Fesoterodine Fumarate

医道社：传承和发展民间中医 来源：海外网站 作者：医道社整理  版权归原作者所有，如有违规、侵权请联系我们删除！ 👆关注不迷路，更多创新药前沿资讯 精神分裂症药物研发，过去数十年有一个几乎令人绝望的事实： 绝大多数药物，最终仍绕不开多巴胺D2受体。 这当然不是因为D2不重要。恰恰相反，D2阻断对阳性症状有效，至今仍是治疗基石。但它也带来了临床医生每天都在面对的代价：锥体外系反应、迟发性运动障碍、泌乳素问题、代谢异常、体重增加、镇静，以及患者最终“不愿意吃药”。 更棘手的是，D2路线对认知损害和阴性症状的改善始终有限。 所以，真正的问题从来不是“还能不能再做一个抗精神病药”，而是： 能不能绕开D2，仍然压住精神病性症状；并且，不能只在临床试验里有效，还要让患者长期吃得下去。 2026年7月27日，MapLight公布ML-007C-MA在精神分裂症急性加重患者中的II期ZEPHYR顶线结果。210/3 mg、每日两次给药（BID）组达到主要终点：第5周PANSS总分相对安慰剂改善4.5分，p=0.015，效应量Cohen’s d=0.37。 单看这条结果，它还远不足以宣布“颠覆”。 但把它放回胆碱能抗精神病药近年的临床演进中，就会发现：ML-007C-MA最值得研究的，可能不是一条PANSS曲线，而是其将“双M1/M4机制、脑暴露和外周副作用控制”同时装进一个固定复方制剂的技术路径。01胆碱能抗精神病药，已经证明“方向对了” 胆碱能路线不是新概念，却在近两年重新成为精神分裂症研发最热的赛道之一。 其中最具标志性的事件，是xanomeline/trospium组合获批。其核心逻辑很直接： ·xanomeline：在中枢激动M1/M4毒蕈碱受体，产生抗精神病效应； ·trospium：主要在外周阻断毒蕈碱受体，减少恶心、呕吐、出汗、腹泻等胆碱能不良反应。 这条路线的临床意义在于：它证明了不直接阻断D2受体，也可以在急性精神分裂症中获得明确的抗精神病疗效。 不过，xanomeline路线也暴露了一个现实问题：疗效只是第一步，真正决定药物能否进入长期管理的，是耐受性、给药便利性和依从性。 胆碱能激动剂的历史，几乎就是一部“疗效信号很早出现，但外周副作用阻断了临床转化”的历史。 ML-007C-MA想解决的，正是这道老难题。 02ML-007C-MA的真正技术优势：不是“又一个M1/M4”，而是把机制做成了药物 ML-007C-MA由两部分组成： ·ML-007（betovumeline）：口服、缓释的M1/M4毒蕈碱受体激动剂； ·fesoterodine：公司定义为外周作用的抗胆碱能药，用于对冲外周胆碱能不良反应。 这看起来与xanomeline/trospium有相似之处，但ML-007C-MA的技术重点不止是“激动剂+外周拮抗剂”的组合，而是三个层面的协同。1. 不是押注M4单靶点，而是回到M1与M4协同 过去几年，M4被认为可能是胆碱能抗精神病效应的“主开关”。 这个判断有其生物学基础。M4在纹状体直接通路神经元中表达丰富，能够影响多巴胺驱动的运动和行为反应；而M1则广泛分布于皮层、海马和纹状体，在认知、皮层兴奋性及基底节环路调控中都具有重要作用。 但问题在于：“M4重要”不等于“M4单独足够”。 MapLight发表于《Neuropsychopharmacology》的临床前研究给出了一组值得重视的数据： ·ML-007在小鼠安非他命诱导高活动、PCP诱导高活动、条件性回避反应等多个精神病模型中均显示活性； ·在这些模型中，ML-007所需有效剂量约为xanomeline的十分之一； ·在M1敲除和M4敲除小鼠中，ML-007逆转安非他命诱导高活动的效力均下降； ·换句话说，缺失M1或M4中的任何一个，药物的效应都会受到影响。 这不是说“M1和M4缺一个就完全失效”。论文显示，高剂量下单独保留一个受体仍可能产生一定行为学效应。 但真正值得注意的是： ML-007的临床前疗效不是由单一受体独立完成，而是M1和M4共同贡献。 这与近年来M4单靶点开发所遇到的波折形成了鲜明对照。M4正向变构调节剂emraclidine早期临床曾给市场带来很高预期，但后续II期EMPOWER研究未达到主要终点。一次失败当然不能否定M4的价值，却足以提醒研发者： 精神分裂症不是一个“找到单一开关、按下去就结束”的疾病。 对复杂环路疾病而言，双靶点协同可能比“极致选择性”更接近真实生物学。2. 临床前“十倍效力”背后，真正的主角是脑内游离药物暴露 ML-007还有一个很容易被忽略、但对药物化学和临床药理团队更重要的发现。 在体外细胞实验中，ML-007其实并不比xanomeline更强。 以人源受体为例： 指标 ML-007 Xanomeline 人M1 EC50 约120 nM 约2.3 nM 人M4 EC50 约830 nM 约5.5 nM 如果只看体外EC50，xanomeline明显更强。 但进入动物后，结果反转：ML-007在多个精神病模型中约比xanomeline低十倍剂量即可产生相似效应。 为什么？ 答案是：暴露。尤其是中枢游离暴露。 论文中，小鼠腹腔给药后： ·ML-007的腹腔给药生物利用度约为94.6%； ·xanomeline约为8.6%； ·0.3 mg/kg ML-007的脑脊液Cmax约为115 ng/mL，即约698 nM； ·3 mg/kg xanomeline的脑脊液浓度低于定量下限。 作者据此估算，在等行为效应剂量下，ML-007在脑内可获得的游离药物暴露至少显著高于xanomeline。 这组数据带来的研发启示非常直接： 药物不是在受体筛选板上治病，而是在患者脑内治病。 一个分子在体外“看起来不够强”，并不意味着临床上没有竞争力；反之，一个体外纳摩尔级强效分子，如果吸收差、首过代谢高、脑内游离浓度不足，也可能无法真正击中靶点。 需要强调的是，鼠脑脊液浓度不能直接等同于人体脑内暴露，更不能直接推导临床剂量。但ML-007的这一案例再次说明：决定中枢药物成败的，不只是受体药理，更是PK/PD耦合。3. 固定复方和缓释设计，可能比“靶点名称”更决定临床可用性 很多人把ML-007C-MA理解为“又一个M1/M4药物”。这不够准确。 它更像是一个围绕真实临床痛点设计的系统工程产品： 中枢需要足够、稳定的M1/M4激动； 外周副作用必须同步被压住； 两者的药代动力学不能脱节。 MapLight强调，ML-007C-MA是缓释固定剂量复方，通过同步激动剂和拮抗剂的药代过程，力图降低外周胆碱能反应。 这件事看似是制剂问题，实质上却是疗效问题。 因为对精神分裂症患者而言，任何需要复杂滴定、严格空腹、频繁因胃肠道反应减量或停药的方案，最终都会折损疗效——不是药不够有效，而是患者无法稳定暴露于有效剂量。 ZEPHYR中，210/3 mg BID方案的几个临床细节因此尤其值得关注： ·不要求空腹； ·仅需一次剂量滴定； ·没有患者因耐受性问题无法达到目标剂量； ·因不良事件减量者为4例，其中3例完成治疗； ·胃肠道事件导致停药者为2例，占2.0%。 这些结果尚不足以证明真实世界依从性更高，因为试验环境与门诊长期治疗完全不同。但至少说明，ML-007C-MA正在把胆碱能药物最棘手的外周耐受性问题，前置到产品设计阶段处理，而不是留给临床医生“事后补救”。03ZEPHYR结果：信号明确，但还没有到“庆功时刻” ZEPHYR是一项在美国25个中心开展的随机、双盲、安慰剂对照II期研究，共纳入307例急性加重的住院精神分裂症成人患者，分为： ·安慰剂； ·ML-007C-MA 210/3 mg BID； ·ML-007C-MA 330/6 mg QD。 