DPP-8

Designation for BXCL701 in combination with a checkpoint inhibitor (CPI) for treatment of patients with metastatic SCNC with progression on chemotherapy and no evidence of microsatellite instability BXCL701 is an investigational, oral innate immune activator designed to inflame the tumor microenvironment and augment CPI activity Company to discuss registration path at upcoming meeting with FDA NEW HAVEN, Conn., Feb. 12, 2024 (GLOBE NEWSWIRE) --BioXcel Therapeutics, Inc. (Nasdaq: BTAI), a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience and immuno-oncology, today announced that the U.S. Food and Drug Administration (FDA) has designated as a Fast Track development program the investigation of BXCL701 in combination with a CPI for the treatment of patients with metastatic small cell neuroendocrine prostate cancer (SCNC) with progression on chemotherapy and no evidence of microsatellite instability. The FDA grants Fast Track designation to facilitate the development and expedite the review of medicines to treat serious conditions, fill unmet medical needs, and bring promising medicines to patients more quickly. Therapies granted this designation are given the opportunity for more frequent interactions with the FDA, a rolling review, and potential eligibility for accelerated approval and priority review. “The FDA’s Fast Track designation for the investigation of BXCL701 in SCNC is an important recognition of our most advanced immuno-oncology asset and an acknowledgment of its potential to address the considerable unmet medical need in these patients. At the same time, it further validates the unique AI-based drug re-innovation approach that we used to discover this asset,” said Vimal Mehta, Ph.D., CEO of BioXcel Therapeutics. “BXCL701 has already demonstrated considerable potential in our clinical trials to date, and we plan to further define its development path while exploring strategic options for our OnkosXcel Therapeutics subsidiary.” SCNC, classified as a “cold” tumor, represents an underserved, growing patient population, with cases increasing due to earlier and more widespread use of androgen receptor inhibitors. In 2024, the American Cancer Society estimates that 299,0101 men will be diagnosed with prostate cancer in the United States, with approximately 20% expected to progress to the more aggressive metastatic castration-resistant form, including an estimated 11,960 patients expected to progress to SCNC2. “SCNC is characterized by poor prognosis and a low survival rate, and current treatment options are suboptimal,” said Vincent J. O’Neill, M.D., Executive Vice President, Chief of Product Development and Medical Officer of BioXcel Therapeutics. “We are encouraged by the potential of BXCL701, which has demonstrated clinical proof of concept in both SCNC and adenocarcinoma. Following the positive survival results from our Phase 2 trial that we reported at the end of last year, we look forward to further discussing the registration path at an upcoming meeting with the FDA.” About BXCL701 BXCL701 is an investigational, oral innate immune activator designed to initiate inflammation in the tumor microenvironment. Approved and experimental immunotherapies often fail to address cancers that appear “cold.” Therefore, BXCL701 is being evaluated to determine if it can render “cold” tumors “hot,” making them more detectable by the adaptive immune system and thereby facilitating the development of a strong anticancer immune response. OnkosXcel Therapeutics’ preclinical data support BXCL701’s potential synergy with both current checkpoint inhibitors and emerging immunotherapies directed to activate T-cells. BXCL701 is currently being developed as a potential therapy for the treatment of aggressive forms of prostate cancer and advanced solid tumors that are refractory or treatment naïve to checkpoint inhibitors. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in five indications: SCNC, acute myelogenous leukemia, pancreatic cancer, stage IIb to IV melanoma, and soft tissue sarcoma. An 800+-subject clinical database, with data collected by the Company and others, supports the ongoing development of BXCL701. About BioXcel Therapeutics, Inc. BioXcel Therapeutics, Inc. (Nasdaq: BTAI) is a biopharmaceutical company utilizing artificial intelligence to develop transformative medicines in neuroscience. Its wholly owned subsidiary, OnkosXcel Therapeutics, is focused on the development of medicines in immuno-oncology. The Company’s drug re-innovation approach leverages existing approved drugs and/or clinically validated product candidates together with big data and proprietary machine learning algorithms to identify new therapeutic indications. For more information, please visit bioxceltherapeutics.com. Forward-Looking Statements This press release includes “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. We intend such forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act of 1933, as amended (the “Securities Act”) and Section 21E of the Securities Exchange Act of 1934, as amended (the “Exchange Act”). All statements contained in this press release other than statements of historical fact should be considered forward-looking statements, including, without limitation, the potential benefits from treatment with BXCL701 and from fast track designation, potential meeting with the FDA and strategic options for the OnkosXcel Therapeutics subsidiary. When used herein, words including “anticipate,” “believe,” “can,” “continue,” “could,” “designed,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “target,” “will,” “would” and similar expressions are intended to identify forward-looking statements, though not all forward-looking statements use these words or expressions. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon the Company’s current expectations and various assumptions. The Company believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. The Company may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, its dependence on the success and commercialization of IGALMI™, BXCL501, BXCL502 BXCL701 and BXCL702 and other product candidates; its lack of experience in marketing and selling drug products; the risk that IGALMI or the Company’s product candidates may not be accepted by physicians or the medical community in general; the failure of preliminary data from its clinical studies to predict final study results; failure of its early clinical studies or preclinical studies to predict future clinical