Levosimendan

同写意20周年大会：中国医药创新未来之路！“意”同创新，穿越周期，赢取未来。7月中旬，苏州金鸡湖畔，让我们与“新药写意人”一起为中国医药创新“同写意”！ 风险与收益的关系式，对于下个月成立满6年的Aerovate Therapeutics来说，眼前就只剩下风险了。 作为Biotech，Aerovate并未完全摸着石头过河。它的唯一资产是针对明星抗癌药Imatinib（Gleevec，格列卫）开发的吸入剂，用以治疗肺动脉高压（PAH）。此前，诺华开展的相关研究证实，口服Imatinib可以带来不错的疗效，仅由于“全身性”副作用功败垂成。 Aerovate相信自己能完成这项未竟之业，不少投资机构也是——一个成熟产品的大适应症扩展，加上既往的数据支撑，怎么看，都会是确定而丰厚的下注。 凭借一款代号为AV-101的新药，Aerovate经过RA Capital Management孵化，2020年拿到超过7000万美元的A轮融资后，2021年便登陆纳斯达克，募资约1亿美元。但令人始料未及，AV-101在最新的IIb期临床满盘皆输。 数据公布后，6月17日，昔日被寄予厚望的Aerovate股价跳水93%。18日，Aerovate在二级市场继续下跌15%左右。到20日，每股价格跌破1.4美元。按照美股规则，公司股价持续低于每股1美元将被退市。 市值还比不过手头流动资金的Aerovate，也许尚未完全弄清自己如沦落至此。但它的失败，在多大程度笼罩着想要攻克PAH的后来者，无疑关系着不断增长的百亿美元市场未来。 1 催生“重磅炸弹”之地 至少在2024年以前，PAH一直是困恼业界、无法治愈的顽疾。它导致患者肺部血管变窄、阻塞或结构破坏，继而使肺动脉压持续升高，心脏负荷增加，心肌乏力，最终可能危及生命。 根据既往研究，患上PAH主要有两种方式：一种病因不明，被称为特发性PAH；另一种是遗传性PAH，由特定的基因突变引起，在全部PAH患者中占比15%到20%。不论哪一种，PAH患者的5年生存率都不高，只有61%至65%。 Aerovate的招股书曾指出，美国确诊PAH患者数量在3万至4万人之间，全球PAH患病率估计为每百万10至52例。综合其他预测，到2032年，全球PAH市场规模将达到122亿美元。 与一些高发肿瘤相比，这个容量空间显得相形见绌，但实际上，PAH已经催生出好些重磅商业化产品。例如血管扩张剂，市场规模已达60亿美元。自1995年Flolan率先获得批准，用于PAH的血管扩张剂等药物数量不断增加。 MNC阵营里，强生一度凭借Uptravi和Opsumit占据PAH治疗领域的主导地位。 其中，Uptravi属于前列环素受体激动剂，2023年销售额为16亿美元，同比增长20%；Opsumit则是一种内皮素受体激动剂，去年营收增长14%，达到20亿美元。今年3月，Opsumit还跟United Therapeutics开发的Adcirca组合，以Opsynvi的商品名获得FDA批准。 值得注意的是，这些疗法都治标不治本。换言之，光缓解症状便能成就几十亿美元的营收，倘若有一款釜底抽薪式的药物，那将改变整个游戏的规则。 用Imatinib治疗PAH，正源自如此思路下的探索。Imatinib是首款上市的酪氨酸激酶抑制剂（TKI），由诺华在2001年推出，被广泛用于抗肿瘤领域。随着研究的深入，科学家发现了这款产品扭转PAH的潜力。 从机制来看，肺血管炎症、血管重构，是所有PAH的共同特征和关键角色。而肺血管重构病理改变，包括肺动脉平滑肌细胞（PASMC）过度增殖、迁移和收缩。在参与PASMC过度增殖和迁移的多种生长因子之列，就有血小板衍生生长因子（PDGF）的身影。Imatinib可以有效抑制PDGF受体，从根本上阻断PAH的理论闭环自此形成。 为此，诺华对Imatinib治疗PAH的可行性进行了广泛测试。一项名为IMPRES的III期全球试验中，诺华共招募202名患者，他们此前都接受过两种背景疗法。 IMPRES的结果是，口服Imatinib的患者在6分钟步行距离测试（6MWD）这一主要临床终点上表现良好，与安慰剂组拉开统计学差距。就另一个重要的肺血管阻力（PVR）终点而言，Imatinib实现32%的改善。 但由于出现严重的系统性不良事件，诺华还是放弃该项目。Aerovate却不以为然。它相信，Imatinib似乎PAH患者非常有效，只需控制住副作用就好了。 2 一家Biotech的“革命” 平心而论，Aerovate的想法不无道理。 IMPRES试验设计的每天400毫克——这是治疗一些癌症的用药标准——Imatinib剂量下，PAH患者6MWD基线水平得到显著好转。从第12周开始，差异变得显著并一直保持。到试验结束的第24周，试验组6MWD平均改善了32米。 Aerovate称，该幅度非常难得，因为当时没有任何其他PAH药物在至少两种背景疗法的基础上开展的III期临床显示出如此大的变化。 2021年，强生申报的Uptravi静脉注射剂获得FDA批准。在GRIPHON这项III期临床中，针对6MWD，Uptravi只带来12米的治疗效果。并且，Aerovate特别提及，GRIPHON入组患者还没有IMPRES那样严格。 于是，疗效、安全性两个都想要的AV-101应运而生。 AV-101旨在将Imatinib直接输送至肺部，以最大限度地增加目标组织中的药量，同时减少全身暴露，提高治疗的耐受性。 Imatinib的口服剂型的主要成分是甲磺酸伊马替尼，它因为吸水带来的稳定性问题，加之吸水后影响输送性能，并不适合作为吸入制剂。此外，考虑到甲磺酸基团会带来遗传毒性风险，甲磺酸盐多种晶型特性增加制备难度，以及可能增加咳嗽倾向，Aerovate决定另辟蹊径。 最终，这家Biotech找到了Imatinib的其他盐和多晶型物，并确定更适合吸入疗法又不改变活性分子的配方，将之开发成可通过干粉吸入器给药的干粉。 Aerovate解释说，干粉吸入是患者最方便的肺部给药方式。 它可以列出一系列的优势：比如，此类制剂可通过方便、便携且易于使用的给药系统给药；再比如，避免了雾化器可能需要的电线、电池或笨重设备；又比如，由于粉末含水量低，微生物污染风险较低；以及，与雾化器制剂相比，Imatinib干粉有望改善肺部滞留，从而减少剂量、给药频率和循环中的峰值暴露量，等等。 研究前期确实如Aerovate的预期那样发展。2022年5月，AV-101的I期临床结果对外公布。在所有剂量下，AV-101均表现出低于口服Imatinib的全身暴露量。单次剂量递增和多次剂量递增队列都未报告严重的治疗不良事件。 到2023年11月，AV-101完成IMPAHCT研究的IIb期患者入组，总计招募受试者202，与此同时III期部分也实现首位患者入组。 今年5月，Aerovate参加美国胸科学会2024年国际会议，展示IIb期临床的基线数据。Aerovate首席医学官Hunter Gillies表示，结合“无缝衔接且适应性强的IMPAHCT IIb/III期试验设计”，他们相信自己“有能力高效推进AV-101进入III期开发，同时又不影响优化药物剂量所需的科学严谨性。” 然而，不到一个月后，现实急转直下。 