Chlorpromazine Hydrochloride

iStock/ ktsimage From Eli Lilly to Karuna Therapeutics to current owner Bristol Myers Squibb, the newly approved schizophrenia drug had quite the journey to market. Former Karuna and Lilly executives discuss the “accidental” and “serendipitous” discovery. What began as a therapeutic candidate for Alzheimer’s disease at Eli Lilly completed its development journey Thursday in the hands of Bristol Myers Squibb as Cobenfy, the first novel treatment for schizophrenia in 35 years . Andrew Miller, former CEO of Karuna Therapeutics who co-invented the drug, said this trajectory is not uncommon in neuropsychiatric diseases. “The only treatments we have for schizophrenia was because chlorpromazine, which was an anesthetic drug in the ’50s, was discovered to have antipsychotic effects . . . and that was kind of the parent of all of the currently available treatments for schizophrenia,” Miller told BioSpace . Similarly, he added, the first approved treatment for depression was an anti-tuberculosis medicine. “When you look at the history of psychiatric drug development, the source of innovation, in many respects, is serendipitous, human to human findings,” Miller said. Weight Loss Rivals Were Once Alzheimer’s Partners In the mid-1990s, Lilly and current obesity and diabetes archrival Novo Nordisk were collaborating on a muscarinic acetylcholine receptor stimulator agonist to treat cognitive impairment in Alzheimer’s disease. Acetylcholine is the neurotransmitter through which cholinergic neurons, which are involved in memory and learning, send their messages. Steven Paul People with Alzheimer’s lose these neurons early in the disease process, said Steven Paul, who oversaw the program at Lilly. “So, our idea in those days was if we could stimulate the receptors for acetylcholine, maybe in the absence of those neurons we could still enhance memory and learning,” Paul told BioSpace . This idea birthed xanomeline, an acetylcholine receptor agonist that the partners studied in a large Phase II trial. The results showed xanomeline had a “modest” but “significant” effect in improving memory, Paul said. However, the trial also revealed adverse events such as nausea, vomiting and excess salivation—effects associated with stimulating muscarinic receptors. Ultimately, the companies made the decision not to proceed with xanomeline “because we felt we didn’t have the requisite tolerability safety margin for patients with Alzheimer’s,” Paul said. But, as part of the trial, the companies had also studied xanomeline’s effect on “abnormal behaviors” in Alzheimer’s such as hallucinations and delusions. “The drug seemed to treat these psychotic symptoms, and it seemed to prevent the emergence of these psychotic symptoms in these patients,” Paul said. With the exception of the adverse events, “that was the most striking finding.” Paul and colleagues published their findings in a 1997 paper . “This was by accident,” Paul said. “We didn’t really think this might happen.” A few years later, researchers at Lilly wondered if these same