studies; its ability to receive regulatory approval for its product candidates; its ability to enroll patients in its clinical trials; undesirable side effects caused by the Company’s product candidates; and its novel approach to the discovery and development of product candidates based on EvolverAI, as well as the other important factors discussed under the caption “Risk Factors” in its Quarterly Report on Form 10-Q for the quarterly period ended September 30, 2023, as such factors may be updated from time to time in its other filings with the SEC, which are accessible on the SEC’s website at These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While the Company may elect to update such forward-looking statements at some point in the future, except as required by law, it disclaims any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this press release. Contact Information Corporate BioXcel Therapeutics Erik Kopp 1.203.494.7062 ekopp@bioxceltherapeutics.com Investor Relations BioXcel Therapeutics Brennan Doyle 1.475.355.8462 bdoyle@bioxceltherapeutics.com Media Russo Partners David Schull T: 858-717-2310 David.schull@russopartnersllc.com Scott Stachowiak T: 646-942-5630 Scott.stachowiak@russopartnersllc.com Source: BioXcel Therapeutics, Inc. BT BIOXCEL THERAPEUTICS is a registered trademark of BioXcel Therapeutics, Inc. All other trademarks are the properties of their respective owners. Copyright © 2024, BioXcel Therapeutics, Inc. All rights reserved. References 1 American Cancer Society. Key Statistics for Prostate Cancer. Accessed February 8, 2024 's%20estimates,34%2C700%20deaths%20from%20prostate%20cancer 2. B.R. Alabi, S. Liu and T. Stoyanova, Current and emerging therapies for neuroendocrine prostate cancer, Pharmacology and Therapeutics (2022),

2023年似乎是“减肥星人”的狂欢之年，诺和诺德的司美格鲁肽口服片剂连续传来积极消息、礼来的加强版GLP-1替尔泊肽成功获批减肥适应症、多款GLP-1竞品纷纷揭露减肥数据……一时之间，GLP-1赛道已是红海态势。创新药研发的热闹不止于此，有不少其他领域的药物仍在奋力突破，有不少疾病治疗的空白将在2024年被填充。医药魔方依据clinicaltrials.gov网站筛选出656项2024年将要/预计完成的注册性III期临床试验，并筛选出8项最值得期待的研究，供大家参考。注：1.仅统计企业方发起的注册性III期临床试验；2.预计完成时间以clinicaltrials.gov网站登记的时间为依据；3.筛选依据主要为：①治疗突破性；②机制创新性；头对头研究的重要程度；4.序号与重要程度无关。NO.1 “万能”GLP-1的适应症拓展GLP-1是2023年当之无愧的“网红”，不仅司美格鲁肽和替尔泊肽出尽风头，而且其它后来者也激起了不小的水花。说起来，减肥只是GLP-1在降糖之外的其中之一“遗珠”优点，早已有诸多研究证明了其“无所不能”的应用潜力。阿尔兹海默病、阻塞性睡眠呼吸暂停、非酒精性脂肪性肝炎（NASH）等皆有可能成为GLP-1的下一个破圈点。今年，司美格鲁肽先后在糖尿病肾病和心血管风险上告捷，进一步为以司美格鲁肽为代表的GLP-1类药物拓宽了应用边界。明年，替尔泊肽治疗阻塞性睡眠呼吸暂停的III期SURMOUNT-OSA研究也将揭晓结果，GLP-1药物所带来的“溢出效应”将被进一步验证。SURMOUNT-OSA研究（来源：TrialCube数据库）NO.2 首个DPP-1抑制剂有望问世二肽基肽酶（DPP）是一类肽切割酶，可以从多肽的N-末端切割X-脯氨酸二肽。其底物为含脯氨酸的肽，包括生长因子、趋化因子、神经肽和血管活性肽，参与免疫调节、信号传导和凋亡过程。DPP家族包括9位成员，其中DPP-1、DPP-3、DPP-4、DPP-8、DPP-9正在/已被探索其治疗潜力。科学界对DPP-1和DPP-4的研究较为深入，前者具备抗炎能力，后者主要用于开发降糖药物。目前，全球仅3款临床在研DPP-1抑制剂，其中brensocatib是唯一一款处于III期阶段的产品。brensocatib的首发适应症为支气管扩张，该疾病与中性粒细胞过度活跃导致的炎症反应相关。中性粒细胞被激活后会分泌丝氨酸蛋白酶，而这种酶是参与多种炎症反应的关键蛋白，DPP-1便是其开关。因此，DPP-1抑制剂具备治疗支气管扩张的潜力。在II期WILLOW研究中，支气管扩张患者接受brensocatib治疗后，首次出现症状加重的时间显著延后（134 vs. 67天，P=0.03），症状恶化风险也降低了42%（HR=0.58）。为进一步验证brensocatib的有效性和安全性，Insmed启动了III期ASPEN研究，该研究将于2024年3月完成。支气管扩张的治疗手段仍停留在老药上，例如一些抗生素和组胺受体拮抗剂，若brensocatib能够顺利完成III期研究，该疾病的治疗方法也能得到革新。NO.3 艾伯维打造修美乐的继任者乌帕替尼2022年，蝉联多年“药王”的修美乐（Humira，阿达木单抗）年销售额到达顶峰（见：2022年全球药品销售额TOP100）。自今年1月份以来，多款阿达木单抗生物类似药终于得以进入美国市场，结束了修美乐长达20年的“统治”，而修美乐的销售额也因此大幅下跌（前三季度收入111亿美元，同比下降29.1%）。