IIb期试验数据显示，AV-101虽然在所有剂量组的耐受性表现很好，可与安慰剂相比，并没有达到改善PVR这一主要终点，也错过了6MWD变化的次要终点。在其他几个次要终点上，该药同样未能显示出有意义的疗效。 可以说，AV-101这次输得十分彻底，以至于Aerovate首席执行官Tim Noyes都坦言，“结果出乎意料，令人失望”。 基于最新结果，Aerovate与独立研究咨询委员会达成一致，叫停IMPAHCT试验III期部分的入组和长期扩展研究。 3 谁能改变游戏规则？ 所有当初用脚投票的投资者，大概都想知道，AV-101为什么失败了？但鉴于Aerovate尚未公布完整的IIb期临床数据，这个问题可以反过来表达：为什么大家会认为AV-101能成功？ 一些分析师的看法是，Imatinib的原理、IMPRES这项大型研究显示的疗效临床数据，都可以提供背景支持。而从AV-101自身的I期临床安全性说，成药希望也颇高。最后，吸入剂相较于口服剂的优势，还能在其他PAH治疗案例中印证，像前列环素药物Remodulin的吸入剂疗效就好过口服剂。 这些理由似乎都算不得一锤定音，尤其在复杂的新药开发领域，“早期了了晚未必佳”的故事比比皆是。按照Biomedtracker对过去10年行业数据的分析，II期临床的成功率仅有28%，III期临床不过刚过一半。 一个需要考虑的细节是，PAH之所以长期缺乏根治疗法，很有可能是背后的发病机制并不唯一。今年3月，默沙东推出的Winrevair多少可以说明这一点。 Winrevair是首个获得FDA批准的活化素信号抑制剂疗法，用于治疗PAH。这一新的治疗类别通过改善促进和抑制细胞增殖的信号平衡，来调节血管细胞的增殖。换言之，它直接干预PAH的病变，而非只改善表面症状。 也因此，是Winrevair而非AV-101，最先开启了PAH治疗的新纪元。 根据默沙东披露的信息，2022年10月，Winrevair达到III期临床主要终点，第24周的6MWD测试中，试验组的运动能力平均提高41米，粗略对比，这超越了当初诺华凭借Imatinib口服剂所能达到的32米成绩。在其他9个次要终点，Winrevair基本都实现统计学意义上的改善。 Aerovate的受挫，让Imatinib进军PAH领域的努力，终究步了诺华后尘。 给Imatinib判死刑为时尚早，除了Aerovate，另有两家Biotech——Tenax Therapeutics和Aerami Therapeutics——在尝试改良这款抗肿瘤“重磅炸弹”。但是，这些同行大相径庭的方法论，实在让外界难以继续充满乐观。 Tenax坚守口服剂的道路。它希望优化Imatinib的配方，最终研发出一种缓释片TNX-201，以减少在胃部的释放，同时保持生物利用度。 2022年5月，Tenax宣布完成TNX-201新制剂的开发，并预计在下半年启动III期试验。然而同年10月，该公司将这项工作推迟到2023年。现阶段，Tenax的官网上并没有更多与TNX-201进展有关的消息。 至于与Aerovate一样的“吸入派”Aerami，却选择了雾化剂，开发出自己的候选资产AER-901。AV-101失败有可能是“干粉理论”的错误，不过，AER-901进入II期临床之前修改IND申请，似乎也并不是什么积极信号。 在眼下，AER-901同样缺乏后期临床的具体数据。纵使如此，对于Tenax和Aerami而言，处境却跟Aerovate大有不同。 Tenax手中还有另一款从Orion引进的心衰药物Levosimendan，正在开发静脉注射（TNX-101）、皮下注射（TNX-102）和口服（TNX-103）等剂型，适应症不限于PAH；Aerami虽深耕PAH赛道，也另储备了Exenatide吸入剂AER-1001。 All in一款AV-101的Aerovate没得选。截至6月17日临床失败公告发布，Aerovate只有约1亿美元的现金、现金等价物和短期投资，对半打折的市值，更令它在二级市场增发募资无望，另起炉灶的转型更无从谈起。 Noyes不久前回应说，AV-101与Winrevair互为补充，跟其他机制的PAH药物也具备联用可能。现在，这些愿景都变得缥缈。 按照Pharmaceutical Technology报道，截至2023年12月，大约有110家公司、研究所和大学正在开发129种PAH药物。默沙东之后，最先成功的大概是Gossamer Bio。 既往资料称，Gossamer的候选新药Seralutinib是首个专门为治疗PAH而开发的TKI，同样采用了吸入给药的方式，目前处于III期临床阶段。一篇发表于International Journal of Molecular Sciences的研究指出，区别于其他TKI，Seralutinib能有效抑制PAH特有的异常细胞增殖，而不会改变正常的内皮细胞屏障功能，暗示了它的潜力。 Leerink Partners的分析师认为，Seralutinib跟AV-101都能作用于PDGF受体，不过前者还可以抑制PAH病理中起作用的多种激酶，这或许会导致差异化的临床结果。 然而风险在于，Gossamer只有这一款在研新药。如果III期结果不及预期，Aerovate的命运就不是过去式。无论如何，Gossamer能否跳出Aerovate的循环，这个答案很快就会明了。按照时间表，Seralutnib的III期临床结果将于2025年底公布结果。 参考文献：（上下滑动查看更多） 1.Aerovate Therapeutics Announces 24-Week Topline Results from the Phase 2b Portion of IMPAHCT Evaluating AV-101 for the Treatment of Pulmonary Arterial Hypertension；Aerovate 2.Aerovate Therapeutics Readies $100 Million IPO Effort；Seeking Alpha 3.Aerovate Therapeutics Launches with $72 Million and Repurposed Cancer Drug for PAH；BioSpace 4.Aerovate: Imatinib Delivery Change Leads To Targeting Of Massive PAH Market；Seeking Alpha 5.潜在抗肺动脉高压新型靶向药物——伊马替尼；《医药导报》 6.Aerovate: Developing An Exciting PAH Drug, Initiating With A Buy；Seeking Alpha 7.Why Are Clinical Development Success Rates Falling?