Glepaglutide

For many people, the end of the year is a mad rush to wrap things up before the holidays, and so it was for the FDA. Notable regulatory decisions include the first drug approval for a prevalent chronic condition and a novel regenerative medicine approach to help trauma patients. In one case, a new drug approval comes as its developer takes on a new identity in the new year. Here’s a look back at some highlights from a busy regulatory month: presented by Health IT Transforming Patient Care: The Role of AI-Powered Assistants The progress in artificial intelligence (AI) is reshaping patient care, across various dimensions, from facilitating faster discharge to curating treatment plans and suggesting lifestyle changes. By IT Medical Notable Firsts —The prevalent sleeping disorder obstructive sleep apnea has historically been managed with a medical device that helps breathing. Eli Lilly’s Zepbound is now the first FDA-approved drug treatment for the chronic condition. Obesity is a risk factor for sleep apnea and clinical trial results showed that weight reductions from treatment with Zepbound were accompanied by breathing improvement. Approval in obstructive sleep apnea adds another potential blockbuster indication for a metabolic medication that has fast become one of Lilly’s top-selling products. —Patients who have the rare inherited metabolic disorder familial chylomicronemia syndrome lack the ability to break down triglycerides, a type of fat from food. The only way to avoid potentially fatal complications to the pancreas is by maintaining an extremely restrictive diet. Approval of Ionis Pharmaceuticals’ olezarsen gives patients a therapeutic option. The once-monthly injected genetic medicine, which is designed to block the body’s production of a liver protein that regulates triglyceride metabolism, will be marketed under the brand name Tryngolza. Ionis previously brought drugs through late-stage development and commercialization under partnerships with larger companies. Tryngolza will be the first product Ionis commercializes on its own. —When trauma to an arm or leg requires replacement of a blood vessel, the standard treatment is grafting a vein from the patient or implanting a synthetic vein. Now there’s a new regenerative medicine option. Humacyte won FDA approval for Symvess, a bioengineered blood vessel for restoring blood flow to avoid the loss of a limb when grafting a vein from the patient is not feasible. Here’s more about the biotech’s regenerative technology. Sponsored Post The Funding Model for Cancer Innovation is Broken — We Can Fix It Closing cancer health equity gaps require medical breakthroughs made possible by new funding approaches. By Eve McDavid - CEO of Mission-Driven Tech —Mesoblast’s regulatory approval was a long time coming. In 2020 and 2023, the FDA turned down the Australian company’s application for remestemcel, an allogeneic cell therapy for graft versus host disease, an immune response that develops when donor T cells attack the recipient’s cells following a transplant procedure. Remestemcel, brand name Ryoncil, is a made from mesenchymal