核心结果如下： 终点 210/3 mg BID vs 安慰剂 PANSS总分，第5周 -4.5分，p=0.015，d=0.37 完成5周治疗者PANSS -6.0分，p=0.002，d=0.50 CGI-S d=0.48，p=0.002 PANSS阳性症状Marder因子 d=0.39，p=0.012 基线认知受损亚组Cogstate +0.44分，p=0.041，d=0.51 先说结论： 这是一组有一致性的阳性II期结果。 主要终点阳性，CGI-S和PANSS阳性因子也同步支持，方向一致，比单一终点“踩线过关”更有说服力。 更吸引人的，是认知结果。 在基线存在认知损害的预设亚组中，Cogstate认知测评显示效应量* d*=0.51；公司称认知改善与PANSS变化不相关，提示这可能不是“精神病症状改善后，患者更愿意配合做题”所带来的次级效应。 如果这一信号能在后续试验中重复，意义确实不同寻常。因为在精神分裂症中，认知损害是功能结局、就业能力、社会回归和长期残疾的重要决定因素，而目前并没有获批的认知损害治疗药物。 但同样必须泼一盆冷水： ·认知分析是预设终点，但针对的是基线认知受损人群，具体样本量尚未充分公开； ·多终点检验的统计学控制细节仍需看完整数据； ·5周时间太短，无法回答认知获益是否稳定、是否转化为功能改善； ·完成者分析的效应量更高，不代表其比mITT结果更“真实”，因为完成治疗本身可能引入选择偏倚； ·尚无与已上市抗精神病药的头对头比较； ·长期代谢、心血管、泌尿系统和认知安全性仍需更大样本、更长时间验证。 因此，最科学的表述应当是： ML-007C-MA已经给出了一个值得认真对待的疗效和认知信号，但它仍需要一项高质量、可重复的确认性研究。04QD失败，反而可能揭示了这个项目最重要的药理学事实 ZEPHYR中，330/6 mg每日一次（QD）方案在PANSS总分主要终点上仅呈数值改善，未达到统计学显著性。 这不是一个应被轻描淡写的结果。 值得注意的是，QD组每日总ML-007暴露低于210 mg BID组。也就是说，BID组每日ML-007剂量为420 mg，而QD组为330 mg。 这可能提示： 对ML-007而言，“一天吃过药”不等于“全天维持足够的中枢M1/M4激动”。 M1/M4通路的临床疗效，也许依赖于更高的总暴露、足够的谷浓度，或者更平稳的受体激动时间窗。究竟是哪一个，仍需PK/PD数据来回答。 但从研发视角看，QD组没有成功未必全是坏消息。它至少给出了一个清晰的剂量—暴露—疗效问题：这个药的有效暴露阈值在哪里？缓释制剂是否能进一步优化？能否做出真正可行的QD方案？ 这比“所有剂量都差不多有效”更能指导后续开发。05下一步最该盯住的，不是新闻稿里的形容词，而是这五个问题 对于临床医生和研发人员，ML-007C-MA接下来最值得追问的，是以下五件事： 第一，疗效能否复制？公司计划与FDA进行EOP2沟通，并推进另一项确认性试验。ZEPHYR加一项阳性确认性研究，才是其潜在注册价值真正落地的关键。 第二，认知信号是否经得住重复？需要看到完整Cogstate域分析、亚组样本量、缺失值处理、多重性控制，以及认知改善是否最终转化为功能结局。 第三，M1/M4“双靶点”能否在人身上被证明？小鼠敲除实验很有启发性，但人体中仍需要更直接的靶点占有、暴露—效应关系或生物标志物证据。 第四，fesoterodine的“外周保护”能否在长期中成立？固定复方的核心价值，在于既抑制外周胆碱能副作用，又尽量不抵消中枢M1/M4疗效。长期尿潴留、心率、认知及药物相互作用数据必须完整呈现。 第五，它能否真正改善长期治疗体验？没有空腹要求、滴定简单，是很好的产品特征；但是否减少停药、复发、再住院，仍需要真实世界和长期维持治疗数据回答。结语ML-007C-MA最大的价值，是提醒行业：中枢创新不能只讲靶点 ML-007C-MA的故事，目前还不是“一个新药已经成功”的故事。 它更像一个值得全行业认真研究的命题： 精神分裂症的下一代治疗，可能不再是寻找一个更强的D2阻断剂； 也不只是寻找一个更漂亮的单靶点分子； 而是把环路生物学、双受体协同、脑内游离暴露、外周副作用对冲和患者依从性，做成一个可以真正交付给临床的产品。 从这个角度看，ML-007C-MA的看点并不止于PANSS -4.5分。 它真正挑战的是一个长期存在的研发惯性：我们到底是在开发“分子”，还是在开发“患者能够长期使用的治疗方案”？ ZEPHYR给出了第一轮回答。接下来，确认性研究和长期数据，才是决定这个答案能否成立的时刻。参考资料 1.Chatterjee S, et al. Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors. Neuropsychopharmacology. 2026;51:840-845. DOI: 10.1038/s41386-025-02256-3. 2.MapLight Therapeutics. Positive Topline Results from Phase 2 ZEPHYR Trial of ML-007C-MA in Schizophrenia. 2026-07-27. 公司新闻稿，未同行评议。 3.Brannan SK, et al. Muscarinic Cholinergic Receptor Agonist and Peripheral Antagonist for Schizophrenia. N Engl J Med. 2023;388:518-527. DOI: 10.1056/NEJMoa2210749. 4.Foster DJ, Choi DL, Conn PJ, Rook JM. Activation of M1 and M4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia. Neuropsychiatr Dis Treat. 2014;10:183-191. 5.Krystal JH, et al. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. Lancet. 2023. 6.美国FDA：Cobenfy（xanomeline/trospium）处方信息及审批资料。 前期优质文章： 大冢 Centanafadine（Simtriyo）7/27 获FDA批准——全球首款NDSRI类多动症治疗药 从发现病灶后无药可用，到在炎症真正失控前争取窗口期。CHMP给出肯定意见之后：leriglitazone不是又一个ALD药，而是在抢救移植前的时间 不是新靶点，而是重写暴露路径：IKT-001能否解开肺动脉高压（PAH）“伊马替尼悖论”？ 医道社自己专业的医疗科普微信公众号：

