Amifampridine phosphate

同写意20岁庆！中国医药创新未来之路！“意”同创新，穿越周期，赢得未来。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”！ 今年风险投资家和制药公司都大力投资于免疫和炎症疾病的新疗法，这已经成为制药行业非常明显的趋势。分析师预测，全球免疫学和炎症市场可能从2023年的980亿美元增长到2032年的2570亿美元。企业并购、内部开发、外部融资，都成为了今年炎症和免疫学产品开发的显著途径。 1 渤健18亿美元并购交易获取免疫学资产 渤健日前宣布了18亿美元价格收购 Human Immunology Biosciences Inc.的交易，目的是增强它们的炎症及免疫管线。渤健将首先为这笔交易支付11.5亿美元的预付款，之后视情况支付6.5亿美元的潜在里程碑付款。 渤健交易的核心是靶向CD38C的抗体资产felzartamab，后者已经被FDA授予突破性疗法头衔，针对原发性膜性肾病（PMN）和肾移植后的并发症进行II期开发。除此之外，felzartamab也在针对IgA肾病、抗体介导的排斥反应和狼疮性肾炎等适应症进行开发。 PMN是一种罕见的自身抗体介导的自身免疫性肾病，也是全球成人肾病综合征 （NS）的主要原因。80%的患者表现为肾病综合征（即水肿、>3.5 g/天蛋白尿、低蛋白血症）。大约80%的PMN是由识别磷脂酶A2受体（PLA2R）抗原的自身抗体引起的。抗PLA2R既是一种诊断性生物标志物，又是一种预后生物标志物。目前还没有批准的治疗PMN的疗法。 渤健的这笔收购明显是针对它们的自免疫产品式微的现状做出的反应。渤健非常依赖它们的多发性硬化症资产，这个板块在2024年的第一季度为渤健带来了10.76亿美元的销售额，占据公司全部收入的47%。然而多发性硬化症资产的第一季度销售额同比下降4%，尤其是其当家花魁Tysabri（natalizumab）2024年第一季度收入4.31亿美元，同比下降8.9%，为渤健拉响了警报。 虽然同卫材共同开发的阿尔茨海默病资产Leqembi今年第一季度的收入环比增长将近200%，但销售收入目前只有1900万美元，不足以弥补多发性硬化症资产的损失，而且Leqembi即将面临礼来的donanemab的竞争。渤健的首席执行官Chris Viehbacher表示，渤健今年可能会达成数十亿美元的并购交易。渤健去年斥资73亿美元巨资收购了Reata Pharmaceuticals Inc. 及其批准的治疗罕见神经系统疾病弗里德赖希共济失调的疗法的Skyclarys (omaveloxolone)。然而渤健2024年第一季度罕见疾病疗法收入4.24亿美元，同比下降4%。Skyclarys在2024年前三个月实现了7800万美元的收入。 渤健在第一季度财报公布后立即开始了寻找新发展点的工作，felzartamab就是他们看好有望在自免疫领域成为重磅炸弹的资产。原发性膜性肾病和肾移植后的并发症这两种适应症有望为渤健带来超过10亿美元的回报。 2 制药巨头免疫产品突破连连 赛诺菲和再生元最近公布了III期NOTUS试验的结果，显示他们的重磅单抗药物Dupixent（dupilumab）可以作为附治疗，显著减少慢性阻塞性肺病患者的病情加重。其主要终点（重度病情加重减少）和关键次要终点（12周时肺功能增加）都得到了实现。 赛诺菲和再生元目前正在等待FDA针对Dupixent治疗慢性阻塞性肺病的申请做出监管决定。预计FDA将于2024年6月27日做出决定。再生元和赛诺菲也在欧盟和中国寻求Dupixent针对慢性阻塞性肺疾病的批准。 Dupixent是一种人单克隆IgG4抗体，靶向和阻断IL-5和IL-13细胞因子，防止其下游促炎信号级联反应。这种作用机制使Dupixent能够抑制2型炎症，这通常是许多免疫疾病的潜在病理途径。Dupixent目前被批准用于治疗特应性皮炎、嗜酸性食管炎、结节性痒疹、慢性鼻窦炎伴鼻息肉和哮喘等炎症和免疫疾病。Dupixent 2023年全球销售额高达116亿美元，在所有重磅药物中排名第7，同比增长33.5%。预测其峰值销售将在2028年到来，实现超过200亿美元的峰值销售，并且在2028年实现1200亿美元的总销售额。 在Dupixent适应症扩大的同时，葛兰素史克的潜在重磅炸弹depemokimab也在炎症和免疫学领域取得了了突破。这款长效IL-5抑制剂针对严重哮喘的两项III期临床研究获得了令人鼓舞的数据。如果depemokimab能够与现有抗IL-5的功效相媲美，那么它较低的给药频率可能会使其占据显著的市场份额。 除此之外，depemokimab针对慢性鼻窦炎伴鼻息肉的III期数据也将于今年公布。IL抑制剂针对哮喘的疗法中目前占据主导的恰好是赛诺菲的Dupixent（IL-4/13抑制剂，2023年哮喘销售额23亿美元）、GSK自家的Nucala （IL-5抑制剂，21亿美元）和阿斯利康的Fasenra（IL-5抑制剂，16亿美元）（图1）。GSK预计depemokimab的峰值销售额将达到38亿美元。 图1. IL抑制剂类哮喘药物销售额走势图（图片来源：Scrip） 3 免疫学生物科技公司融资不断 Blackstone Life Sciences最近表示，将斥资3亿美元成立一家专注于免疫学和炎症的新公司Uniquity Bio。Uniquity很快将开始其药物solrikitug的2期试验，这是一种针对TSLP的单克隆抗体，用于治疗慢性阻塞性肺病和哮喘。Blackstone认为这是一个快速增长的领域。此前，专注于免疫学的Zenas BioPharma宣布了2亿美元的C轮融资。 Attovia Therapeutics也在近期高盛领投的B轮融资中筹集了1.05亿美元。他们正在开发所谓的“attobodies”，即由抗体衍生缀合在一起的复合物，这些分子有可能比传统抗体疗法更有效、更持久。Attovia计划利用这笔融资将其两种主要候选药物ATTO-1310和ATTO-002纳入临床试验，最初的重点是特应性皮炎（湿疹），之后可能会扩展到以瘙痒为特征的其他疾病。 旧金山初创公司Alumis Inc. 也已在C轮融资中筹集了惊人的2.59亿美元，重点针对斑块状银屑病进行开发。Alumis的主导药物ESK-001是一种口服药物，通过抑制TYK2信号蛋白来治疗最常见类型的银屑病。TYK2蛋白在免疫系统反应过度的疾病中发挥作用，已经成为近年来热门的药物靶点。Alumis计划利用C轮融资在今年下半年启动ESK-001针对中度至重度斑块型银屑病的III期临床。除此之外，ESK-001还针对系统性红斑狼疮和非感染性葡萄膜炎进行两项II期研究。 前Prometheus Therapeutics首席执行官Mark McKenna在默沙东110亿美元收购Prometheus之后，于日前同几位前同僚成立了一家新生物技术公司Mirador Therapeutics，开发针对影响胃肠道、肺部和皮肤的免疫驱动疾病的疗法。他们最初计划从投资者那里筹集约2亿美元，但最终在ARCH Venture Partners 领投的融资融资中筹集了超过4亿美元的资金。ARCH一直在寻找免疫和炎症领域的投资机会。