；Citeline 8.FDA Approves Merck’s WINREVAIR™ (sotatercept-csrk), a First-in-Class Treatment for Adults with Pulmonary Arterial Hypertension (PAH, WHO* Group 1)；Merck 9.TNX-201 Phase III delay gives AV-101 advantage as first imatinib treatment in PAH；GlobalData Healthcare 10.Aerami Therapeutics Announces Completion of Dosing in Phase 1 Trial of AER-901 (inhaled imatinib), a Critical Milestone Toward the Planned Initiation of a Phase 2 Trial in Pulmonary Arterial Hypertension (PAH)；Aerami 11.Pharmacology and Rationale for Seralutinib in the Treatment of Pulmonary Arterial Hypertension；Int J Mol Sci 12.Aerovate's shares plummet as inhaled version of Novartis' Gleevec misses the mark in PAH trial；Fierce Pharma 近期直播推荐:

Company aligned with FDA on key CMC topics Tonix also has completed the second and final pre-New Drug Application (NDA) meeting and discussed nonclinical, clinical pharmacology and clinical matters with the FDA, formal minutes pending On track to submit NDA to the FDA in the second half of 2024 CHATHAM, N.J., June 20, 2024 (GLOBE NEWSWIRE) -- Tonix Pharmaceuticals, Inc. (Nasdaq: TNXP) (Tonix or the Company), a fully-integrated biopharmaceutical company with marketed products and a pipeline of development candidates, today announced receipt of the formal minutes from a recent pre-New Drug Application (NDA) Type-B Chemistry, Manufacturing, and Controls (CMC) meeting with the U.S. Food and Drug Administration (FDA) for Tonmya™ for the management of fibromyalgia. The purpose of the meeting was to seek alignment and agreement with the FDA on key CMC topics to support a planned NDA submission for Tonmya for the management of fibromyalgia. Based on formal written feedback, the Company believes it is aligned with the FDA on key topics, including proposed drug substance and drug product commercial specifications, shelf life assignment, manufacturing and commercial drug packaging. In addition, the Company has completed the second and final pre-NDA meeting for Tonmya with the FDA and discussed nonclinical, clinical pharmacology and clinical matters. The Company awaits formal minutes after which it expects to announce the results of that meeting. The Company remains on track to submit the NDA for Tonmya for the management of fibromyalgia to the FDA in the second half of 2024. “We remain encouraged and excited about the prospect of bringing the first new treatment to market for fibromyalgia patients in over a decade, and this encouraging meeting with the FDA is an important milestone as we head into the final stages of completion of the NDA package,” said Seth Lederman, M.D., Chief Executive Officer of Tonix Pharmaceuticals. “During the pre-NDA CMC meeting, the FDA affirmed alignment with Tonix on CMC content and commercial strategy for Tonmya, and we are very appreciative of the FDA’s guidance as we prepare for our NDA submission. We are currently actively preparing a dual manufacturing launch strategy with global contract development and manufacturing organization (CDMO) Almac Pharma Services and another CDMO.” About Fibromyalgia Fibromyalgia is a chronic pain disorder that is understood to result from amplified sensory and pain signaling within