Flortaucipir F-18

本次以“突破瓶颈 打造健康产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。 凭借在降糖减重、AD市场“两开花”，礼来的市值可谓一骑绝尘，已达到8000亿美元水平。 8月，礼来发布的上半年财报超出预期，并将2024年的营收指引上调了30亿美元。随着Zepbound、Mounjaro等供应问题的解决，以及Kisunla逐步放量，这家巨头的跨过万亿美元市值门槛指日可待。 可从更大的视角来说，游戏还未终局。 一方面，作为GLP-1药物领导者，诺和诺德也正跑马圈地，缺货局面已大大缓解；而想要站稳于AD这块“新药坟场”，礼来得准备更多底牌，可惜近期，LY3372689传出失败的消息。 更重要的是另一方面。无论减肥抑或AD治疗，礼来眼下的享受都是长期努力探索后的果实。专利悬崖与“重磅炸弹”模式下，它还需要着眼未来。 放射性药物领域，正是礼来看中的下一片蓝海。去年，它以14亿美元的并购，正式涉足该市场。 GlobalData的报告称，2023年，放射性药物一跃成为备受追捧的项目，相关风险投资交易增长了722%，达到5.18亿美元。对比2017年的6300万美元，这是显著的提升。如果将礼来的收购算上，交易规模还会更大。 诺华旗下产品表现——其中，Pluvicto上市第二年，营收就达到9.8亿美元，同比增长261%——证明着放射性药物领域的可观机会。同时，这些竞争对手也是礼来得翻越的山头。 值得注意，礼来的打法背后，一张大网正徐徐张开。 1 高举高打买工厂 按照用途，放射性药物可分为诊断类、治疗类。前者用于获得人体器官组织的影像或功能参数，后者是将放射性核素输送到病变部位，进而产生杀伤作用。 早在2010年，礼来以3亿美元预付款，外加最高5亿美元的里程碑付款，将一家分子成像产品开发公司Avid Radiopharmaceuticals买下。此后，礼来手握Flortaucipir F-18（TAU）和Flortaucipir F-18（APP）两款诊断用放射性药物，它们可帮助评估AD等患者的脑部状况。 但是，对于治疗用放射性药物，即眼下投资关注的主要细分领域，巨头礼来就可谓是刚进“新手村”。 2023年9月，礼来参与了Mariana Oncology的B轮1.75亿美元融资，这是一家专注于开发新型靶向肽放射性药物的Biotech，彼时核心管线MC-339尚未进入临床。因此，礼来的动作更像是试水之举。 次月，通过一笔14亿美元的收购，该MNC才算真正下场。 “我们对这种新兴治疗方式的潜力感到非常兴奋。”礼来肿瘤学部门总裁Jacob Van Naarden称，他们并将收购Point Biopharma视为“投资开发多种治疗癌症的放射性药物的开始”。 Point管线进展情况 管线上，交易披露时，礼来获得两款处于III期临床的药物，以及几个处于早期阶段项目。 其中，PNT2002是一种前列腺特异性膜抗原靶向放射性配体疗法，用于二线治疗后的转移性去势抵抗性前列腺癌（mCRPC）。去年底，SPLASH研究显示，该药将未接受化疗的受试患者进展或死亡风险降低29%。 PNT2003属于生长抑素受体靶向放射性配体疗法，针对胃肠胰神经内分泌肿瘤患者。 这两款在研新药，与诺华的两款商业化产品适应症存在重合，意味着它们的上市和销售道路可能并不容易走。然而，这笔14亿美元巨额收购的更大价值，或许是让礼来拥有一个工厂平台。 Point是自带生产能力的Biotech，18万平方英尺的园区，属于世界上最大的放射性药物制造工厂之一。并且，陆空交通区位的优势，让货物可以快速进出，覆盖欧美等主要市场。 减肥药开发热潮和经验表明，供应若得不到保障，就是对创新产品生命周期的侵蚀。而众所周知，放射性药物产业链复杂且独特，每个环节都充满专业深度和技术壁垒，更需以终为始。Point在核素制造和供应链方面的专长，无疑有助于礼来解决放射性药物开发和商业化的瓶颈。 2 抢靶点，抓技术 礼来不打算将鸡蛋放在一个篮子里。相反，它要发挥自己的体量优势，多次下注，尤其是在靶点技术方面，以此提高成功概率。 2024年，礼来加快了进军放射性药物的步伐。 5月，它将向Aktis Oncology支付6000万美元预付款，引进后者的新型小蛋白技术平台生产放射性药物。Aktis负责发现阶段的工作，不过有机会获得高达11亿美元的临床前、临床、监管和商业化里程款。 Aktis的主要资产，是一种靶向Nectin-4的新型α放射疗法。Nectin-4作为不少恶性肿瘤过表达的肿瘤相关抗原，逐渐受到业界的关注，例如ADC开发领域。 “α放射疗法是放射性药物的未来，通过利用α粒子的力量——其效力是β粒子的近1000倍——我们相信，Aktis的方法有可能为患者提供改变游戏规则的结果。”Aktis肿瘤学总裁兼首席执行官Matthew Roden说。 疗效和便利性上，业界认为，α射线确实有显著优势。 Lutathera、Pluvicto都是利用Lu-177提供β辐射，接受治疗的患者在治疗后一周内必须远离孕妇和儿童，而α放射疗法则有望减少隔离要求，这对于患者和家庭来说是一个“大加分项”。 差异化让Aktis成为资本的宠儿。礼来之前，2021年，BMS和诺华都参与了这家Biotech的A轮7200万美元融资。次年，默沙东也向其注资8400万美元。 7月，礼来又跟另一家Biotech签署了投资协议，预付1.4亿美元以获得期权。如果礼来行使这项权利，Radionetics Oncology最终会以10亿美元的价格被收购，扩充前者在放射性药物上的布局。 Radionetics旗下建立了专有的发现平台，以及靶向GPCR的小分子放射性配体疗法管线。进展最快的，是2023年下半年开始的一项I期临床试验，针对罕见且具有侵袭性的肾上腺癌症。Radionetics透露，它还在开发其他项目，用于治疗乳腺癌、肺癌和其他尚未得到满足的癌症。 细胞外多巴胺与多巴胺受体结合，激活G蛋白 科学家已经证实，GPCR参与人体的多种生理过程。Radionetics在2021年被从Crinetics Pharmaceuticals分拆前，该团队致力于开发靶向GPCR的口服小分子药物，以治疗通常的内分泌疾病和相关肿瘤。 有意思的是，礼来之所以能搭上Radionetics这趟快车，离不开先前买下Point的交易推动。Radionetics首席执行官Paul Grayson暗示，Point的加盟很大程度充实了礼来这一领域的积累。 