Mirador还将利用其 部分A轮融资来引进新的免疫学项目，其鸿鹄之志不仅包括寻找下一款修美乐，还希望开发一系列有影响力的免疫学资产。 另一家新成立的生物技术公司Oruka Therapeutics也已获得2.75亿美元投资，重点开发银屑病和银屑病关节炎的疗法，而且每年只需一到两次用药。Oruka管线中有两种慢性皮肤病的主要候选药物：ORKA-001（IL-23 抑制剂）和 ORKA-002（IL-17 抑制剂），计划明年开始临床研究。诺华的重磅药物 Cosentyx也针对IL-17受体，但必须每月服用。强生的Stelara和Tremfya也是IL-23抑制剂，每隔一个月使用一次，而艾伯维的新贵药物Skyrizi必须在两次起始剂量后每年使用四次。Oruka的现金储备预计将为他们提供直至2027年的开发资金。 4 免疫领域为何走高 制药商加大免疫产品开发投资的趋向，是由免疫市场规模、目前市场存在未满足情况，以及免疫疗法潜在的重磅资质所决定的。 01 免疫疗法市场表现 2023年全球销售额排名前20的药物数量中，免疫学产品占据4款（Humira 144.04亿美元、Dupixent 115.88亿美元、Stelara 108.58亿美元和Skyrizi 77.63亿美元），同代谢疾病和肿瘤相等。而从总销售额的角度来看，top20中的炎症及免疫学疗法在2023年共获得了446亿美元，从适应症的角度来看仅次于肿瘤学产品的527亿美元，而高于包括代谢疾病在内的其它疾病领域（图2）。 图2. 2023年销售额全球top20药物适应症数量和销售额关联图 02 重磅免疫产品隐退后的巨大商机 免疫学疗法开发火热的另一原因在于，一些超重磅免疫学产品因为独占期失去而为竞争者留下的巨大的市场空间，不仅对生物类似药如此，那些新一代免疫学疗法的开发同样面对着历史性机遇。老药王修美乐自从失去市场独占权后，销售额已经出现了明显下滑，2023年收入144亿美元，同比下降32%。除此之外，很多重磅免疫学资产，包括Dupixent, Entyvio, Rinvoq, Tremfya, Ultomiris等，它们的峰值销售预计将在2028年到来，随着这些重要免疫产品的下行，市场必然会为新一代产品提供大量商机，这需要生物制药公司提前做好准备工作。 03 免疫学疗法的PIP属性 免疫疗法大热的另一个潜在原因，在于这个领域可以孕育出像修美乐那样的PIP重磅炸弹。所谓PIP（Pipeline-in-a-pill），字面意思就是自带管线的资产。也就是说，一款药物可以针对众多潜在适应症。放眼医药领域，这种PIP产品都成为了叱咤风云的重磅资产，远有退位的药王修美乐，如今有当今药物Keytruda，未来还将孕育出GLP-1板块产品。免疫类疾病，因为其相关的病理学和靶点，有可能实现“达则兼济天下”的理想。例如修美乐获得的FDA批准数为12次，适应症从克罗恩病到类风湿性关节炎再到银屑病。 04 免疫学疗法的抗体专属性 从开发挑战角度来看，免疫学重磅产品大多数为抗体类药物。2023年销售额排名前4的肿瘤学产品均为抗体（Humira，Dupixent，Stelara和Skyrizi） ，2014年后上市的重要炎症及免疫产品中，也只有艾伯维的Rinvoq为小分子，其余均为抗体。这种模态的单一性比较适合新型的生物科技公司开发，可以利用他们各自的生物技术平台开发免疫学抗体疗法。另一方面，随着肿瘤免疫学疗法的不断进步，肿瘤学和免疫学疗法之间的身份互换也越来越频繁，很多原本开发肿瘤学资产的公司纷纷将其管线产品，包括CAR-T这样的先进疗法转移到免疫学赛道，这也促进了免疫学当下的大热。 05 免疫学疗法开发的高成功率 从开发难度的层面来看，单抗药物的开发成功率从历史数据来看相对较高。根据生物技术创新组织针对2011-2020年间的数据，单抗药物的LOA (批准可能性) 在众多模态中排名较高，其12.1%的LOA仅次于CAR-T和RNA类，而远高于小分子的7.5%（图3）。相对小分子资产相对密集的肿瘤领域，以单抗为绝对主流的免疫类疾病在开发成功率上似乎也得到了加持。 图3. 2011-2020年药品成功率与模态关联图（图片来源：生物技术创新组织） 从疗法LOA与适应症的关联角度来看，自免疫领域疗法开发在2014-2023年的批准可能性（9.3%）排名也在均值（6.7%）之上，更是远远高于肿瘤学疗法开发的4.7% 获批率（图4）。 图4. 适应症与药物开发成功率关联图（数据来源: Biomedtracker；图片来源：Citeline） 综上而言，免疫疗法的开发已经越来越受到众多生物制药和技术公司的关注，管线拓展、企业并购、资产引进、管线转移、新公司创立与融资活动在2024年都异常活跃。随着免疫学科研发展的不断加深，相信这一领域依然会创造出像修美乐那样的超级重磅炸弹。 参考文献：（上下滑动查看更多） 1.Felzartamab Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for Primary Membranous Nephropathy (PMN). I-Mab Press Release. 11. 02. 2023. 2.Smith, G. Biogen to Pay Up to $1.8 Billion for Immune Drug Developer. Bloomberg. 22. 05. 2024. 3.Biogen reports first quarter 2024 GAAP EPS growth of 1% and Non-GAAP EPS growth of 8%. Biogen Press Release. 24. 04. 2024. 4.Chen, E. Yet another big financing round in immunology. STAT. 09. 05. 2024. 5.DeAngelis, A. Startup Alumis raises $259 million as it prepares for psoriasis trial. STAT. 06. 03. 2024. 6.DeAngelis, A. Prometheus team launches new startup with $400 million to tackle immune-driven disorders. STAT. 21. 03. 2024. 7.DeAngelis, A. Investors funnel $275 million into Paragon Therapeutics spinout. STAT. 03. 04. 2024. 8.Chen, E. Blackstone wants in on red-hot immunology market. STAT. 16. 05. 2024. 9.Manalac, T. Sanofi, Regeneron Post Strong Phase III COPD Data for Dupixent as FDA Decision Looms. Biospace. 21. 05. 2024. 10.Cairns, E. GSK Tailors SWIFT Readout Towards Asthma Approval. Scrip. 21. 05. 2024. 11.Thomas, D. W. et al. Clinical development success rates 2006-2015. Biotechnology Innovation Organization, Washington DC. June 2016. 12.Chancellor, D. Why Are Clinical Development Success Rates Falling? In Vivo. 16. 05. 2024. 更多优质内容，欢迎关注↓↓↓