effects might translate to patients with schizophrenia. To answer this question, the company conducted a small study at Indiana University. “And sure enough, the drug seemed to work in those patients as well,” Paul said. But the adverse effects remained, and the companies did not pursue this indication either. KarXT Is Born Enter PureTech Health, where Miller, who was vice president in 2009, had an idea: Instead of tweaking xanomeline for more selectivity and fewer side effects—which Paul said “probably wasn’t going to work anyway”—why not combine it with a muscarinic antagonist molecule that blocks the peripheral side effects while leaving efficacy unaffected? In 2009, PureTech founded Karuna Pharmaceuticals, which later changed its name to Karuna Therapeutics, to take the candidate forward, with Miller at the helm. Andrew Miller “It took a lot of effort to get from that concept to the actual, real matter of KarXT,” Miller said. Perusing the scientific literature, Karuna identified 65 acetylcholine receptor agonist molecules and 114 muscarinic antagonist molecules. “So that gives you 7,410 possible combinations.” Ultimately, Karuna selected 95 parameters, some specific to the agonist molecule, others specific to the antagonist, and still others about how combinations would function. At the end of this process, the researchers stuck with xanomeline as the agonist and selected trospium as the antagonist, and the combination became KarXT. Interestingly, “[Karuna] couldn’t raise any money. There was very little interest,” said Paul, who joined the company as CEO in 2018 after Karuna published Phase I data. “Sometimes these are the best companies, when people turn you down.” The Phase I trial , in which 70 healthy volunteers received either KarXT or xanomeline plus placebo, showed a significant difference in terms of side effects: 64% of patients in the xanomeline/placebo group saw the most common xanomeline-associated side effects vs. 34% in the KarXT cohort. These early results generated some excitement. In 2018, Karuna raised $42 million in a Series A round, followed six months later by a $68 million Series B , which was later topped up to $80 million . That same year, Paul and Miller took the company public . Then, in November 2019, KarXT met the primary efficacy endpoint in the Phase II EMERGENT-1 trial , where it was also found to be generally well-tolerated, “and our stock just went off the roof,” Paul said. According to Biopharma Dive , Karuna’s value increased from around $400 million to nearly $3 billion following this data drop. BMS Buys Karuna for $14B By December 2023, Karuna had two successful Phase III trials under its belt, and BMS came knocking. Paul said they’d actually been in discussions with BMS since the J.P. Morgan Healthcare Conference in January 2023 but it wasn’t until the company submitted the New Drug Application for KarXT in September 2023 that the pharma company was ready to commit to buying Karuna. “I presented to them the story, and we didn’t hear from them afterwards until later that year,” Paul