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WAYNE, Pa., Feb. 27, 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 fourth quarter and full year of 2023 and provided a corporate update. “As we enter 2024, we are financially strong, focused and motivated,” stated Dr. Neal Walker, co-founder and Interim Chief Executive Officer & President of Aclaris. “Returning to the CEO role, I look forward to building on our strong foundation and deep expertise in kinase discovery and development as we look to shape the future of Aclaris.” Research and Development Highlights: 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, and is currently seeking a development and commercialization partner for this program. ATI-2138, an investigational oral covalent ITK/JAK3 inhibitor Aclaris is assessing the most effective development pathway, including the lead indication, for ATI-2138. Aclaris reported positive results from its Phase 1 MAD trial of ATI-2138 in September 2023. 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.ATI-2231, Aclaris’ second MK2 inhibitor, was previously being developed for oncology and Aclaris was supporting Washington University in an investigator-initiated Phase 1a trial of ATI-2231 in patients with advanced solid tumor malignancies. However, Aclaris and Washington University agreed to instead study zunsemetinib in oncology in order to expedite the development timeline by eliminating the need to conduct the Phase 1a trial due to zunsemetinib’s more advanced clinical package. Discovery Aclaris plans to continue to advance discovery programs through KINect®, its proprietary drug discovery platform. Financial Highlights: Liquidity and Capital Resources As of December 31, 2023, Aclaris had aggregate cash, cash equivalents and marketable securities of $181.9 million compared to $229.8 million as of December 31, 2022. Financial Results Fourth Quarter 2023 Net loss was $1.5 million for the fourth quarter of 2023 compared to $27.6 million for the fourth quarter of 2022.Total revenue was $17.6 million for the fourth quarter of 2023 compared to $7.8 million for the fourth quarter of 2022. The increase was primarily driven by a one-time upfront payment under the license agreement with Sun Pharmaceutical Industries, Inc. (Sun Pharma) received in the fourth quarter of 2023. Research and development (R&D) expenses were $26.6 million for the quarter ended December 31, 2023 compared to $21.1 million for the prior year period. The $5.5 million increase was primarily the result of an increase in expenses associated with drug candidate manufacturing for zunsemetinib.General and administrative (G&A) expenses were $8.2 million for the quarter ended December 31, 2023 compared to $7.1 million for the corresponding prior year period. The increase was primarily due to an increase in personnel and stock-based compensation expenses. Licensing expenses were $5.7 million for the quarter ended December 31, 2023 compared to $0.6 million for the prior year period. The increase was primarily attributable to amounts payable to third parties in connection with amounts earned under the Sun Pharma license agreement. Revaluation of contingent consideration resulted in a $26.3 million gain for the quarter ended December 31, 2023 compared to a charge of $7.1 million for the prior year period. Intangible asset impairment charges were $6.6 million for the quarter ended December 31, 2023, representing the full balance of the in-process research and development (IPR&D) intangible asset. The impairment charge resulted from Aclaris’ decision to discontinue further development of the drug candidate for immuno-inflammatory diseases. Full Year 2023 Net loss was $88.5 million for the year ended December 31, 2023 compared to $86.9 