AXN-027

DALLAS, Jan. 06, 2026 (GLOBE NEWSWIRE) -- Instil Bio, Inc. (Nasdaq: TIL) (“Instil”) today announced that Axion Bio, Inc. (“Axion”), a wholly-owned subsidiary of Instil, has decided to discontinue clinical development of AXN-2510 and that Axion and ImmuneOnco Biopharmaceuticals (Shanghai) Inc. (HKEX: 1541.HK) (“ImmuneOnco”) have entered into an agreement terminating their license and collaboration agreement for AXN-2510 and AXN-27M (“Termination Agreement”). Under the terms of the Termination Agreement, all rights previously licensed to Axion, including global development and commercial rights outside Greater China, have reverted to ImmuneOnco, subject to a limited license to Axion to wind down its clinical development activities. About Instil Bio Instil Bio is a biopharmaceutical company focused on developing novel therapies. For more information visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “anticipates,” “believes,” “expects,” “exploring,” “future,” “intends,” “may,” “plans,” “potential,” “projects,” “targets” and “will” or similar expressions are intended to identify forward-looking statements. Forward-looking statements include express or implied statements concerning Instil's expectations regarding the termination agreement with ImmuneOnco, and other statements that are not historical fact. Forward-looking statements are based on management's current expectations and are subject to various risks and uncertainties that could cause actual results to differ materially and adversely from those expressed or implied by such forward-looking statements, including risks and uncertainties related to discontinuing US clinical development of AXN-2510; risks related to macroeconomic conditions, including as a result of international conflicts and U.S.-China trade and political tensions, as well as interest rates, inflation, tariffs and other factors, which could materially and adversely affect our business and operations and those of our collaborators; the risks and uncertainties associated with the time-consuming and uncertain regulatory approval process and the sufficiency of Instil's cash resources; and other risks and uncertainties affecting Instil's plans and development programs, including those discussed in the section titled “Risk Factors” in Instil's Quarterly Report on Form 10-Q for the quarter ended September 30, 2025 filed with the SEC, as well as Instil's other filings with the SEC. These forward-looking statements do not constitute guarantees of future performance, and you are cautioned not to place undue reliance on these forward-looking statements. These forward-looking statements speak only as the date hereof, and Instil disclaims any obligation to update these statements except as may be required by law. Contacts: Investor Relations: 1-972-499-3350 investorrelations@instilbio.com Media Relations: Kimberly Ha KKH Advisors 917-291-5744 kimberly.ha@kkhadvisors.com