stromal cells sourced from the bone marrow of healthy donors. The product’s approval covers acute graft versus host disease that is refractory to treatment with steroids in patients age 2 months and older. It’s the first affirmative regulatory decision for a cell therapy made from mesenchymal stromal cells. Approvals in Immunology —Vtama, an Organon drug acquired from Roivant Sciences earlier this year, received FDA approval as a treatment for atopic dermatitis in adults and children age 2 and older. The drug is topical cream that was initially approved in 2022 as a treatment for plaque psoriasis. Approval in atopic dermatitis brings the product to a much larger dermatologic indication, albeit one served my many branded and generic medications. —In other atopic dermatitis news, Galderma landed FDA approval for nemolizumab, brand name Nemluvio. The drug is an antibody designed to block IL-31, a signaling protein associated with the itch and inflammation of the chronic skin disorder. FDA approval of Nemluvio covers use of the drug in patients age 12 and older who have moderate-to-severe atopic dermatitis. It’s the second approval in the past year for Nemluvio, which was first approved over the summer as a treatment for prurigo nodularis. Rare Disease Regulatory Decisions —Neurocrine Biosciences received approval for Crenessity, a treatment for the rare inherited hormone disorder congenital adrenal hyperplasia. The small molecule helps bring the hormone imbalance back to more normal levels. The FDA approved a pill formulation for adults and an oral solution for pediatric patients. Analysts project Crenessity could achieve blockbuster sales, pending regulatory approvals in other countries. —Novo Nordisk is best known for metabolic medicines, but its rare disease portfolio is getting a boost with FDA approval of Alhemo, a drug that reduces bleeding episodes in patients with either hemophilia A or B. Alhemo, known in development as concizumab, is an antibody designed to bind to TFPI, preventing that protein from blocking factor Xa, a different protein that plays a role in blood clotting. That’s the same mechanism of action as Pfizer’s Hympavzi, which won its FDA approval in October. Both drugs are subcutaneous injections that provide alternatives to intravenously infused hemophilia therapies. But Pfizer’s once-weekly Hmypavzi has a dosing edge over Alhemo, which must be injected once daily. —Vertex Pharmaceuticals is adding a new cystic fibrosis (CF) drug to its portfolio with FDA approval of Alyftrek, which combines three compounds in a single therapy. Like Vertex’s other CF therapies, Alyftrek is a modulator of the CFTR a protein that regulates the movement of chloride ions into and out of cells. Alyftrek’s approval is based on clinical data comparing the once-daily therapy to Trikafta, a Vertex triple combination drug initially approved in 2019 as a twice-daily CF treatment. Results showed Alyftrek was non-inferior to Trikafta on a key measure of lung function and was superior in reducing sweat chloride levels, which is a surrogate indicator of the function of CFTR proteins. Besides the dosing