3 闭环关键：核素 关于Point并购案，前文尚未展开的一面，是核素布局。 放射性药物的作用机制决定了，它们离不开具有放射性的同位素。现阶段，诺华旗下的两款商业化产品，以及临床试验中的大多数疗法，都在使用Lu-177。 对于任何一家药企，获取临床级放射性同位素都面临不小挑战——它们需要在回旋加速器或核反应堆中产生。Pluvicto一度面临短缺的主要原因，就在于难以制造该药物的关键成分Lu-177。自两款放射性药物上市以来，诺华一直在解决核素的储备问题。 Point已与德国Lu-177生产商ITM Isotope Technologies Munich签订并扩大供应协议，一定程度减轻了礼来的压力。 此外，Point还对核素进行优化，在PNT2003中使用一种被称为非载体添加的Lu-177。这带来的好处是，避免像Lutathera那样担心引入杂质（Lu-177m，半衰期为5个月以上，增加使用过程中的管理开支）。 不过话说回来，光有Lu-177尚且不够。正如癌症是一种多种原因促成的疾病，放射性药物同样有赖于多种核素。 已有相当一部分药企在探索Ac-225、I-131、Cu-67等放射性同位素。其中，Ac-225的辐射强度大，半衰期只有约10天，很快从体内清除，这种特性让它成为不少药企的心头好。 Ac-225是一种理想的放射性同位素 8月，礼来通过可转换贷款方式，向一家名为Ionetix的同位素供应商投资了1000万美元。 Ionetix位于美国的工厂运行着一台回旋加速器，该机器通过用质子束轰击Ra-226来生产Ac-225。Ionetix正在安装另一台回旋加速器，估计到2025年底，每周将能够生产约1居里的Ac-225，每年可为约2.6万名患者提供治疗的剂量。 The Financial Times的文章认为，礼来对Ionetix的小额投资，是MNC进一步布局供应链上游以确保Ac-225供应的罕见例子。 由于Point此前已经向Ionetix发放了1000万美元的可转换贷款，因此，礼来总共拥有该公司2000万美元的债权。Ionetix还在推进新一轮融资，其估值将超过3亿美元——届时，礼来预计会把其贷款转换为股权。 问题是，由于Ac-225并非天然存在，礼来必须四处寻找可以提取同位素的材料。 被BMS以41亿美元收购的RayzeBio，不久前也因Ac-225短缺而被迫暂停其一款放射性药物III期试验的新患者招募。 Morgan Stanley分析师表示，放射性药物领域的增长因同位素供应不足而受到阻碍，预计到2032年，该领域的销售额为390亿美元。礼来想要在其中分一杯羹，不排除今年剩下的时间里，继续物色这方面的投资标的。 毕竟，对即将进入万亿美元市值俱乐部的礼来而言，手头最不差的就是钱。 参考资料： 1.Lilly bets on radiopharmaceuticals；C&EN 2.Intrigued by Novartis and Lilly deals, investors pour money into radiopharmaceuticals； 3.Fierce Pharma 4.Aktis Oncology enters into Strategic Collaboration with Lilly；Aktis 5.Eli Lilly Puts $1B on the Line to Expand its Cancer Radiopharmaceuticals Prospects；MedCity News 6.Eli Lilly inks another radiopharma deal, gaining option to buy startup；BioPharma Dive 7.IONETIX closes financing led by Tees River and Eli Lilly and Company；Ionetix 8.Eli Lilly enters nuclear isotope business to back cancer treatment；The Financial Times 9.POINT Pharma：核药新贵，靠实力推开巨头大门！；胖猫的生命医学札记 同写意媒体矩阵，欢迎关注↓↓↓

Drug reviewers at the European Medicines Agency have given a thumbs up for Merck's PAH drug Winrevair and a second thumbs down to Apellis' geographic atrophy treatment Syfovre. For the second time in six months, Europe’s Committee for Medicinal Products for Human Use (CHMP) has given a thumbs down to Apellis’ Syfovre for the treatment of patients with geographic atrophy (GA) caused by age-related macular degeneration. In a release, Apellis noted that there were “multiple dissenting votes” by CHMP members to the opinion. The company added that it plans to seek a reexamination of the opinion, with a final decision expected in the fourth quarter of this year. “Although the studies showed that Syfovre slowed the growth of geographic atrophy lesions, this did not lead to clinically meaningful benefits for patients,” the CHMP said. “It was noted that benefits of a treatment should impact patients’ everyday functioning, and this was not demonstrated in the studies.” “In terms of safety,” the CHMP continued, “regular injections into the eye carry a significant risk of adverse events, including the development of other forms of AMD or inflammation in the eye, that could further worsen vision.”  