编者按：2024年10月，Axonis Therapeutics成功完成了1.15亿美元的A轮融资，成为近年来中枢神经系统（CNS）领域规模最大的私募融资之一。乘此东风，该公司正推动其核心候选药物AXN-027进入1期临床试验。作为一款潜在“first-in-class”口服KCC2小分子增效剂，AXN-027为一系列CNS疾病提供了一种恢复神经元抑制功能的全新治疗路径。与此同时，Axonis还布局了另外两个靶向KCC2的研发项目，致力于构建针对特定患者群体需求的小分子增效剂产品矩阵。近日，我们与Axonis的联合创始人兼首席科学官Shane Hegarty博士展开对话，探讨该公司如何迎接神经病学领域靶向治疗与机制驱动疗法的新纪元。 Shane Hegarty博士是Axonis Therapeutics的联合创始人兼首席科学官，在神经系统疾病创新疗法研发领域具有深厚的学术积淀和丰富的产业经验。他在神经保护、神经调控及神经再生研究领域积累了15年前沿研究经历，累计发表30余篇高水平学术论文，并持有多项专利成果。近年来，Hegarty博士完成了多项生物科技创业项目，并成功实现成果转化。 感谢您接受我们的采访。首先祝贺Axonis完成1.15亿美元A轮融资。您认为贵公司最打动投资人的因素是什么？这笔资金将如何推动贵公司的发展战略？ Shane Hegarty博士：我们最初将KCC2确定为CNS疾病中一个经临床验证的重要靶点。我们的研究起点并非KCC2本身，而是聚焦于中枢神经系统兴奋-抑制（E/I）失衡这一更广泛的基础病理机制。通过在成年中枢神经E/I失衡模型中对神经调节化合物进行无偏倚的体内表型筛选，我们发现增强KCC2是唯一能通过纠正E/I失衡持续产生显著功能益处的干预手段。目前我们已在多种疾病模型中验证了KCC2增效剂恢复E/I平衡的疗效：包括耐药性癫痫、疼痛、神经创伤、神经退行性疾病，甚至精神疾病和神经发育障碍的行为模型。无论何种病理情况，当KCC2功能受损时，受影响的神经环路会丧失对抑制性神经递质的正常响应能力，从而导致神经元抑制失调和过度兴奋。这一机制为我们确立KCC2作为潜在“first-in-class”新药靶点提供了关键的理论和数据支撑。我们相信KCC2有望从根本上改变当前对多种神经系统疾病的治疗策略——这些疾病共同特征是神经元抑制功能受损导致神经环路代偿失调，并对基于功能性抑制的疗法产生耐药性。 在我们进行A轮融资期间，KCC2作为靶点所受到的广泛关注，得益于精准的时机把握——历经二十载的KCC2临床前研究、遗传学研究和临床研究已趋于成熟，其向临床转化的风险显著降低。但更宏观地看，我认为当前这个十年堪称CNS领域史上最具前景的黄金时期。我们正站在巨人的肩膀上——众多研究人员，比如我们的顾问委员会成员Corey Goodman教授、何志刚教授和Yves DeKoninck教授等等，数十年来持续推动着CNS领域的进步。而真正驱动这场变革的核心动力，在于学界和业界日益认识到CNS领域巨大未被满足的医疗需求及其沉重负担。长期以来，该领域主要依赖针对广泛人群的对症治疗手段。如今我们正见证着向精准医学的转型：针对经过基因分型或病理分型的特定患者亚群，靶向明确的作用机制进行治疗。这一转变真正开启了疾病修饰疗法的大门。最终，随着对疾病生物学机制理解的深入，加之治疗手段和递送技术的突破，我们现在能够比以往任何时候都更精准地将作用机制与患者相匹配。 贵公司主打的在研药物AXN-027是一款小分子药物，最近小分子药物引起了很多业界关注。在您看来，是什么推动了这一趋势？我们又该如何更好地发掘小分子药物在CNS新药开发中的潜力？ Shane Hegarty博士：在我看来，口服生物可利用型小分子药物仍然是一种理想的治疗模式，这主要得益于其便捷性和与患者日常生活的良好兼容性。例如，小分子药物具有治疗灵活性——如果疗效不佳，患者可以随时停药。相较那些不可逆的治疗干预手段，这无疑是一个显著优势。 近期小分子药物的复兴，很可能源于我们对创新生物靶点有了更深入的理解。随着对CNS疾病发病机制的认识不断加深，新的靶向干预机会也随之涌现。如今的小分子药物比以往更加多样化——它们既可以用作降解剂、激活剂、抑制剂，也能发挥调控或增效作用。以我们的在研药物AXN-027为例，它是一种口服小分子KCC2增效剂。归根结底，关键在于选择最匹配患者需求的治疗方式。当小分子药物能够精准匹配临床需求时，其便捷性和适应性就会使其成为CNS药物开发极具吸引力的选择。 图片来源：123RF 在CNS药物研发领域，人们一直在讨论如何推进临床试验现代化。随着AXN-027进入1期临床试验阶段，能否请您从宏观角度谈谈，推动该领域临床开发进程需要哪些关键变革？ Shane Hegarty博士：我们已见证了CNS临床试验令人振奋的进展——尤其是液体活检生物标志物、影像学生物标志物的应用，以及当前电生理学生物标志物的引入。这些创新工具能提供更客观、波动性更小的临床研究终点，有望显著缩短试验周期并提升效率。核心挑战在于：需通过坚实的大数据集验证这些生物标志物，促使监管机构将其从次要终点提升为能同步衡量临床事件与治疗获益的主要终点。 以失神性癫痫为例，该病症既往依赖患者自述或临床观察进行评估，测量起来存在极大困难。而如今特定脑电图（EEG）生物标志物已被广泛认可，可直接捕捉失神性癫痫发作活动。这正是我们期待在各类CNS适应症中实现的突破：建立清晰、客观、可量化且与疾病机制紧密关联的终点。 另一关键要素是患者分层。若能在机制层面深入解析疾病驱动因素，并将其与疾病进展的具体阶段精准匹配，我们便能像肿瘤学领域那样，为合适的患者匹配最适宜的治疗方式。这正是精准神经科学的愿景所在，也是我认为该领域的发展方向。 图片来源：123RF 从更宏观的角度来看待神经科学，您认为当前是否存在被低估却值得重点关注的趋势？ Shane Hegarty博士：在我看来，当神经退行性病变已高度进展时，再试图改善认知功能可能为时已晚。当前最令人振奋却未获足够重视的领域之一，便是预防医学。随着生物标志物的日益普及——例如近期获批的阿尔茨海默病血检技术——我们现已具备发现早期疾病、并在不可逆损伤发生之前进行干预的潜力。将治疗机制与疾病早期阶段精准匹配，其效果可能远优于针对晚期病理状态的治疗尝试。例如，当神经退行性病变已导致严重认知衰退时，干预效果往往有限；而若能在疾病进程更早期纠正E/I失衡，则可能产生更显著的疗效，甚至延缓疾病进展。 另一个亟待关注的领域是联合用药策略，即合理的组合疗法。大脑的复杂性决定了不同病理诱因可能激活重叠的疾病机制，指望单一疗法解决所有症状往往不切实际。随着我们对疾病本体（即病理演变轨迹）认知的深化，将有机会实现更早期、更精准的干预——理想状态下是在功能尚未严重受损时就维持健康状态，而非被动应对晚期病变。以帕金森病为例，据报道，患者在确诊时其黑质纹状体轴突输入通路大部分已发生退行性病变。 因此我认为，医药与生物技术领域的未来方向应当是：不再是致力于逆转晚期疾病状况的治疗策略，而是转向预防医学模式——旨在保持健康，并在疾病的早期阶段进行干预，因为此时疾病负担最轻、干预窗口最佳。 图片来源：123RF 最后，如果您能做出一项变革，能够提升未来5-10年内CNS领域药物的研发效率和患者获益，您会怎么做？ Shane Hegarty博士：这是个非常好的问题，我确实有很多期待。但如果必须选择一项，我希望看到更多关注和实际行动投入到CNS领域的超罕见和孤儿病。这些疾病大多鲜少获得投资——并非源于科学认知的不足，而是当前市场环境下缺乏开发这些疗法的商业动力。事实上，在某些情况下，我们对这些罕见疾病（如单基因神经发育性疾病）的致病机制理解得比常见疾病更为透彻。 因此，我的愿景是促成投资者、支付方、监管机构和药物开发商之间的多方协作，共同建立支持这些常被忽视疾病疗法开发的创新机制。这不仅需要资金激励，更需要构建一条高效畅通的研发路径，确保当其他适应症的治疗方式突飞猛进时，超罕见病患者不会被遗忘在医疗进步的浪潮之外。在Axonis，我们始终致力于追求尖端科学突破，希望我们的工作能助力打造一个创新成果真正惠及所有患者群体的未来。 