million for the year ended December 31, 2022.Total revenue was $31.2 million for the year ended December 31, 2023 compared to $29.8 million for the year ended December 31, 2022. The increase was primarily driven by a one-time upfront payment under the license agreement with Sun Pharma received in the year ended December 31, 2023. The increase was partially offset by both a one-time upfront payment received under a license agreement with Eli Lilly and Company and a one-time upfront payment received under a license agreement with Pediatrix Therapeutics, Inc. in the year ended December 31, 2022. R&D expenses were $98.4 million for the year ended December 31, 2023 compared to $77.8 million for the prior year period. The $20.6 million increase was primarily the result of higher: Zunsemetinib development expenses, including costs associated with clinical activities for the Phase 2b trial for rheumatoid arthritis and drug candidate manufacturing costs;ATI-2138 development expenses, including costs associated with the Phase 1 MAD trial and other preclinical activities; andCompensation-related expenses due to an increase in headcount. G&A expenses were $32.4 million for the year ended December 31, 2023 compared to $25.1 million for the prior year period. The $7.3 million increase was primarily the result of higher compensation-related costs due to increased headcount and the impact of equity awards granted during the year ended December 31, 2023.Bad debt expense recorded from Aclaris’ determination that collection of amounts due from EPI Health are uncertain as a result of their filing for Chapter 11 bankruptcy protection also contributed to the increase. Revaluation of contingent consideration resulted in a $26.9 million gain for the year ended December 31, 2023 compared to a charge of $4.7 million for the corresponding prior year period. Intangible asset impairment charges were $6.6 million for the year ended December 31, 2023, representing the full balance of the IPR&D intangible asset. The impairment charge resulted from Aclaris’ decision to discontinue further development of the drug candidate for immuno-inflammatory diseases. 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 development plans for its development programs, including its plans to seek a development and commercialization partner for ATI-1777 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.Consolidated Statements of Operations(unaudited, in thousands, except share and per share data) Three Months Ended Year Ended December 31, December 31, 2023 2022 2023 2022 Revenues: Contract research $566 $866 $3,035 $4,395 Licensing 17,004 6,722 28,214 25,100 Other — 165 — 257 Total revenue 17,570 7,753 31,249 29,752 Costs and expenses: Cost of revenue (1) 725 877 3,423 4,023 Research and development (1) 26,646 21,072 98,384 77,813 General and administrative (1) 8,214 7,146 32,412 25,133 Licensing 5,703 637 14,658 7,937 Revaluation of contingent consideration (26,300) 7,100 (26,900) 4,700 Intangible asset impairment 6,629 — 6,629 — Total costs and expenses 21,617 36,832 128,606 119,606 Loss from operations (4,047) (29,079) (97,357) (89,854)Other income, net 2,189 1,444 8,509 2,946 Loss before income taxes (1,858) (27,635) (88,848) (86,908)Income tax benefit (367) — (367) — Net loss $(1,491) $(27,635) $(88,481) $(86,908)Net loss per share, basic and diluted $(0.02) $(0.41) $(1.27) $(1.33)Weighted average common shares outstanding, basic and diluted 70,866,315 66,685,580 69,808,855 65,213,944 (1) Amounts include stock-based compensation expense as follows: Cost of revenue $337 $314 $1,456 $1,151 Research and development (2,367) 1,517 6,801 3,745 General and administrative 3,296 2,982 12,285 10,143 Total stock-based compensation expense $1,266 $4,813 $20,542 $15,039 Aclaris Therapeutics, Inc.Selected Consolidated Balance Sheet Data(unaudited, in thousands, except share data) December 31, 2023 December 31, 2022 Cash, cash equivalents and marketable securities $181,877 $229,813 Total assets $197,405 $254,596 Total current liabilities $30,952 $21,938 Total liabilities $40,226 $56,975 Total stockholders' equity $157,179 $197,621 Common stock outstanding 70,894,889 66,688,647 Aclaris Therapeutics, Inc.Selected Consolidated Cash Flow Data(unaudited, in thousands) Year EndedDecember 31, 2023 Year EndedDecember 31, 2022 Net loss $(88,481) $(86,908) Depreciation and amortization 863 797 Stock-based compensation expense 20,542 15,039 Revaluation of contingent consideration (26,900) 4,700 Intangible asset impairment charge 6,629 — Deferred taxes (367) — Changes in operating assets and liabilities 9,389 (1,195) Net cash used in operating activities $(78,325) $(67,567) Aclaris Therapeutics Contact: investors@aclaristx.com

Investors sent Aclaris’ shares down 14% to $1.10 in pre-market trading. Aclaris Therapeutics has touted the latest phase 2 results for its “soft” JAK 1/3 inhibitor as a win for the beleaguered biotech, but investors appeared less enthusiastic about the wider set of mixed data. The phase 2b study involved 250 adults and children in the U.S. with mild to severe atopic dermatitis receiving either twice daily treatment with the therapy, called ATI-1777, as a spray at concentrations of 0.5%, 1% or 2%, or a once daily treatment of 2% or vehicle. At week four, the change in eczema from baseline as assessed by the Eczema Area and Severity Index (EASI) score was 69.7% for patients who received the 2% concentration twice daily compared with 58.7% for those who received the vehicle. The statistical significance of this difference, which equated to a p value of 0.035, met the trial’s primary efficacy endpoint, Aclaris said in a Jan. 10 release. However, while patients who received the once daily 2% concentration also saw a “trend toward significance”—with a 68.3% change compared to 59.5% among those receiving a vehicle—this was not “statistically superior,” the biotech admitted. Investors appeared dubious about the readout, sending Aclaris’ shares down 14% to $1.10 in pre-market trading from a Tuesday closing price of $1.28. While the trial had not been statistically powered for a response as measured by the Investigator Global Assessment Treatment Success, which the company noted is the FDA’s regulatory endpoint, Aclaris said the drug had shown improvement here as well, with changes of 37.2% and 36.6% for the once daily and twice daily 2% concentrations, respectively, compared to 27.1% and 26.3% in the respective vehicle cohorts. Aclaris did not share data on the efficacy of the 0.5% and 1% concentrations in the release. ATI-1777 had not produced any of the adverse events most commonly associated with JAK inhibitors, such as serious infections, malignancies, major adverse cardiovascular events or thromboses, according to the company. The most common adverse events among treated patients were nasopharyngitis and application site itch. “We are excited that ATI-1777 demonstrated response rates on par with existing market competition, along with a differentiated safety profile relative to JAK inhibitors given the low systemic absorption seen in both phase 2 studies,” Neal Walker, chairman of Aclaris’ board of directors, said in the release. “These results are particularly encouraging given the higher than anticipated vehicle response and the mid-study inclusion of a milder patient population,” Walker added. “The convenience of a spray formulation along with the potential to move to once-a-day dosing, potentially offer additional distinct advantages to