The trial, designed and sized to support registration, met its primary endpoint, with the 210/3 mg BID dose demonstrating a statistically significant improvement in PANSS total score compared to placebo at Week 5 with an effect size of 0.37 (LS mean difference vs PBO -4.5, p=0.015) Cognitive performance was improved (ES=0.51, p=0.041) in those with baseline cognitive impairment on a prespecified secondary endpoint 210/3 mg BID dose also achieved significant separation on key secondary endpoints, including CGI-S (ES=0.48, p=0.002) and PANSS Positive Marder Factor (ES=0.39, p=0.012) ML-007C-MA was generally well tolerated at both doses studied, with no serious or drug-related severe adverse events and low rates of GI-related discontinuations ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); No fasting requirement and a one-dose titration support a tolerability pro to translate into real-world adherence Data support proceeding with an additional trial, also designed to be registrational, to replicate this result; Company to engage with FDA at End-of-Phase 2 Meeting Company to host live webcast today at 8:00 AM ET SAN FRANCISCO and BOSTON, July 27, 2026 (GLOBE NEWSWIRE) -- MapLight Therapeutics, Inc. (Nasdaq: MPLT), a clinical-stage biopharmaceutical company focused on improving the lives of patients suffering from debilitating central nervous system disorders, today announced positive topline results from its Phase 2 ZEPHYR trial evaluating ML-007C-MA, an oral M1/M4 muscarinic agonist (betovumeline) co-formulated with a peripherally acting anticholinergic (fesoterodine), in adults with an acute exacerbation of schizophrenia. The trial met its primary endpoint, with the 210/3 mg twice-daily (BID) dose demonstrating a statistically significant and clinically meaningful reduction in Positive and Negative Syndrome Scale (PANSS) total score compared to placebo at Week 5. In the modified intent-to-treat (mITT) population, the BID arm achieved an effect size of 0.37 ( Cohen’s d ) and these participants experienced a mean 4.5-point improvement in PANSS total score versus placebo (p=0.015). In a prespecified analysis of participants who completed five weeks of treatment, in which there are no modelled assumptions for missing data, the effect size was 0.50 (LS mean difference from placebo -6.0, p=0.002), driven by greater improvement in the treatment arm rather than the placebo arm. ML-007C-MA also achieved significance on key secondary endpoints in the BID arm, including Clinical Global Impression of Severity (CGI-S) (effect size=0.48; p=0.002), PANSS positive Marder factor (effect size=0.39; p=0.012), and multiple other secondary and exploratory outcomes. Notably, ML-007C-MA demonstrated a robust and clinically meaningful improvement in cognitive performance in the BID arm, based on the pre-specified secondary endpoint assessed via the Cogstate battery in participants with baseline cognitive impairment (effect size=0.51; 0.44 points versus placebo; p=0.041). This cognitive benefit did not demonstrate correlation with the change in PANSS score, suggesting the effect was independent of, and not secondary to, improvement in psychotic symptoms. “We are very encouraged by these results, which show that ML-007C-MA delivered clinically meaningful antipsychotic efficacy alongside a favorable tolerability pro to translate into real-world use," said Chris Kroeger, M.D., Co-Founder and Chief Executive Officer of MapLight. "Just as importantly, we observed a robust signal on a pre-specified secondary cognition endpoint that