The Right Time for Translating Innovation in CNS Therapeutics: A Conversation with Dr. Shane Hegarty, Co-Founder and Chief Scientific Officer of Axonis Therapeutics Editor’s Note: In October 2024, Axonis Therapeutics secured a landmark $115 million Series A financing—one of the largest private biotech raises in the central nervous system (CNS) space in recent years, especially for founder-led biotech. Riding this momentum, the company is advancing its lead candidate, AXN-027, through Phase I clinical trials. A first-in-class, orally bioavailable small molecule potentiator of KCC2, AXN-027 offers a novel approach to restoring neuronal inhibition across a range of CNS disorders. In parallel, Axonis is developing two additional KCC2-targeted programs, aiming to build a robust portfolio of small molecule potentiators tailored to the needs of specific patient populations. Recently, we had a conversation with Dr. Shane Hegarty, Co-Founder and Chief Scientific Officer of Axonis, to discuss how the company is helping to usher in a new era of targeted, mechanism-driven therapies in neurology. Shane, thanks for joining us—and congratulations on Axonis’s $150 million Series A. What do you think most resonated with investors, and how will this funding drive your development strategy? Shane Hegarty: We initially identified KCC2 as a compelling clinically validated target in CNS pathologies. Our starting point wasn’t KCC2 itself—it was the broader, fundamental pathological issue of excitation-inhibition (E/I) imbalance in the CNS. Through an unbiased in vivo phenotypic screen of neuromodulatory compounds in an adult CNS E/I imbalance model, KCC2 was the only intervention that consistently delivered robust functional benefit by correcting E/I imbalance. We have now demonstrated this restoration of E/I balance via KCC2 potentiation across various models: drug-resistant epilepsy, pain, neurotrauma, neurodegenerative diseases and even behavioral models of psychiatric and neurodevelopmental conditions. Regardless of the pathology, when KCC2 function is impaired, the affected CNS circuits lose their ability to respond to inhibitory neurotransmission appropriately, thus leading to neuronal disinhibition and hyperexcitability. This mechanism is a key part of how we’re building confidence and data to support KCC2 as a first-in-class CNS therapeutic target. We believe KCC2 has the potential to fundamentally change how we treat a wide range of neurological diseases, where impaired inhibition is driving maladaptive circuit pathologies and drug resistance to therapies relying on functional inhibition. The momentum around KCC2 as a target during our Series A fundraising was also the result of great timing, where two decades of KCC2 preclinical, genetic and clinical research has matured to derisk its translation into the clinic. But more broadly, I believe that this decade is the most promising time in history for the CNS field. We are standing on the shoulders of giants that have pushed CNS field forward over decades, such as our advisors Professors Corey Goodman, Zhigang He and Yves DeKoninck. What’s really driving this recent transformation is the growing recognition and burden of the massive unmet need in CNS. For a long time, the field relied heavily on symptomatic treatments aimed at broad populations. Now, we’re seeing