advantage, Alyftrek addresses 31 additional mutations that are not addressable by other CFTR modulators. The Dec. 20 approval of Alyftrek came nearly two weeks ahead of the Jan. 2 target date for a regulatory decision. Developments in Cancer Drugs —The FDA awarded accelerated approval to Merus Therapeutics drug zenacutuzumab as a treatment for advanced cases of two types of cancer: non-small cell lung cancer and pancreatic adenocarcinoma. It’s the first approval for a drug that addresses a genetic signature called an NRG1 gene fusion. Netherlands-based Merus will market the bispecific antibody under the brand name Bizengri. In a deal struck days prior to the approval announcement, Partner Therapeutics licensed U.S. commercialization rights to Bizengri. —The blockbuster AstraZeneca drug Imfinzi expanded its FDA-approved uses to include limited-stage small cell lung cancer that has not progressed following concurrent platinum-based chemotherapy and radiation therapy. The checkpoint inhibitor was first approved in 2017 for bladder cancer and added extensive-stage lung cancer as a new indication in 2020. The drug’s latest approval is based on Phase 3 results showing a 27% reduction in the risk of death compared to a placebo. AstraZeneca said the FDA decision makes Imfinzi the first immunotherapy approved for limited-stage small cell lung cancer. —Xcovery Holdings drug ensartinib, brand name Ensacove, was approved to treat adults with advanced cases of non-small cell lung cancer that is positive for ALK mutations. Patients prescribed the once-daily pill must not have previously received an ALK inhibitor. —Pfizer cancer drug Braftovi landed accelerated approval as a first-line treatment for metastatic colorectal cancer driven by the BRAF V600E mutation. The approval covers use of the drug in combination with Eli Lilly’s Erbitux and the chemotherapy regimen referred to as FOLFOX, both standard colorectal cancer therapies. Braftovi, a small molecule inhibitor of BRAF V600E, was initially approved in 2018 for advanced cases of melanoma. The drug came from Pfizer’s 2019 acquisition of Array Biopharma. —Tevimbra, a cancer immunotherapy developed by BeiGene, received FDA approval as a first-line treatment for gastric and gastroesophageal junction cancers when used in combination with chemotherapy. It’s the second FDA approval for the checkpoint inhibitor, which was approved last March for treating advanced or metastatic esophageal squamous cell carcinoma after prior treatment with chemotherapy. The new year means a new identity for BeiGene. The cancer drug developer is changing its name to BeOne Medicines. Starting Jan. 2, the company’s stock symbol on the Nasdaq will be “ONC.” Rejections, Warnings & More Bad News in Biotech —Astellas Pharma’s bid to bring patients less-frequent eye injections of its drug Izervay was rejected by the FDA. Izervay, approved for treating geographic atrophy in 2023, is administered monthly to slow progression of the vision-loss disorder. Astellas sought approval for every-other-month dosing based on two-year Phase 3 data. According to Astellas, no safety benefit/risk issues