appears independent of antipsychotic effect. Cognitive impairment affects the majority of people living with schizophrenia and remains an area where no therapy has yet been approved. We believe the combination of a significant effect on PANSS and other concordant endpoints, along with a meaningful effect on cognitive performance, represents a powerful, comprehensive overall efficacy pro schizophrenia, and strengthens the rationale for our ongoing VISTA trial in Alzheimer's disease psychosis and the broader indication expansion for ML-007C-MA." The 330/6 mg once-daily (QD) dose, which results in lower daily exposure than BID dosing, demonstrated numerical improvement over placebo, but did not achieve statistical significance on the primary endpoint. However, it did demonstrate separation on CGI-S (p=0.036), PANSS positive Marder factor (p=0.045), and Readiness for Discharge Questionnaire (p=0.027) and numerical separation on several other endpoints. The Company is conducting further analyses to inform the potential path forward for a once-daily regimen. Safety and Tolerability ML-007C-MA was generally well tolerated across all doses studied. Treatment-emergent adverse events (TEAEs) were mostly mild and primarily cholinergic in nature, and there were no serious adverse events or drug-related severe TEAEs with either dose. The only severe TEAE in an active arm was a case of pneumonia, which was assessed as unrelated to study treatment. One serious TEAE of worsening schizophrenia occurred in the placebo arm. All-cause discontinuation across both active arms was low, at 19.9%. At the 210/3 mg BID dose, TEAEs were reported in 74.7% of participants compared with 48.1% receiving placebo, with most events mild in severity. Gastrointestinal events were mostly mild and rarely associated with discontinuation (two participants, 2.0%), and there were low rates of moderate GI events. No participant failed to reach target dose due to tolerability, and dose reductions due to TEAEs were infrequent (four participants, or 4.0%, three of whom completed treatment). The rates of anticholinergic events were low, and no clinically meaningful signals were observed with ML-007C-MA for urinary retention, metabolic or hepatic parameters, extrapyramidal symptoms, or blood pressure. Small increases in heart rate were observed, consistent with the known pro fesoterodine. With no fasting requirement and a short, one-dose titration, these clinical trial results are expected to translate into real-world use, supporting patient adherence and compliance. "Despite recent advances in schizophrenia treatment, patients and clinicians continue to need therapies that pair meaningful symptom control with a tolerability pro can sustain over time," said John M. Kane, M.D., Professor of Psychiatry and Molecular Medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Co-Director of the Institute for Behavioral Science at the Feinstein Institutes for Medical Research, and member of MapLight Therapeutics' Clinical Advisory Board. "The ZEPHYR results are notable on both fronts: a statistically significant improvement on the primary endpoint and cognitive performance, alongside a meaningfully differentiated safety pro matters