said. “Then, once we filed the NDA with the FDA, we had them and another company kind of beating down our door.” While Paul wouldn’t reveal the name of the other suitor, he did say that Karuna had “narrowed it to a bit of a bake-off with those two companies.” Prior to agreeing to the buyout deal with BMS, Paul said Karuna had intended to launch KarXT itself. “We were building a sales force. We were building a commercial presence.” In the end, however, Karuna decided BMS’ offer was in the best interest of its stakeholders. “When I joined the company, as a private company of maybe $20- $30-, $40 million bucks . . . we went public, and maybe we were worth at most $400 [million]. And then we were offered $14 billion dollars for the company, in less than five years.” He called the decision bittersweet “because if the drug had been approved, if we had ourselves commercialized it, if it became a mega billion-dollar blockbuster drug ourselves, well, the company’s value would be much greater than $14 billion dollars.” Paul calls KarXT “one of my early children” and said he is pleased with its progress. “They’re [BMS] doing a great job with it, so far as I can tell,” he said. While BMS is starting with schizophrenia, KarXT/Cobenfy’s journey may be far from over. A recent post-hoc analysis showed that a subset of patients in the pivotal Phase III EMERGENT-1 and EMERGENT-2 studies with predominantly negative symptoms of schizophrenia—such as apathy and social withdrawal—at baseline saw a larger effect on negative symptoms than the overall trial population. And the drug may also treat the disease’s cognitive symptoms, including poor memory and low attention span, said Paul, adding that another paper on this was recently accepted for publication. In a return to its roots, BMS has also shared plans to test Cobenfy in Alzheimer’s disease psychosis, as well as bipolar disorder. “Our expectation is that KarXT is our first foray into schizophrenia and serious mental illnesses,” Carlos Dortrait, SVP and general manager of U.S. immunology and neuroscience at BMS, previously told BioSpace , “but we are looking at expanding and looking very broadly across many diseases.”

百时美施贵宝悬着的心可以放下了。 近日，精神分裂症领域迎来历史性一刻，Karuna研发的KarXT获得FDA批准上市。这意味着，百时美施贵宝的百亿豪赌初战告捷。去年12月22日，百时美施贵宝豪掷140亿美元收购Karuna，为的就是KarXT。 KarXT获批上市，还有另一个赢家——再鼎医药。目前，再鼎医药拥有KarXT在大中华区的权益。考虑到国内精神分裂症患者超过800万，且再鼎医药的引进成本并不高，有望获得足够丰厚的收益。 当然，这一切只能说是尘埃落定，并不令人感到意外。 现有的精神分裂症治疗药物大多是上世纪90年代批准的古老品种。KarXT不依赖多巴胺能或血清素能通路，是数十年来该领域首个新机制药物，不同的机制意味着患者有更多选择。 从探索来看，KarXT也的确实现了显著的临床疗效，同时减轻了不良反应。《柳叶刀》上发表的一篇评论，将KarXT称之为“过去十年中精神分裂症研究中最有希望的突破”。 因此，KarXT成为“变革者”是意料之中的。 百亿美金一款药 在获批之前，KarXT已经名声大噪。 上市之初Karuna市值不到7亿美金。但随着KarXT临床的逐步推进，在精神分裂症领域的积极数据读出，Karuna市值水涨船高，一度超过百亿美金。最终，百时美施贵宝对其收购的出价，是140亿美金。 确实，从临床需求角度来说，精神分裂症市场是一个值得大药企押注的市场。 所谓精神分裂症是一种严重、复杂和使人衰弱的心理健康障碍，其特征是一系列症状，包括妄想、幻觉、言语或行为紊乱、言语迟缓和情感迟钝。 这一患者群体规模极大。一项针对全球129项研究的数据分析显示，2016年全球精神分裂症发病率约为0.28%。这意味着，全球超2000万人深受该疾病之困。 根据我国卫健委和科学部发起的一项研究，国内发病率似乎更高，达到0.6%[1]。以14亿人口计算，国内患者人数在840万左右。 对于患者本身来说，这一疾病对于他们来说是长期、持续性折磨，不仅危害身心健康，还包括生命安全；而对于家庭和社会来说，这一疾病同样会带来沉重负担。 