patients suffering from atopic dermatitis.” Aclaris had been pinning its hopes on ATI-1777’s success after the company announced in the final weeks of the year that it was laying off almost half of its workforce as it resurrected plans to explore its MK2 inhibitor zunsemetinib despite a couple of mid-phase fails. At the time, Aclaris said that it would use a positive set of phase 2 data for ATI-1777 to hunt for a suitable partner for the asset.” In this morning’s release, the biotech’s CEO Douglas Manion, M.D., confirmed that the company would now “seek a development and commercialization partner for this program, which could include additional indications such as vitiligo.”

前言        一家公司被寄予厚望的候选药物在临床接连失败后，会怎么做？放弃开发，改进药物，还是硬着头皮继续做？都不是……2023年12月19日，Aclaris公司宣布将暂停主要候选药物zunsemetinib（ATI-450）所有在研适应症的开发，转而研究其对胰腺癌和转移性乳腺癌的辅助治疗效果，更离谱的是，为了保证这项研究能顺利进行，Aclaris甚至为这个八字没一撇的项目裁员46%，事情显然没有这么简单……埋雷的临床试验2020年1月9日，Aclaris宣布研究性口服MK2抑制剂zunsemetinib的单次和多次升剂量1期试验结果良好，对 TNFα、IL1β、IL8 和 IL6等促炎细胞因子有显著的抑制作用，因此，Aclaris打算在2020年上半年启动该药物针对类风湿性关节炎患者的首个2期临床试验。图片来源：Aclaris官网2021年1月19日，Aclaris公布了该试验的2a期试验的阳性初步研究数据。结果显示，在治疗12周后，疾病活动性或缓解性较低的受试者比例在治疗组中为40％，而在安慰剂组为0％。此外，一些炎症标志物，包括TNFα，IL1β，IL6和IL8等也有明显和持久的抑制作用。Aclaris后续也相继启动了针对中度至重度化脓性汗腺炎（HS）和银屑病关节炎两项临床试验，股价更是一夜从每股6.08美元暴涨至18.8美元。但是，似乎所有人都没注意到公告中不显眼的一句话：“由于这项试验的目的是进行概念验证，因此没有能力检测疗效终点的显著统计学结果”，这个看似省钱又巧妙的试验设计，却在日后几乎炸平了Aclaris。图片来源：Aclaris官网2023年3月6日，Aclaris草草宣布zunsemetinib用于治疗中度至重度化脓性汗腺炎的2a期试验未达主要终点，甚至连P值都没有在公告中体现……股价也在当天大跌至每股6.93美元。2023年11月13日，Aclaris迎来了最大的“滑铁卢”。Aclaris宣布zunsemetinib用于治疗中度至重度类风湿性关节炎的2b临床试验中，12周时，20mg或50mg剂量组受试者均未达到缓解的主要终点或任何次要疗效终点，给药组和安慰剂组疗效上无显著性差异。图片来源：Aclaris官网介于zunsemetinib两项试验接连失利，Aclaris宣布将停止公司核心候选药物zunsemetinib所有的开发工作，包括银屑病关节炎的2期试验。上午消息一出，使 Aclaris 已经遭受重创的股价在盘前交易中又下跌了 85%，从上周五的收盘价 4.75 美元跌至仅剩0.69美元。至此，zunsemetinib三个在研适应症全部夭折……手上还有几张牌？目前，Aclaris仅剩下三条管线。图片来源：Aclaris官网其中，进展最快的是一款外用JAK1/3抑制剂（ATI-1777），目前已处于2期临床阶段，主要适应症为轻度、中度或重度特应性皮炎。据Aclaris2023年Q1财报显示，该项试验将在2024前公布结果，也就是说，仅剩一周了……不过，从该公司披露的2a期数据来看，给药组在治疗四周后，病灶面积和严重程度指数均有显著改善，且安全性良好。图片来源：Aclaris官网另一个候选药物为口服共价ITK/JAK3抑制剂ATI-2138，已经完成了1期临床，结果显示可能对T细胞介导的疾病产生积极影响。该公司原计划在2024年开展ATI-2138治疗溃疡性结肠炎的2期试验。但是，继2021年FDA批准BMS的溃疡性结肠炎药物ozanimod上市后，今年辉瑞的etrasimod和礼来的etrasimod相继在FDA获批，对于Aclaris来说，即使做到了BIC，市场占有率也不一定打得过前三家，更何况该药甚至还未开启2期临床……Aclaris还有一条肿瘤相关管线。该管线的候选药物为口服MK2抑制剂ATI-2231，目前正在进行治疗晚期实体瘤的1a期试验。不过，在2023年11月19日Aclaris的新闻稿中称，将暂缓ATI-2231的开发。如今，zunsemetinib将重启，并替代了ATI-2231。真的吗？这究竟是Aclaris的破釜沉舟，还是为了薅掉股民的最后一根羊毛？我们不妨先看一下zunsemetinib的具体机制。细胞核中，非活性 MK2 和 p38α 以高亲和力复合物的形式对接，产生一个由两种蛋白质并列壁形成的结合袋，Zunsemetinib 可与口袋的两壁结合，稳定复合物并阻止 MK2 激活，进而抑制多种治疗相关的细胞因子，如TNF、IL-6、IL-17和IL-1β，多适用于治疗患有多种炎症的患者。图片来源：Aclaris官网2021年，该公司就Zunsemetinib的潜在适应症研究，在《Science Translational Medicine》发表了一篇文章。文章称，Zunsemetinib是一种可使胰腺癌细胞更容易受到化疗影响的药物化合物，同时，接受Zunsemetinib+化疗的小鼠比单一化疗小鼠表现得更健康，也就是说该药可能存在减轻化疗副作用的效果。图片来源：The MK2/Hsp27 axis is a major survival mechanism forpancreatic ductal adenocarcinoma under genotoxicstress值得一提的是，该靶点暂无上市产品，保守点说，Aclaris算是该领域的前三，一旦成功，极有可能是一款FIC。这么说来，Aclaris这般操作也不算是空穴来风。另外，要展开一项研究，除了药物和适应症靠谱外，资金也是重要组成部分。根据Aclaris 2023年11月13日最新披露，截至 2023 年 9 月 30 日，Aclaris 的现金、现金等价物和有价证券总额为 1.87 亿美元，预计可支持公司运营至2025年，再加上即将裁员46%，似乎还是能坚持到Zunsemetinib治疗胰腺癌和转移性乳腺癌的2期临床结果出炉的。不过，有一个问题。Aclaris既然一早便选定了Zunsemetinib为公司的核心候选药物，同时有着相比其他管线更先进的临床开发包，为什么没有在一开始就展开后续相关研究，而是选择不在核心管线的ATI-2231呢？参考文献：1.Aclaris官网2.https://www.fiercebiotech.com/biotech/aclaris-lays-46-staff-resurrects-zunsemetinib-potential-cancer-treatment3.https://www.fiercebiotech.com/biotech/aclaris-stock-sinks-further-biotech-abandons-mk2-inhibitor-over-latest-phase-2-fail4.https://www.fiercebiotech.com/biotech/aclaris-stock-halves-after-phase-2a-skin-study-misses-goals5.雪球6.https://www.science.org/doi/full/10.1126/scitranslmed.abb54457.其他公开资料封面图来源：123rfAlnylam失败之后：新的挑战者即将到来，这次是阿斯利康和Ionis……“扫货”、联用？盘点2023最后一个季度ADC大事件点击阅读原文，查看更多精彩内容！