In January of this year, the CHMP adopted its first negative opinion on Syfovre. The drug was approved by the FDA in February of 2023 and generated $275 million in sales last year despite early reports of inflammation for some users. In May, the company said that it holds an 85% share of the market in GA, but admitted to challenges with its launch. In the indication, Apellis is competing with Astellas’ Izervay, which has filed for approval in Europe. Mizuho Securities analyst Graig Suvannavejh noted that there was a 5% drop in Apellis' share price on Friday morning. "There have yet to be data convincingly demonstrating Syfovre use leading to clear, clinically meaningful functional benefit," Suvannavejh wrote in a note to clients. "Moreover, from a drug approval perspective, we view the European Medicines Agency as typically more conservative than the FDA. As such, we lower our probability of success for Syfovre's EU approval from 20% to 10%." Other CHMP rejections Syfovre was not the only drug that was beaten back by the CHMP more than once. The European drug reviewers have once again recommended not renewing the marketing authorization for PTC Therapeutics’ Translarna as a treatment for Duchenne muscular dystrophy. This negative opinion follows the European Commission’s May decision to not adopt the CHMP’s negative opinion from January. By that time, The CHMP had already reviewed and declined to renew the drug’s conditional nod twice. According to PTC, the scientific advisory group convened for the latest review concluded that the evidence of significant efficacy provided by the STRIDE trial "should not be ignored." And yet, the agency still maintained its previous stance. Now, PTC plans to request a reexamination of the CHMP’s third opinion. After that, the European Commission will make a decision. Based on the timeline of these procedures, PTC said it expects Translarna to remain on the market through the end of 2024 even if the negative opinion holds. Elsewhere, the CHMP also refused to recommend a marketing authorization for AB Science’s masitinib, a treatment for the nervous system disorder amyotrophic lateral sclerosis (ALS). The France-based company said it will ask for a reexamination. The CHMP also recommended that the marketing authorization for Advanz's Ocaliva be revoked for the treatment of patients with primary biliary cholangitis. Positive CHMP opinions Meanwhile, the CHMP this week issued positive recommendations