the central nervous system. Fibromyalgia afflicts an estimated 6 million to 12 million adults in the U.S., the majority of whom are women. Symptoms of fibromyalgia include chronic widespread pain, nonrestorative sleep, fatigue, and morning stiffness. Other associated symptoms include cognitive dysfunction and mood disturbances, including anxiety and depression. Individuals suffering from fibromyalgia struggle with their daily activities, have impaired quality of life, and frequently are disabled. Physicians and patients report common dissatisfaction with currently marketed products. About Tonmya* (also known as TNX-102 SL) Tonmya is a centrally acting, non-opioid, non-addictive, bedtime medication. The tablet is a patented sublingual formulation of cyclobenzaprine hydrochloride developed for the management of fibromyalgia. In December 2023, the company announced highly statistically significant and clinically meaningful topline results in RESILIENT, the second pivotal Phase 3 clinical trial of Tonmya for the management of fibromyalgia. In the study, Tonmya met its pre-specified primary endpoint, significantly reducing daily pain compared to placebo (p=0.00005) in participants with fibromyalgia. Statistically significant and clinically meaningful results were also seen in all six key secondary endpoints related to improving sleep quality, reducing fatigue and improving overall fibromyalgia symptoms and function. RELIEF, the first statistically significant Phase 3 trial of Tonmya in fibromyalgia, was completed in December 2020. It met its pre-specified primary endpoint of daily pain reduction compared to placebo (p=0.010) and showed activity in key secondary endpoints. *Tonmya™ is conditionally accepted by the U.S. Food and Drug Administration as the tradename for TNX-102 SL for the management of fibromyalgia. Tonmya has not been approved for any indication. Tonix Pharmaceuticals Holding Corp.* Tonix is a biopharmaceutical company focused on developing, licensing and commercializing therapeutics to treat and prevent human disease and alleviate suffering. Tonix’s development portfolio is focused on central nervous system (CNS) disorders. Tonix’s priority is to submit a New Drug Application (NDA) to the FDA in the second half of 2024 for Tonmya1, a product candidate for which two statistically significant Phase 3 studies have been completed for the management of fibromyalgia. TNX-102 SL is also being developed to treat acute stress reaction as well as fibromyalgia-type Long COVID. Tonix’s CNS portfolio includes TNX-1300 (cocaine esterase), a biologic designed to treat cocaine intoxication that has FDA Breakthrough Therapy designation that is in Phase 2 development and is supported by a grant from the National Institute of Drug Abuse. Tonix’s immunology development portfolio consists of biologics to address organ transplant rejection, autoimmunity and cancer, including TNX-1500, which is a humanized monoclonal antibody targeting CD40-ligand (CD40L or CD154) being developed for the prevention of