were cited but the FDA took issue with a statistical matter related to labelling language proposed by the company. The rejection will limit Izervay’s ability to compete against Apellis Pharmaceuticals’ geographic atrophy drug Syfovre, which is approved for both monthly and every-other-month dosing. —In other Astellas news, the label for menopause drug Veozah now sports a black box warning for the risk of serious liver injury. The warning follows a FDA safety communication issued in September after a postmarketing report of a patient who developed signs and symptoms of liver injury after taking the once-daily pill for about 40 days. Veozah won FDA approval in 2023 as the first in a new class of therapies for menopause. —Applied Therapeutics received a double dose of bad regulatory news. First the FDA rejected the biotech’s application for govorestat, a drug developed as a treatment for the rare metabolic disease galactosemia. According to Applied, the agency cited “deficiencies in the clinical application.” Days after the FDA complete response letter, the FDA sent Applied a warning letter. The trial and the drug are redacted in the public version of the letter, but in a regulatory filing, Applied acknowledged the FDA’s concerns are about the govorestat galactosemia trial. Applied said the warning letter identified issues with electronic data capture and a dosing error in the dose-escalation portion of the study — both of which the company believed it had already addressed with the agency. Applied said it would respond to the FDA warning letter. —Bad news keeps stacking up for Intercept Pharmaceuticals and its drug, Ocaliva, a treatment for the rare liver disease primary biliary cholangitis (PBC). On Dec. 12, the FDA issued a safety alert, warning of the risk of serious liver injury in patients without advanced liver cirrhosis. The alert came one month after the FDA turned down Intercept’s application seeking full approval for Ocaliva, which won its accelerated approval in PBC in 2016. The FDA’s rejection letter for the drug cited safety concerns. When Ocaliva first reached the market, it was the only FDA-approved second-line treatment for PBC. In the past year, drugs from Ipsen and Gilead Sciences have each won accelerated approvals as new second-line therapies for the rare disease. Two weeks after the FDA turned down full approval of Ocaliva, the European Commission revoked the conditional marketing authorization for the drug. Advanz Pharma holds rights to Ocaliva in Europe. The company said the commission decision is subject to an ongoing annulment procedure in the EU’s General Court and a ruling is expected in 2025. —The FDA turned down Zealand Pharma’s glepaglutide as a treatment for short bowel syndrome, a rare disorder that develops when the small intestine is damaged or shortened, making it difficult for the organ to absorb nutrients. The drug is a long-acting GLP-2 analog intended to enhance the intestine’s ability to absorb nutrients, reducing patients’ dependence on intravenous feeding. According to Zealand, the FDA said the application needed more evidence of efficacy and