for several therapies, including Merck’s blockbuster-to-be Winrevair for pulmonary arterial hypertension (PAH). Winrevair, which gained a high-profile approval from the FDA in March, is the first disease-modifying treatment for the condition. Winrevair, which was acquired by Merck in an $11.5 billion buyout of Acceleron in 2021, has been pegged by J.P Morgan analyst Chris Schott to achieve peak sales between $3 billion and $4 billion. The CHMP also recommended ARS Pharmaceuticals’ marketing application for the adrenaline nasal spray Eurneffy to be approved. It would become the first needle-free adrenaline option in Europe for the treatment of emergency Type 1 allergic reactions (anaphylaxis), which include those to food and insect bites. ARS expects to receive authorization from the EU in the third quarter and to launch Eurneffy in the fourth quarter. The company also hopes for approval of the product from the FDA, with a decision date set for October 2 of this year. The CHMP recommended Johnson & Johnson’s Balversa for the treatment of patients with unresectable or metastatic urothelial carcinoma, a type of bladder cancer. The FDA signed off on Balversa in the indication in January of this year, turning a 2019 accelerated approval into a full nod. Moderna’s respiratory syncytial virus (RSV) vaccine mRasvia has made the grade with the CHMP, too, gaining a recommendation for adults ages 60 and older. The shot, which was approved by the FDA four weeks ago, is the first mRNA vaccine targeting a pathogen other than the coronavirus to receive a positive opinion from the CHMP. Regeneron’s CD20xCD3 bispecific T-cell engager Ordspono (odronestamab) netted a positive opinion from the CHMP to treat two types of blood cancers—follicular lymphoma and diffuse large B-cell lymphoma. The thumbs up comes three months after the FDA sent two complete response letters to Regeneron for the same indications, questioning the timelines of the company’s confirmatory trials. The CHMP recommended Roche’s Piasky (crovalimab) for marketing authorization, just four days after the FDA endorsed it for patients age 13 and older with paroxysmal nocturnal hemoglobinuria (PNH), a rare, genetic life-threatening disorder of the immune system that causes premature breakdown of the red blood cells. The CHMP also has issued a positive opinion on Eli Lilly’s Tauvid (flortaucipir), the first drug used to image a characteristic of Alzheimer’s disease in the brain called tau pathology. The FDA signed off on Tauvid four weeks ago. Also making the grade from the CHMP was Celltrion’s Steqeyma, which is a biosimilar of J&J’s Stelara. It has been recommended for patients with Crohn’s disease, plaque psoriasis and psoriatic arthritis.