因为家庭需要付诸陪护等措施，据统计，只有10%到20%的精神分裂症患者能够获得一份稳定工作，大部分患者并不能自给自足。总体来说，精神分裂症患者有着极为急切的治疗需求。 然而，现有治疗药物均存在依从性不高、覆盖面不足等缺点。 依从性不高，是因为现有治疗药物涉及严重的神经和代谢副作用，导致患者依从性不高，治疗难以持续。 目前，精神分裂症主要使用抗精神病药物治疗，包括第一代（典型）抗精神病药物，如氟哌啶醇和氯丙嗪，以及第二代（非典型）抗精神病药物，如利培酮、奥氮平和氯氮平。 从比例来看，大约10%的患者将第一代药物作为一线治疗，而90%的患者将第二代药物作为一线治疗。但这两类药物均存在较大的副作用，包括男性乳房增大、体重增加、锥体外系症状、代谢紊乱和心脑血管疾病等。 这导致停药率较高。有数据显示，现有药物治疗的患者，18个月内依从率约60%，停药率74%。而停药的患者复发率很高，一年时复发率为35%。 覆盖面不足，则主要由以下两点原因造成。 其一，部分患者对药物治疗缺乏反应，也被称之为“难治性精神分裂症”，这一患者群体比例达30%。遗憾的是，我们至今仍然不清楚，治疗有效和治疗无效患者之间的差异是什么。 其二，针对阴性症状缺乏有效治疗手段。根据症状不同，精神分裂症分为阳性、阴性群体，因为阴性症状并不明显，临床开发难度更大，目前尚无针对阴性患者有效的药物上市。 大规模的患者群体、有待新疗法面世的临床需求，精神分裂症自然成了大药企的掘金之地。 而KarXT，恰恰是最有“实力”的那个选手。 新机制选手秀肌肉 关于精神分裂症病因的主要理论之一是，乙酰胆碱和多巴胺的失衡。现有抗精神病药物依赖多巴胺能或血清素能通路，因此毒副作用始终难以避免。 而KarXT则是另辟蹊径，核心成分是毒蕈碱受体激动剂。毒蕈碱受体的激活可防止乙酰胆碱的释放。早在上世纪90年代，多项研究已经证明，刺激毒蕈碱受体，能够减轻精神病症状和认知障碍。 虽然毒蕈碱受体激动剂不仅会刺激中枢神经中的毒蕈碱受体，也会刺激外周组织中的毒蕈碱受体，导致副作用较大难以成药。 但Karuna找到了解决之道，其研发的KarXT，通过采用毒蕈碱受体激动剂和拮抗剂复方剂的方式，解决了此类药物副作用过高的难题： KarXT应用强效激动剂酒石酸，辅以无透过血脑屏障能力的拮抗剂曲司氯铵，使得复方制剂在刺激中枢神经系统中的毒蕈碱受体的同时，抑制外周组织中的毒蕈碱受体被过度激活，最大程度避免外周毒性。 Karuna的押注成功了。截至目前，Karuna已经公布了3项注册性研究，分别是EMERGENT-1、EMERGENT-2、和EMERGENT-3。 无一例外，均显示出起效快和显著的阳性和阴性症状改善。并且，最为关键的安全性方面，KarXT总体耐受性良好，影响相对可控。 根据荟萃分析来看，对比现有治疗药物，KarXT呈现疗效显著、不良反应减轻的特点。如下图所示，KarXT对比与Aripiprazole（阿立哌唑）、Risperidone（利培酮）效果处于领先地位，并且接受该药物治疗的患者体重得到了有效的控制，没有出现明显“增肥”的效果。 长期随访数据进一步证实了KarXT能够为精神分裂症治疗带来显著的改变。今年上半年发布的52周随访数据显示，患者的PANSS评分平均下降从20分左右提升到了33.3分。 入组患者PANSS总分基线平均为98.4分，通常65分以上即可确诊为精神分裂症，因此33.3分的下降效果极为显著。症状改善的百分比更能说明这一点。长期随访数据显示，超过75%的患者症状改善超过30%。从历史上看，即使是降低5个百分点的变化也足以支持获得批准。 在安全性方面，KarXT的表现一如既往的出色。52周的随访显示，患者的体重和长期代谢指标稳定或有所改善，耐受性普遍良好，副作用与之前的研究一致，未出现当前抗精神病类药物常见的不良事件。 鉴于突出的综合能力，KarXT有能力成为精神分裂症领域的game changer，获得监管认可并不令人感到意外。 赌局还未结束 以变革者的身份登场，KarXT的未来已经足够令人期待。 根据现有适应症的净现值计算，Evaluate预测的前十大最有价值的管线中，KarXT位列第九，预计将在2030年的销售额达到近25亿美元。 随着FDA的获批结果，市场可能会更乐观。华尔街著名投行Jefferies发表了“BMY:KRTX label hits our bulls case”的报告，分析认为，KarXT的获批结果是超预期的。核心原因在于，KarXT没有被标注黑框警告，意味着FDA充分认可其安全性。而现有的精神分裂症治疗药物均有黑框警告，因此KarXT后续更容易获得医生和患者的认可。 显然，KarXT有望为百时美施贵宝、再鼎医药未来营收增长带来重要助力。 当然，这并不是KarXT全部的潜力。这场以满足临床需求为出发点的探索仍在继续。 目前，KarXT除了针对阴性症状患者开展临床探索外，还开展了辅助治疗精神分裂症等临床研究。 若最终临床试验成功，KarXT将成为首款全面覆盖精神分裂症的治疗药物；而其辅助治疗的特性，也意味着它与现有药物除了竞争关系外，还有可能形成合作关系，进一步扩大覆盖人群。 更重要的是，KarXT的应用前景不仅限于精神分裂症领域，还包括阿尔茨海默症相关的精神疾病，这同样是一个预期较高的市场。 高达50%的阿尔茨海默症患者表现出精神症状，但迄今为止，FDA尚未批准任何专门治疗阿尔茨海默症精神病症状的药物。这些患者只能接受现有抗精神病药物的超适应症治疗，效果无法得到保障，并且常常受到副作用的困扰。 在前期探索中，KarXT针对阿尔茨海默症相关的精神病患者已经展现出不错的疗效和安全性。多个研究的结果将在2026年陆续公布。届时，KarXT的预期可能会继续升温。 2022年，全球抗精神病药物的销售额超过140亿美元，预计到2030年将超过260亿美元。面对庞大的市场需求和相对较少的竞争，持续进取的KarXT似乎有望占据更大的市场份额。 无论KarXT的最终潜力如何，它目前所展现的故事已经足够鼓舞人心。这也进一步提醒药企，要想获得市场的认可，关键在于深入研究需求，用具有足够竞争力的产品去打动市场。 在创新药物的世界里，没有“躺平”的选项。即便是再鼎医药，也是通过实实在在地参与全球临床研究，推动了KarXT的发展，才有望获得未来足够丰厚的回报。今年8月，再鼎医药已经完成KarXT用于精神分裂症的注册性研究UNITE-1的所有中国内地患者的入组。再鼎医药表示，有望于2024年到2025年上半年获得研究的关键数据并在中国内地提交KarXT用于精神分裂症的新药上市申请。 而且，再鼎医药能够一次又一次地在开盲盒过程中收获艾加莫德、KarXT等重磅产品，绝不仅仅是因为“运气好”，而是其多年积累的综合能力的释放。 市场有热有冷，产业界也许疯狂，也许平静，但创新药竞争的本质不会变，只有通过科学的战略布局和高效的执行力，才能在变幻莫测的市场中抓住机遇，持续实现突破。 非理性的热情，也许会让人们短暂忘记常识，但创新药行业竞争到最后，一定会回归常识。也只有一家尊重商业常识的创新药企，能够穿越周期、稳健发展。 来源 | 氨基观察（药智网获取授权转载） 撰稿 | 蔡九 责任编辑 | 八角 声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。 商务合作 | 王存星 19922864877（同微信）  阅读原文，是受欢迎的文章哦