multi-stage portfolio of drug candidates powered by a robust R&D engine exploring protein kinase regulation. For additional information, please visit www.aclaristx.com. Cautionary Note Regarding Forward-Looking Statements Any statements contained in this press release 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 “anticipate,” “believe,” “expect,” “intend,” “may,” “plan,” “potential,” “will,” and similar expressions, and are based on Aclaris’ current beliefs and expectations. These forward-looking statements include expectations regarding its plans for its development programs, including its plans to seek a development and commercialization partner for lepzacitinib, the clinical development of ATI-2138, and its plan to support Washington University in St. Louis in its investigator-initiated Phase 1b/2 trials of zunsemetinib, as well as Aclaris’ expectations regarding the wind down of discontinued R&D programs and costs associated with its recent reduction in force and the associated impact on anticipated cash burn, and its strategic review of its business. 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, Aclaris’ ability to enter into strategic partnerships on commercially reasonable terms, the uncertainty regarding the macroeconomic environment 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, 2023, and other filings Aclaris makes with the U.S. Securities and Exchange Commission from time to time. These documents are available under the “SEC Filings” page of the “Investors” section of Aclaris’ website at www.aclaristx.com. Any forward-looking statements speak only as of the date of this press release and are based on information available to Aclaris as of the date of this release, 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. Aclaris Therapeutics, Inc.Condensed Consolidated Statements of Operations(unaudited, in thousands, except share and per share data) Three Months Ended March 31, 2024 2023 Revenues: Contract research $657 $889 Licensing 1,741 1,639 Total revenue 2,398 2,528 Costs and expenses: Cost of revenue (1) 809 808 Research and development (1) 9,845 22,587 General and administrative (1) 6,844 8,790 Licensing 1,031 1,061 Revaluation of contingent consideration 2,800 (800)Total costs and expenses 21,329 32,446 Loss from operations (18,931) (29,918)Other income, net 1,990 1,758 Net loss $(16,941) $(28,160)Net loss per share, basic and diluted $(0.24) $(0.42)Weighted average common shares outstanding, basic and diluted 71,074,858 66,872,778 (1) Amounts include stock-based compensation expense as follows: Cost of revenue $252 $299 Research and development (29) 2,602 General and administrative 1,866 3,905 Total stock-based compensation expense $2,089 $6,806 Aclaris Therapeutics, Inc.Selected Consolidated Balance Sheet Data(unaudited, in thousands, except share data) March 31, 2024 December 31, 2023 Cash, cash equivalents and marketable securities $161,365 $181,877 Total assets $174,065 $197,405 Total current liabilities $20,080 $30,952 Total liabilities $32,051 $40,226 Total stockholders' equity $142,014 $157,179 Common stock outstanding 71,248,017 70,894,889 Aclaris Therapeutics, Inc.Selected Consolidated Cash Flow Data(unaudited, in thousands) March 31, 2024 March 31, 2023 Net loss $(16,941) $(28,160)Depreciation and amortization 243 198 Stock-based compensation expense 2,089 6,806 Revaluation of contingent consideration 2,800 (800)Changes in operating assets and liabilities (9,006) (4,397)Net cash used in operating activities $(20,815) $(26,353) Aclaris Therapeutics Contact: investors@aclaristx.com

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Indication	Highest Phase	Country/Location	Organization	Date
Bone metastases	Phase 2	US	Aclaris Therapeutics, Inc.	31 Dec 2024
Hormone receptor positive HER2 negative breast cancer	Phase 2	US	Aclaris Therapeutics, Inc.	31 Dec 2024
Arthritis, Psoriatic	Phase 2	US	Aclaris Therapeutics, Inc.	12 Jul 2022
Arthritis, Psoriatic	Phase 2	PL	Aclaris Therapeutics, Inc.	12 Jul 2022
Hidradenitis Suppurativa	Phase 2	US	Aclaris Therapeutics, Inc.	29 Dec 2021
Cryopyrin-Associated Periodic Syndromes	Phase 2	US	Aclaris Therapeutics, Inc.	23 Oct 2020
Rheumatoid Arthritis	Phase 2	US	Aclaris Therapeutics, Inc.	16 Mar 2020
Metastatic Pancreatic Ductal Adenocarcinoma	Phase 1	US	Aclaris Therapeutics, Inc.	31 Dec 2024
Metastatic breast cancer	Phase 1	US	Aclaris Therapeutics, Inc.	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT05279417 (ATI-450-RA-202, Corporate Publications) Manual	Phase 2	Rheumatoid Arthritis	251	ATI 450 (20 mg BID) + MTX	kjrucuymsq(svjxgsgnnc) = ATI-450 20 mg BID and 50 mg BID did not differentiate from placebo in ACR20 and other measures ebtlqeorts (sqsdpwfkug ) Not Met	Negative	13 Nov 2023
				ATI 450 (50 mg BID) + MTX
NCT04524858 (CTgov)	Phase 2	Cryopyrin-Associated Periodic Syndromes	1	ATI-450	hbbocnxvxy(wtkejihknk) = wnbqokpfci lvihasydhv (fxhibqojbo, kyxbieszzk - tivrlrlbxa) View more	-	21 Sep 2023
NCT04247815 (CTgov)	Phase 2	Rheumatoid Arthritis	25	ATI-450+Methotrexate (ATI-450 Plus Methotrexate)	uxmrllnsca(gystgysbsr) = uypdaycfwv wwvdxdrkwe (huhesnezvw, ogemtfvcfj - vhlvygbzfg) View more	-	29 Mar 2023
				Placebo oral tablet+Methotrexate (Placebo Plus Methotrexate)	uxmrllnsca(gystgysbsr) = exlfptiilf wwvdxdrkwe (huhesnezvw, pascqlkmnr - yczhnngsml) View more
ACR2021	Not Applicable	Rheumatoid Arthritis	-	ATI-450 + MTX	nkqiaxkaxz(jgieceymnt) = thvfofzwfn vxxtxeqdwf (lzxawyfcpb ) View more	-	09 Nov 2021
NCT04247815 (GlobeNewswire) Manual	Phase 2	Rheumatoid Arthritis	19	Zunsemetinib	vambyppfqh(dkqwjrcdhs) = urinary tract infection (UTI), elevated lipids and ventricular extrasystoles muyvsqtnbt (gpuogjohzp )	Positive	19 Jan 2021
				Placebo+methotrexate
EULAR2020	Phase 1	phospho-HSP27 (pHSP27) \| TNFα \| IL1β ... View more	77	ATI-450 10mg	uebbvktgny(dxprvvezcc) = The most common adverse events (reported by 2 or more subjects who received ATI-450) observed during the trial were dizziness, headache, upper respiratory tract infection, constipation, nausea, and abdominal pain ehwfdyxbqn (mvszoxlinr )	-	03 Jun 2020
				ATI-450 30mg

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