a transition toward precision medicine—targeting well-defined mechanisms in genetically or pathologically stratified subgroups. This evolution opens the door to true disease-modifying therapies. Ultimately, better understanding of disease biology—combined with advances in modality and delivery—means that we can now match mechanisms to patients more effectively than ever before. Recently there’s been a renewed interest in small molecules, including your lead compound, AXN-027. In your view, what’s driving this momentum—and how can we better harness their potential in CNS drug development? Shane Hegarty: In my opinion, orally bioavailable small molecules remain an ideal modality, largely due to their ease of use and compatibility with patients’ lives. For example, small molecules offer flexibility—if the benefit isn’t there, patients can stop treatment. That’s a powerful advantage over more permanent therapeutic interventions. The recent resurgence of small molecules may be fueled by a deeper understanding of novel biological targets. As we uncover more about the mechanisms driving CNS pathologies, new opportunities for targeted intervention emerge. And today’s small molecules are more versatile than ever—serving as degraders, activators, inhibitors, correctors, or potentiators. In our case, AXN-027 is an oral small molecule that potentiates KCC2. Ultimately, it’s about matching the modality to patient needs. When small molecules can achieve that, their convenience and adaptability make them highly attractive for CNS drug development. Source：123RF In CNS drug development, there's ongoing discussion around how to modernize clinical trials. With AXN-027 in Phase I clinical trial, what are your views, broadly speaking, on the changes needed to advance clinical development in this space? Shane Hegarty: We’ve seen encouraging progress in CNS clinical trials, especially with the adoption of fluid, imaging, and now electrophysiological biomarkers. These tools allow for more objective, less variable endpoints—potentially enabling shorter and more efficient trials. The key will be validating these biomarkers with robust datasets so that regulators can view them not just as secondary, but as primary clinical endpoints that measure both the clinical event and benefit. Take absence epilepsy, for example. It's notoriously difficult to measure through self-reporting or observation, yet a specific EEG biomarker is now widely accepted as a direct readout of absence seizure activity. That’s the kind of advancement we need across CNS indications: clear, objective, measurable and mechanistically-relevant endpoints. Equally important is patient stratification. If we can better understand the drivers of disease at a mechanistic level and align them with specific stages of progression, we can match the right modality to the right patient—similar to what oncology has done so successfully. That’s the promise of precision neuroscience, and it's where I believe the field is heading. Source：123RF Looking more broadly at neuroscience, are there any trends you believe are currently underappreciated but deserve more attention? Shane Hegarty: For me, it can betoo late to improve cognition if there's a lot of