most for the management of patients over time. If confirmed in a further study and approved, ML-007C-MA could offer physicians a valuable additional tool in the treatment arsenal for people living with schizophrenia." Future Development The Company plans to engage with the FDA at an End-of-Phase 2 (EOP2) meeting to discuss the path forward for ML-007C-MA in schizophrenia, including the design of a Phase 3 trial which, together with ZEPHYR, would support an initial New Drug Application (NDA) submission. Planning and site identification for this additional, confirmatory trial are already underway ahead of the MapLight's EOP2 FDA interactions. The Company is also planning a separate confirmatory trial to evaluate the BID dose used in ZEPHYR along with other dosing regimens, including a possible QD option. VISTA, MapLight’s ongoing trial designed to support registration for the treatment of hallucinations and delusions associated with Alzheimer's disease psychosis, is also evaluating ML-007C-MA 210/3 mg BID (the same dose associated with the cognitive effect in ZEPHYR), with topline results expected in the second half of 2027. Additionally, the Company recently reported results for IRIS, a Phase 2 trial evaluating ML-004, an 5-HT 1B/1D agonist in autism spectrum disorder (ASD), where a prespecified subgroup analysis in adolescents with significant baseline irritability demonstrated meaningful improvement over placebo on both caregiver- and clinician-rated scales alongside a favorable safety and tolerability profile. Based on these results, the Company intends to engage with the FDA in an EOP2 meeting to determine the next steps for development of ML-004 in irritability associated with ASD. Live Webcast The Company will host a live webcast to discuss the Phase 2 ZEPHYR trial results today, Monday, July 27, 2026, at 8:00 a.m. ET. Those who would like to participate may access the live webcast here , or register in advance for the teleconference here . The event will also be accessible through the "Events and Presentations" page within the Investors section of the Maplight website at . An archived replay will also be available on the website for at least 90 days following the event. About ZEPHYR ZEPHYR is a randomized, double-blind, placebo-controlled trial at 25 US sites that evaluated the efficacy, safety, and tolerability of ML-007C-MA in inpatient adult participants with schizophrenia experiencing an acute exacerbation of psychosis. A total of 307 participants were randomized 1:1:1 to receive either placebo, ML-007C-MA 210/3 mg twice daily, or ML-007C-MA 330/6 mg once daily. The primary endpoint for the trial was the change in PANSS total score from baseline to Week 5. Key secondary endpoints included change in CGI-S score and PANSS-Marder positive and negative factor scores from baseline to Week 5. Change in cognitive function in participants with baseline cognitive impairment from baseline to Week 5 was assessed as a prespecified secondary endpoint. About ML-007C-MA ML-007C-MA is an oral, extended-release, fixed-dose combination of the investigational M1/M4 muscarinic agonist ML-007 (betovumeline), co-formulated with a peripherally acting anticholinergic (fesoterodine). ML-007C-MA