safety. The company said it would discuss the letter with the FDA and proceed with plans to seek European approval in 2025. —Lexicon Pharmaceuticals came up short in its bid to expand approval of its drug, sotagliflozin (brand name Zynquista), to include the treatment of adults with type 1 diabetes and chronic kidney disease. The FDA’s Dec. 20 rejection of the drug followed a negative FDA advisory committee vote in October. The FDA approved sotagliflozin last year as a treatment for heart failure; it’s marketed in this indication under the brand name Inpefa. —Johnson & Johnson received a complete response letter for its injectable version of Rybrevant, a drug that treats cancer driven by EGFR mutations. Intravenously infused Rybrevant was approved in 2021 as a treatment for non-small cell lung cancer. The injectable version is made with technology from Halozyme. J&J said the FDA letter flagged manufacturing issues and did not cite any concerns about the new formulation or its safety and efficacy.

关注并星标CPHI制药在线 云移稚尾开宫扇，日绕龙鳞识圣颜。一卧沧江惊岁晚，几回青锁点朝班。杜甫的这首《秋兴其五》追忆的是长安宫殿巍峨庄严，早朝场面庄严肃穆，反衬如今的萧索落魄盛况不在。这样的描述竟然也有些契合诺和诺德的III期管线减肥候选药CagriSema。 01 CagriSema，天将降大任于斯药？ CagriSema是诺和诺德的第三代减肥药管线资产，上承Saxenda（liraglutide）与Wegovy（semaglutide），寄托着诺和诺德对巩固和扩大减肥药市场统治地位的未来希望。CagriSema是一款联合疗法，其有效成分包括cagrilintide和semaglutide。Cagrilintide是一种胰淀素（Amylin）类似物，而semaglutide是Wegovy和Ozempic的有效成分。CagriSema设计用于每周一次的皮下注射，主要用于治疗肥胖、2型糖尿病和MASH（代谢功能障碍相关脂肪性肝炎）。 CagriSema的治疗策略建立在两种成分强效互补的机制之上。Cagrilintide作为胰淀素受体激动剂，显著抑制食欲并有效延缓胃排空。胰淀素是一种与胰腺β细胞共同分泌的肽，功能与GLP-1相似，既能够强力减缓胃排空，又能显著提升饱腹感，尽管它不会直接刺激胰岛素的分泌。而Semaglutide作为GLP-1受体激动剂，不仅大幅增强胰岛素分泌，还强力抑制胰高血糖素的释放，同时进一步减缓胃排空。这两者的联合作用，使CagriSema在血糖控制和体重管理方面具备卓越的效果，并可能为治疗MASH提供重要的突破。 CagriSema直接跳过了肥胖症的II期试验，得益于其核心成分cagrilintide和semaglutide此前已分别在肥胖症领域进行了临床研究。2022年，诺和诺德启动了CagriSema用于肥胖症的III期临床研究REDEFINE 1。Semaglutide的巨大成功早已让投资者期望值居高不下，这使得CagriSema处于一种"成败皆系一线"的局面：临床结果稍有不佳，其负面冲击将远远超过理想结果对股价的正向提振。所谓的"积极数据"标准，对于CagriSema而言，已经意味着25%的减重率--这一数字几乎与减肥手术效果相媲美。而作为对比，Wegovy在其关键肥胖症试验中的减重率为15%，而礼来的Zepbound在72周后的减重率则达到23%左右。 如此高的期望不仅源于减肥药市场竞争的激烈，更反映了投资者"望山跑死马"的心态，期望下一款药物能超越前者，带来更大的回报。分析师们已对此做出预测：如果CagriSema成功达到25%的减重目标，诺和诺德的股价预计将上涨10%，而礼来的股价可能受蝴蝶效应影响而下跌5%。然而，若CagriSema的减重效果没有达到这个预期，诺和的股价可能暴跌10%-20%；而如果表现更差，诺和的市值恐将瞬间蒸发20%-30%。 02 CagriSema困局：III期数据究竟成功还是不成功？ 事实正如投资者担心的那样，诺和诺德12月20日公布了人们翘首企盼的CagriSema的III期数据：减重率23%。虽然这个数据如果放在时间线的上游将是一个激动人心的数据，但对于胃口已经被Wegovy和Zepbound高高吊起的投资者们来说，这个数据几乎与失败等同。于是诺和的股价在12月20日一开盘便决绝地如同分析师们当初的预测那样暴跌20% (图1)。 图1. 诺和诺德股价在CagriSema III期数据公布前后走势图。（图片来源：Nordnet） 诺和诺德上周五公布的数据显示，在III期研究中，CagriSema治疗组的患者在68周时平均减重20%（包括退出的患者）。如果只考虑坚持治疗的患者，减重比例达到23%。包括退出的患者在内，单独使用semaglutide的患者减重15%，使用cagrilintide的患者减重12%，而安慰剂组患者仅减重3%。在试验中，患者被允许调整剂量。68周时，CagriSema组有57%的患者使用最高剂量，而semaglutide组和cagrilintide组的这一比例分别为70%和83%。尽管联合疗法23%的结果已经相当不错，但却没有达到诺和诺德此前预计的25%的减重率。 诺和诺德高层对于CagriSema的减重效果感到鼓舞，尤其是考虑到只有57%的受试者接受了最高剂量的事实。诺和诺德表示，CagriSema最常见的不良反应是胃肠道反应，且大多数为轻度至中度，并随着时间的推移有所减轻，这与GLP-1药物类别中的其他治疗反应相似。他们计划进一步探索CagriSema的额外减重潜力。CagriSema未来的试验设计包括一个为期两年的延长期，在此阶段，参与者将不接受任何治疗，诺和诺德计划研究CagriSema的效果能持续多久。 03 CagriSema遭受质疑，诺和何去何从？ 随着竞争对手，尤其是礼来等公司快速开发出具有良好减重效果的新药物，诺和诺德正面临日益加剧的压力，因此CagriSema肩负了他们最大的期望。诺和诺德正在进行一项与Zepbound的头对头试验。分析师指出，这表明诺和诺德可能认为CagriSema有望成为比Zepbound更有效的产品。 