allograft rejection and for the treatment of autoimmune diseases. Tonix also has product candidates in development in the areas of rare disease and infectious disease. Tonix Medicines, our commercial subsidiary, markets Zembrace® SymTouch® (sumatriptan injection) 3 mg and Tosymra® (sumatriptan nasal spray) 10 mg for the treatment of acute migraine with or without aura in adults. *Tonix’s product development candidates are investigational new drugs or biologics and have not been approved for any indication. 1Tonmya™ is conditionally accepted by the U.S. Food and Drug Administration (FDA) as the tradename for TNX-102 SL for the management of fibromyalgia. Tonmya has not been approved for any indication. Zembrace SymTouch and Tosymra are registered trademarks of Tonix Medicines. All other marks are property of their respective owners. This press release and further information about Tonix can be found at . Forward Looking Statements Certain statements in this press release are forward-looking within the meaning of the Private Securities Litigation Reform Act of 1995. These statements may be identified by the use of forward-looking words such as “anticipate,” “believe,” “forecast,” “estimate,” “expect,” and “intend,” among others. These forward-looking statements are based on Tonix's current expectations and actual results could differ materially. There are a number of factors that could cause actual events to differ materially from those indicated by such forward-looking statements. These factors include, but are not limited to, risks related to the failure to obtain FDA clearances or approvals and noncompliance with FDA regulations; risks related to the failure to successfully market any of our products; risks related to the timing and progress of clinical development of our product candidates; our need for additional financing; uncertainties of patent protection and litigation; uncertainties of government or third party payor reimbursement; limited research and development efforts and dependence upon third parties; and substantial competition. As with any pharmaceutical under development, there are significant risks in the development, regulatory approval and commercialization of new products. Tonix does not undertake an obligation to update or revise any forward-looking statement. Investors should read the risk factors set forth in the Annual Report on Form 10-K for the year ended December 31, 2023, as filed with the Securities and Exchange Commission (the “SEC”) on April 1, 2024, and periodic reports filed with the SEC on or after the date thereof. All of Tonix's forward-looking statements are expressly qualified by all such risk factors and other cautionary statements. The information set forth herein speaks only as of the date thereof. Investor Contact Jessica Morris Tonix Pharmaceuticals investor.relations@tonixpharma.com (862) 904-8182 Peter Vozzo ICR Westwicke peter.vozzo@westwicke.com (443) 213-0505 Media Contact Katie Dodge LaVoieHealthScience kdodge@lavoiehealthscience.com (978) 360-3151