乌帕替尼（Rinvoq/瑞福）是艾伯维为应对王牌产品专利到期带来的冲击而培养的接班者之一，正在逐步渗透修美乐建立的自免宇宙。目前，乌帕替尼已覆盖类风湿性关节炎、银屑病关节炎、特应性皮炎、溃疡性结肠炎、强直性脊柱炎、非放射学中轴型脊柱关节炎和克罗恩病7项适应症，其中特应性皮炎是修美乐未涉足的领域。特应性皮炎的“统治者”非度普利尤单抗（Dupixent/达必妥）莫属，仅这一项适应症即可为赛诺菲带来几十亿美元的收入。从乌帕替尼的适应症布局来看，艾伯维尚无开发斑块状银屑病这一庞大市场的打算，那么从度普利尤单抗手中抢占更多的特应性皮炎市场份额便成了乌帕替尼走向自免“王牌”产品的一步必走棋。特应性皮炎领域畅销药物TOP5注：*获批时间特指特应性皮炎这一适应症。由此出发，艾伯维于去年11月启动了III期Level Up研究，旨在对比乌帕替尼与度普利尤单抗治疗特应性皮炎的有效性和安全性，该研究预计将于2024年8月完成。届时可关注一下，乌帕替尼迈出的这关键一步，能否助推其年销售额大幅拉升。Level Up研究（来源：TrialCube数据库）NO.4 BTK抑制剂在自免领域的第二次突破BTK早已成为内卷赛道之一，全球已有6款BTK抑制剂获批上市，另有6款处于III期研究阶段。与EGFR抑制剂赛道类似，BTK抑制剂后来者的竞争空间来源于对不同获得性耐药突变的适应，二代BTK抑制剂Pirtobrutinib（匹妥布替尼）的上市便是一个代表性例子。适应症差异化是BTK抑制剂后来者开辟的另一条突围道路，赛诺菲、诺华和罗氏3家的BTK抑制剂产品均是其中的代表。Remibrutinib（诺华）是首款在自免领域大获成功的BTK抑制剂，明年便会申报慢性自发性荨麻疹适应症，有望成为第一款“破圈”的BTK靶向药物。赛诺菲旗下的Tolebrutinib则瞄准了另一自免市场——多发性硬化症（MS）。2020年，赛诺菲在获得II期研究的积极结果后便迅速启动了多项Tolebrutinib治疗MS的III期临床，其中包括两项头对头临床（GEMINI 1和GEMINI 2）。GEMINI 1/2研究旨在评估Tolebrutinib和特立氟胺治疗复发性MS的有效性和安全性，预计将于2024年4月完成。GEMINI 1研究（来源：TrialCube数据库）GEMINI 2研究（来源：TrialCube数据库）MS是BTK抑制剂从肿瘤领域过渡至自免领域的关键第二站，Tolebrutinib的成败与否也牵连着众多同赛道玩家的心，毕竟前不久默克的BTK抑制剂evobrutinib已因疗效未超越特立氟胺黯然退出MS战场（见：默克BTK抑制剂III期研究失败）。NO.5 首个口服Aβ靶向药物有望问世今年，仑卡奈单抗（lecanemab）的上市冲刷了阿杜卡尼单抗带来的Aβ靶点质疑声，也为Aβ赛道后继者拉升了信心（见：20年来首款！卫材/渤健阿尔茨海默病新药Lecanemab获FDA完全批准）。毋庸置疑，Aβ是延缓阿尔兹海默病（AD）进展的有效靶点。仑卡奈单抗即使已具备不错的疗效，但仍然存在改善空间——提高注射依从性，这也是卫材已着手开发仑卡奈单抗皮下制注射剂的原因（见：淀粉样蛋白清除率更高！卫材拟明年递交lecanemab皮下制剂上市申请）。不过，患者对注射剂的依从性毕竟不如口服制剂，因而开发口服Aβ靶向药物也是争夺AD蓝海市场的一个潜力方向。Valiltramiprosate是目前唯一一款III期在研口服Aβ靶向药物。II期研究结果显示，早期AD患者接受Valiltramiprosate治疗104周后，血浆磷酸化tau蛋白（p-tau，Aβ聚集的生物标志物）水平相比基线显著降低了31%（P=0.015）。Valiltramiprosate治疗早期AD的验证性III期APOLLOE4研究将于2024年4月完成。该研究若能获得积极结果，AD治疗领域也将迎来新一次突破性进展。NO.6 强迫症的“春天”强迫症是一种精神障碍疾病，多表现为个体有意识地进行重复性动作（如频繁洗手或检查）以及一些强迫性心理行为（如反复祈祷、数数或思考）。多数强迫症患者执着于内心严格的规则，例如会通过打开和关闭十几次电灯来检查开关是否已关闭。目前强迫症的治疗手段有药物治疗、心理治疗以及手术治疗等，但这些方式的治疗效果有限且存在一定副作用。有统计显示，强迫症治疗有效率约40%-60%，但实现临床治愈的比例只有20%。已上市的强迫症治疗药物均为5-羟色胺转运体（SERT）抑制剂，包括帕罗西汀、氟伏沙明、氟西汀、氯米帕明和舍曲林，该领域已多年无突破。Trigriluzole是一款第三代兴奋性氨基酸转运蛋白2（EAAT2）调节剂，可调节谷氨酸（人体主要的兴奋性神经递质）水平。该分子通过上调神经胶质细胞中EAAT的表达并增强其功能来增加神经元突触对谷氨酸的摄取，从而降低神经元突触中的谷氨酸水平。此前，Trigriluzole已完成一项强迫症II期研究，但结果不佳。102例患者接受200mg Trigriluzole治疗12周后，Yale-Brown强迫症量表（Y-BOCS）评分改善情况与安慰剂组无显著性差异（-5.9 vs. -4.9分，P=0.220）。不过，Trigriluzole对重度强迫症患者倒是有不错的治疗效果（-7.0 vs. -4.6分，P=0.084）。III期BHV4157-302研究是Biohaven为Trigriluzole挽尊所做的一次努力。该研究将于2024年6月完成。作为目前唯一一款处于III期阶段的强迫症创新药物，Trigriluzole的III期研究结果将关系着这类疾病的治疗范式。NO.7 系统性红斑狼疮有望迎来创新机制产品前段时间，一位著名女演员的离世让系统性红斑狼疮（SLE）这种自免疾病冲上了热搜。目前，除了糖皮质激素以外，泰它西普（荣昌生物）、贝利尤单抗（GSK）和anifrolumab（阿斯利康）是仅有的3款可治疗SLE的创新药物。SLE非激素类药物销售额Dapirolizumab pegol是渤健、优时比（UCB）和Nektar三家公司合力开发的一款CD40L单抗，也是SLE领域研发进展最快的CD40L靶向药物。不过，Dapirolizumab pegol（6/24/45mg/kg）的SLE II期研究结果不佳，虽能改善患者的临床和免疫学结局，但并未能显著提高患者的基于BILAG（英国狼疮评定组指数）的复合狼疮评估（BICLA）应答率。目前，Dapirolizumab pegol治疗SLE的III期PHOENYCS GO研究正在进行中，预计明年下半年将有结果披露。这项研究的结果可能会决定这款产品的命运。NO.8 替尔泊肽与司美格鲁肽的减重之战在替尔泊肽问世之前，司美格鲁肽一直稳居GLP-1赛道“老大”，没有一家公司敢贸然将其产品推上PK司美格鲁肽的擂台。2019年礼来敢为人先，在2型糖尿病患者中验证了替尔泊肽与司美格鲁肽（Ozempic）作为附加疗法时的降糖效果孰优孰劣。礼来的底气一方面来源于替尔泊肽在双靶点上的潜在优势，另一方面来源于替尔泊肽在早期研究中所展现的优异疗效。后来，替尔泊肽确实成功打败了司美格鲁肽，并因此收获了一波关注度。今年4月，在完成多项减肥III期研究后，礼来也乘胜追击启动了替尔泊肽对比司美格鲁肽的减肥头对头III期临床（SURMOUNT-5）。该临床预计将在明年11月完成。于GLP-1赛道而言，这两大明星产品之间的对决之战自然是看点十足。SURMOUNT-5研究（来源：TrialCube数据库）Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。推荐阅读标新生物杨小宝：突破制药边界，蛋白降解剂前景无限本导基因蔡宇伽：基因编辑疗法的“终极目标”——体内编辑圣诺医药陆阳：RNAi疗法逆势而上，实体瘤是下一个高地医药魔方Pro新靶点 新技术 新疗法商务合作：13502093012媒体合作：15895423126Copyright © 2024 PHARMCUBE. All Rights Reserved.欢迎转发分享及合理引用，引用时请在显要位置标明文章来源；如需转载，请给微信公众号后台留言或发送消息，并注明公众号名称及ID。免责申明：本微信文章中的信息仅供一般参考之用，不可直接作为决策内容，医药魔方不对任何主体因使用本文内容而导致的任何损失承担责任。