degeneration. One of the most exciting yet underappreciated areas is the concept of preemptive medicine. With the growing availability of biomarkers—like the recently approved blood-based test for Alzheimer’s—we now have the potential to detect disease much earlier and intervene before irreversible damage occurs. Matching therapeutic mechanisms to early disease stages could be far more effective than trying to treat advanced pathologies where, for instance, neurodegeneration-driven cognitive decline may already be too severe. Correcting E/I imbalances earlier in the disease course could lead to more profound benefits and potentially alleviate disease progression. Another area worth more attention is polypharmacy, or rational combination therapies. The brain is incredibly complex, and different pathological triggers can activate overlapping disease mechanisms. Expecting a single therapy to address all aspects of a disorder can often be unrealistic. As we deepen our understanding of disease ontologies—how conditions evolve over time—we’ll be better positioned to intervene earlier and more precisely, ideally maintaining health rather than reacting to the advanced diseases once functions are already too compromised. For example, upon diagnosis in Parkinson’s disease it has been reported that the majority of nigrostriatal axonal inputs have already been degenerated. So I think that’s where the future of medicine and biotech should go: it shouldn’t be treatments aimed at reversing disease in late stages — it should be preemptive, aimed at maintaining health and intervening at the earliest stage of disease, when the burden is more manageable and course correction is more achievable. Source：123RF To close, if you could make one transformative change to boost R&D productivity and patient impact in CNS over the next 5–10 years, what would it be? Shane Hegarty: That’s a fantastic question, and there are many things I’d wish for. But if I had to choose one, it would be to see more attention and action directed toward ultra-rare and orphan CNS disorders. Many of these conditions receive little to no investment—not because we lack scientific understanding, but because there’s no clear commercial incentive to develop therapies in today’s market. In some cases, we actually understand the drivers of these rare pathologies much better than we do for broader population disorders, for example monogenic neurodevelopmental disorders. So my wish would be for a collaborative effort—across investors, payors, regulators, and drug developers—to create mechanisms that support therapeutic development for these often overlooked diseases. It may not just be about financial incentives, but about building a streamlined and efficient development path that ensures patients with ultra-rare conditions aren't left behind when therapeutic modalities are advancing in other indications. At Axonis, we’re committed to pursuing first-in-class science, and I hope our work can help shape a future where innovation is truly inclusive of all patient populations. 参考资料： [1]  Shane V. Hegarty, Ph.D. Retrieved June 20, 2025, from https://axonis.us/executive-team/shane-hegarty-ph-d/ 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，传递医学新知