CagriSema在公布III期结果之前，诺和诺德就已经处在了极大的压力之下，这一点从他们低迷的股价走势就可窥见一斑。面临极大压力的诺和诺德需要证明 CagriSema将成为下一款令人高山仰止的重磅炸弹减肥药。考虑到礼来在诺和公布CagriSema III期数据之前就已经向公众展示了他们的Zepbound在一项头对头试验中优于Wegovy的最新结果，诺和对CagriSema扳回一城的期待就已经拉满。投资者希望CagriSema能展现出显著优于Zepbound的减重成绩，但20-23%的结果相对于Zepbound来说几乎没有优势，况且礼来管线中号称3G减肥药的retatrutide已经在其II期研究中取得了24%的减重效果，他们的管线中还有一款小分子GLP-1减肥药orforglipron。 诺和诺德这边，CB1受体抑制剂减肥候选药monlunabant在IIa期试验中的表现不愠不火，10 mg最低剂量16周的平均减重率为6.4%（安慰剂组0.6%），20和50 mg的试验也在进行之中，诺和这项去年以11亿美元从Inversago Pharmaceuticals收购的项目的期待是"恰当时间"的15%减重率。 04 CagriSema对于胰淀素类似物集团影响几何？ CagriSema的"偶失龙头望"，对于其有效组分之一的cagrilintide背后的胰淀素类似物的减肥药候选物集团将产生怎样的影响？ 在减肥药物开发的征途上，很多制药公司选择了胰淀素受体作为开发靶点。一些开发商表示，胰淀素类似物药物不仅可以显著减轻体重，而且与 GLP-1 类药物相比，恶心和呕吐的发生率也更低。胰淀素类似物的药物非专有名大多数是以lintide作为结尾的，例如阿斯利康已经上市的2型糖尿病多肽药物pramlintide，诺和诺德的cagrilintide，以及Zealand Pharma的petrelintide。礼来也在针对胰淀素类似物进行开发。 目前胰淀素类似物减肥后选药中最令人关注的是Zealand Pharma的petrelintide。今年6 月，Zealand Pharma公布了 petrelintide的 Ib 期顶线结果，在 16 周剂量后，平均体重减轻高达 8.6%（经安慰剂调整后为 6.9%）。这个结果优于诺和诺德的胰淀素类似物候选药物 cagrilintide ，后者在其 II 期研究中实现了 5.0% 的体重减轻。Petrelintide的额外优势在于其在最高测试剂量下仍可耐受，在安全性表现方面远高于 cagrilintide 的研究结果。美国银行分析师在Zealand Pharma公布三季度财报的同一天表示，他们预计petrelintide将主要用于 GLP-1 不耐受或失败市场（约占 20% 的患者），并预计其年销售额将达到 80 亿美元的峰值。 CagriSema的III期临床读数令petrelintide殃及池鱼，使一部分人怀疑其作为胰淀素类似物的减重潜力，这一点从Zealand Pharma的股价同样在12月20日这一天暴跌（后又发生了回弹，Zealand股价暴跌背后的主要原因应该是他们的针对短肠综合症的GLP-2药物glepaglutide的NDA申请被FDA拒绝）可见一斑（图2）。然而Zealand Pharma的首席执行官Adam Steensberg 在接受采访时表示，他仍然相信胰淀素类似物的策略，并对 CagriSema 数据感到鼓舞。 图2. Zealand Pharma股价最近走势图。（图片来源：Nordnet） 在CagriSema的试验中，仅服用cagrilintide的患者体重减轻了 12%。Steensberg 估计，petrelintide 对胰淀素受体的活性比cagrilintide高 9 倍，因此可以减轻更多体重。他表示，CagriSema 的结果证实了 Zealand 针对petrelintide 设定15% 至 20% 的长期减重率目标的合理性。此外，在cagrilintide组中，83% 的患者服用最高剂量，而semaglutide组为 70%，CagriSema 组为 57%。Steensberg 说，这表明患者最能耐受cagrilintide，这同样支持 了Zealand 的观点，即针对胰淀素受体开发的减肥药可以减少胃肠道副作用。 05 药物开发与华尔街，哪个才是修罗场？ CagriSema试验"叫好不叫座"的现象同时表明了投资者在针对减肥药投资过程中的浮躁心态，23%的减重率在世亦时移的情况下竟然成为了诺和诺德股价暴跌的因素，这在几年前是不可想象的情况。股票的大幅波动表明投资者是多么关心 CagriSema 能否实现至少 25% 的减肥目标。但一些分析师质疑这些预期是否符合患者的实际需要，在现有减重率已经逼近手术减肥效果的情况下，单纯地追求个位数的增长效果是否合理。瑞穗分析师Holz表示，已上市的减肥药对于绝大多数的患者来说已经足够好了，并且怀疑正在开发的下一代减肥药是否真的有更大的用途。Holz认为，CagriSema的结果警示人们，必须降低对新肥胖候选药物减肥水平的预期。下一个竞争领域应该是围绕开发更耐受、副作用更小的减肥药物，以及可以轻松大规模生产的口服治疗药物展开。 多伦多大学教授Dan Drucker也认为，CagriSema 等新疗法在现实世界中帮助患者的潜力与投资者对它们的看法之间存在脱节。Drucker明心见性地表示，"这些药物仍然非常好，只是我们生活的世界被华尔街最大化追求减重率而驱动。" Drucker还指出，减肥药的实际贡献不应该狭隘地仅仅通过减重率来衡量，例如semaglutide对于预防心血管问题的功效可能部分来自于与减重无关的机制。Druck教授称，"我们的目标是改善健康。有大量新证据表明，GLP-1 药物改善健康的益处，包括减少心脏病发作、中风、心血管死亡和肾脏疾病，这些与减肥基本无关。因此，我们对 25%、23% 和 22% 减重率的另眼相看可能在改善健康的背景下没有意义。" CagriSema"功成而弗居"的现象意味着，人们可能生活在两个并行的世界之中，一个由科学引领，而另一个则由资本驱动。 Ref. Chen, E. Next-gen obesity treatment from Novo Nordisk misses mark in pivotal trial. STAT. 20. 12. 2024. Armstrong, A. Novo's Next-Gen CB1 Drug Leads to Weight Loss in Phase II, but Neuropsychiatric Events Reported. Biospace. 20. 09. 2024. Chen, E. Novo's new obesity drug shows modest results, raises concerns of psychiatric side effects. STAT. 20. 09. 2024. Chen, E. What Novo Nordisk's disappointing trial results mean for the obesity drug market. STAT. 20. 12. 2024. END 【智药研习社近期直播】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~