Pictured: A scientist with pill bottles in front of FDA headquarters/Taylor Tieden for BioSpace The FDA is welcoming June with four target action dates in the coming two weeks, including one to expand the patient pool for a respiratory syncytial virus vaccine. The regulator will also hold two big advisory committee meetings. Read below for more. Catalyst Seeks Higher Maximum Daily Dose for Rare Disease Drug By June 4, the FDA is set to release its verdict on Catalyst Pharmaceuticals’ supplemental New Drug Application (sNDA), proposing a higher maximum daily dose of its potassium channel blocker Firdapse (amifampridine) for the treatment for Lambert-Eaton myasthenic syndrome (LEMS). Caused by an autoimmune error where antibodies attack the patients’ own calcium channels, LEMS is rare neuromuscular disorder that manifests as weakness of the limbs. LEMS is also often linked to an underlying cancer, most commonly small-cell lung cancer. In some patients, LEMS manifests as the first sign of these cancers. The exact mechanism by which Firdapse treats LEMS is still unknown, according to its label. The FDA first approved Firdapse in November 2018 on the basis of two Phase III studies demonstrating that the drug could elicit significantly greater improvements in muscle strength and physical wellbeing than placebo. Firdapse’s most common side effects include a prickling sensation, upper respiratory tract infection and abdominal pain. The drug’s label was expanded in 2022 to include pediatric patients. Currently, Firdapse can be given at a maximum daily dose of 80 mg. With its sNDA, which the FDA accepted in October 2023, Catalyst is hoping to increase this limit to 100 mg. Lykos Therapeutics’ MDMA-Assisted PTSD Therapy Faces Adcomm On June 4, the FDA’s Psychopharmacologic Drugs Advisory Committee will convene to discuss Lykos Therapeutics’ MDMA-assisted therapy for post-traumatic stress disorder. CEO Amy Emerson said in May 2024 that Lykos’ application will be the “first MDMA-assisted therapy and psychedelic-assisted therapy to be reviewed by the Psychopharmacologic Drugs Advisory Committee,” adding that the meeting itself is a “significant milestone in the field of psychedelic medicine.” Lykos is proposing to use MDMA tablets in conjunction with psychotherapy and supportive mental health interventions for PTSD. The biotech is backing its application with data from the Phase III MAPP1 and MAPP2 studies, which showed significant improvements in patients’ scores in the Clinician-Administered PTSD Scale for DSM-5, currently the gold standard in PTSD symptom evaluation. Last month, however, the Institute for Clinical and Economic Review (ICER) flagged anomalies in Lykos’ study design, pointing out that therapists and patients recruited into the study already held “very strong prior beliefs” about MDMA, which could have skewed the documentation of treatment benefits. ICER also noted that some participants were pressured to keep the results of Lykos’ studies “favorable.” Moreover, due to the psychedelic effects of MDMA, nearly all patients who received the active treatment could identify their assignment, making the study “essentially, unblinded.” GSK Eyes Expanded Label for RSV Vaccine GSK is proposing to use its respiratory syncytial virus (RSV) vaccine Arexvy to inoculate people aged 50 to 59 who are at an increased risk of the infection. The FDA’s decision is due on June 7. If approved, Arexvy would become the first RSV vaccine approved to protect this age group against the virus, helping GSK to maintain its lead in the RSV race. Arexvy became the first FDA-approved RSV vaccine in May 2023, and is currently authorized for use in adults aged 60 years and above. The vaccine has since become the RSV market leader. In its third-quarter 2023 report, GSK revealed that Arexvy had captured more than 60% of retail RSV vaccinations in the U.S. and brought in nearly $860 million in its first full commercial quarter. GSK is backing Arexvy’s supplemental Biologics License Application (sBLA) with a Phase III study that looked at the immune response and safety of the vaccine in a younger senior population. The pharma unveiled early data from this trial in October 2023, showing that the shot could elicit an immune response in people in their 50s that was non-inferior to that in its currently approved patient population. Aside from immunogenicity, the late-stage study also found that Arexvy’s safety and reactogenicity profiles were consistent with what had been determined in prior trials. The most common side effects were headache, pain and fatigue. Ipsen, Genfit Propose Elafibranor for Primary Biliary Cholangitis The FDA has until June 10 to decide on Ipsen and Genfit’s NDA for their dual peroxisome–activated receptor alpha/delta (PPAR α,δ) agonist elafibranor for the treatment of primary biliary cholangitis (PBC). If approved, elafibranor could “change the management of this challenging condition . . . offering a new second-line treatment choice, where the number of effective options are currently limited,” Christelle Huguet, head of R&D at Ipsen, said in a statement announcing the NDA’s acceptance. The FDA has granted elafibranor priority review. PBC is a rare autoimmune liver disease characterized by the progressive destruction of the bile ducts, which in turn impairs the body’s ability to clear toxins. Patients with PBC typically experience fatigue and itch and eventually develop cirrhosis. When left unchecked, PBC can also lead to liver failure and death. Elafibranor is an orally available small molecule drug candidate that works by boosting lipid metabolism. Elafibranor can also reduce inflammation, fibrosis and steatosis, all of which are hallmarks of PBC. It was originally being developed for nonalcoholic steatohepatitis, but those plans were scrapped due to disappointing Phase III