OnkosXcel's IPO decision comes as “a surprise” to Mizuho analysts. In a move that analysts called surprising, BioXcel Therapeutics is moving immuno-oncology subsidiary OnkosXcel towards an IPO.  BioXcel announced the SEC submission yesterday after market close and one week after revealing that it was still reviewing strategic options for OnkosXcel, including potential partnering or third-party investments. The number of shares and potential price for the public listing was not revealed in the Tuesday press release, but the proposed IPO is expected to occur after an SEC review process. According to a Mizuho analysis of early 2022 biotech IPOs, the time from initially submitting IPO paperwork with the SEC to actual IPO pricing took an average of five to six months, potentially placing OnkosXcel’s IPO in August or September. Last year, after BioXcel zoomed in on its neuroscience portfolio and received FDA approval for Igalmi to treat agitation tied to schizophrenia or bipolar I or II disorder, the company spun off its immuno-oncology assets into OnkosXcel. Now, less than a year after its formation, the subsidiary has submitted a confidential draft registration statement with the SEC to list on the public markets. OnkosXcel has a midstage DPP8/9 inhibitor called BXCL701 for advanced prostate cancer and solid tumors. The IPO decision comes as “a surprise” to Mizuho analysts because the firm thought partnering with a pharma to continue development of BXCL701 was “perhaps the more straightforward path.” OnkosXcel’s most advanced asset, BXCL701, is an oral innate immune activator being assessed for aggressive forms of prostate cancer and other solid and liquid tumors. Last month, the company shared data from a phase 2 trial evaluating BXCL701 in combination with Merck & Co.’s blockbuster checkpoint inhibitor Keytruda in people with small cell neuroendocrine metastatic castration-resistant prostate cancer (SCNC). The full phase 2a data showed a composite response rate (CRR) of 25% and an overall favorable safety profile, with no immune-related adverse events reported. Mizuho analysts dubbed the data “impressive” overall, given that the CRR compares to a rough 2-5% response rate seen with Keytruda alone in the specific patient population. There also aren’t any FDA-approved treatments for this specific subset of advanced prostate cancer patients, with a survival rate after unsuccessful first-line treatment measured in just weeks or months, according to Mizuho. The analysts also noted that there doesn’t appear to be any immediate competitors in the SCNC space. OnkosXcel plans to advance BXCL701 into a phase 2b registrational trial in the second half of this year, pending further discussion with the FDA. The company also has plans to launch a midstage trial in small cell lung cancer this year.   Many in the biotech industry have hoped biotech IPOs would pick up steam this year. While some signs of life have broken through the frozen-over market waters so far (re: Mineralys and Structure), the landscape remains fairly bleak.