is designed to activate both M1 and M4 muscarinic receptors in the central nervous system to drive efficacy, while synchronizing the pharmacokinetics of the agonist and antagonist components to mitigate peripheral cholinergic side effects. About MapLight Therapeutics MapLight Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients suffering from debilitating central nervous system disorders. The Company was founded by globally recognized leaders in psychiatry and neuroscience research to address the lack of circuit-specific pharmacotherapies available for patients. The Company’s discovery platform holds the potential to fill this void by identifying neural circuits causally linked to disease and targeting those circuits for therapeutic modulation. For more information, please visit . Forward-Looking Statements Certain statements in this press release may constitute “forward-looking statements” within the meaning of the federal securities laws, including, but not limited to, the clinical development and potential benefits of ML-007C-MA and ML-004, the design, timing and conducting of future clinical trials, the registrational pathway for the Company’s product candidates, including holding EOP2 meetings with the FDA for ML-007C-MA and ML-004 and planned regulatory submissions, the availability and timing of results from the Company’s Phase 2 VISTA trial, and the potential benefits of the Company’s discovery platform. Words such as “may,” “might,” “will,” “objective,” “intend,” “should,” “could,” “can,” “would,” “expect,” “believe,” “design,” “estimate,” “predict,” “potential,” “develop,” “plan” or the negative of these terms, and similar expressions, are intended to identify forward-looking statements. While the Company believes these forward-looking statements are reasonable, undue reliance should not be placed on any such forward-looking statements, which are based on information available to the Company on the date of this release. These forward-looking statements are based upon current estimates and assumptions and are subject to various risks and uncertainties (including, without limitation, those set forth in the Company’s filings with the U.S. Securities and Exchange Commission (SEC)), many of which are beyond the Company’s control and subject to change. Actual results could be materially different. Risks and uncertainties include: the unpredictable relationship between preclinical study results and clinical study results; the risk that results obtained in any clinical trials to date may not be indicative of results obtained in ongoing or future trials; the timing or likelihood of regulatory filings and approvals; expectations regarding the Company’s ability to fund its current operations; and other risks and uncertainties identified in the Company’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2026, and subsequent disclosure documents the Company may the SEC. The Company claims the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. The Company expressly disclaims any obligation to update or alter any statements whether as a result of new information, future events or otherwise, except as required by law. 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