data. In November 2023, Ipsen and Genfit published data from the Phase III ELATE trial demonstrating that the drug candidate can elicit high rates of biochemical response in PBC patients. Elafibranor also normalized alkaline phosphatase levels in a subset of treated patients. FDA’s PCNS Adcomm Convenes to Discuss Lilly’s Donanemab On June 10, the FDA will convene its Peripheral and Central Nervous System Drugs Advisory Committee to discuss Eli Lilly’s application for its anti-amyloid antibody donanemab for the treatment of Alzheimer’s disease. According to a March 2024 announcement, the panel of external experts will focus on the “unique trial design” of Lilly’s TRAILBLAZER-ALZ 2 study, and the potential implications of this design on the trial’s efficacy findings. In TRAILBLAZER ALZ-2, Lilly enrolled more than 1,700 patients with early symptomatic Alzheimer’s disease, as diagnosed with cognitive screening and brain scans. The trial’s treatment protocol was unique in that it allowed patients to stop donanemab treatment after amyloid clumps in their brains had dropped below a pre-defined level. This novel trial design may have cost donanemab accelerated approval, which the FDA rejected in January 2023. At the time, the regulator noted that it needed to see data from at least 100 patients who had been treated with donanemab for 12 or more consecutive months. The donanemab meeting comes as the FDA mulls eliminating the adcomm vote entirely, instead favoring a “more comprehensive discussion” regarding the issues surrounding the product in question, Commissioner Robert Califf said during the 2023 Biopharma Congress meeting. BMS Awaits FDA Verdict for Agutyro in NTRK-Positive Solid Tumors Bristol Myers Squibb is seeking a label expansion for its tyrosine kinase inhibitor Augtyro (repotrectinib), which the pharma wants to use in patients 12 years and above with locally advanced or metastatic solid tumors carrying the neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The FDA has set a target action date of June 15. In its sNDA, which the FDA accepted and granted priority review in February 2024, BMS included data from the Phase I/II TRIDENT-1 study, which showed that Augtyro can elicit “clinically meaningful response rates” in patients. The response was durable, even in patients who had common resistance mutations. The pharma also provided findings from the CARE study, which supplemented TRIDENT-1 with promising data from pediatric patients and young adults whose tumors had ALK, ROS1 or NTRK mutations. Augtyro is an oral drug that works by blocking the proto-oncogene ROS1, as well as various tyrosine kinases. According to its label, his mechanism of action allows Augtyro to block fusion proteins containing ROS1 domains, which would otherwise trigger signaling cascades that culminate in the uncontrolled proliferation of cancer cells. Augtyro was first approved in November 2023 for the treatment of advanced or metastatic non-small cell lung cancer patients positive for ROS1. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.