Solanezumab

来源：药渡 撰文：四月的雨     编辑：哦呼 迟迟未被批准上市的AD新药Donanemab近日迎来了剧情反转，FDA外周和中枢神经系统药物咨询委员会以11:0的投票结果，全票认可礼来用于治疗AD的新药Donanemab对早期AD患者的收益大于风险。通过此次会议，Donanemab距离正式获批上市仅差临门一脚，Donanemab即将成为又一款能够减缓AD患者认知衰退的药物。 早在2023年5月份，礼来已经官宣Donanemab临床3期试验成功，礼来市值也借此突破4000亿美元大关，如今受此消息的影响，礼来美股市值更是突破8000亿美元大关，距离万亿美元俱乐部也是近在咫尺。 如今Donanemab凭借获益大于风险而距离获批又进一步，那么该药物效果如何？风险又在哪里？ Donanemab临床结果分析 获益击败风险？ Donanemab是礼来开发的一款能够特异性识别Aβ的N3pG亚型抗体的药物，能够有效清除沉积在脑内的淀粉样斑块。 2023年7月，礼来在阿尔茨海默病协会国际会议上公布了Donanemab的临床3期试验结果，结果显示，Donanemab对于AD具有优异的治疗效果，但同时不良反应也是不得不考虑的一个风险点。 以下为该临床3期试验结果： （1）首先在轻度认知障碍受试者中，经Donanemab治疗76周后，阿尔茨海默病综合评分量表（iADRS）减缓下降达60%，临床痴呆症评分总表（CDR-SB）上减缓下降达46%（对于因AD导致轻度痴呆的受试者，Donanemab在iADRS及CDR-SB上减缓下降分别达30%、38%）。 图1.给药76周时iADRS与CDR-SB变化 （2）试验数据显示，Donanemab具有年龄获益，该药物在75岁以下的受试者中受益更大。在75岁以下的受试者中，iADRS减缓下降可达48%，CDR-SB减缓下降可达45%；但是在75岁以上的受试者中，iADRS减缓下降为25%，CDR-SB减缓下降为29%，整体不如75岁以下受试者组。 图2.脑淀粉样蛋白、血浆磷酸化Tau 217和疾病进展风险 （3）接受Donanemab治疗18个月后，Donanemab组所有受试者淀粉样斑块平均减少84%，而安慰剂组受试者中仅减少1%。 Donanemab以上的临床3期试验结果也是FDA外周和中枢神经系统药物咨询委员会支持Donanemab的主要依据。 但是FDA曾推迟了对该药物的批准，原因是担心该药物的安全性，下表1为常见的不良反应。 表1.Donanemab不良事件 从中不难看出，Donanemab组相比于安慰剂组，受试者的死亡率更高，所以使用该药物有致死的可能。除此以外，Donanemab组受试者发生ARIA水肿或积液的概率也高于安慰剂组。 也正是这个原因，FDA没有提前批准Donanemab上市，如今以11:0的投票结果，认可礼来研发的Donanemab对早期阿尔茨海默患者的收益大于风险，该投票结果对于礼来以及Donanemab来讲无异于是一场柳暗花明。 痴呆症患者将达到1.4亿 AD新药研发迫在眉睫 2015年，世卫组织公布了全球共有4700万患有老年痴呆症的患者，其中60%来自中低收入国家，随着人口的不断增长以及老龄化加剧，到2050年患老年痴呆症的人数将会增加三倍，达到1.4亿人左右，全世界花在痴呆症上的费用高达万亿。 《2020中国阿尔茨海默病患者诊疗现状调研报告》报告内容显示，我国60岁及以上人群中有1507万人患有痴呆症，其中阿尔茨海默病患者占983万。大量的阿尔茨海默病患者造成了高的经济负担，据估算每年因为阿尔茨海默病所造成的的社会总经济负担高达11406亿元。 面对人口老龄化加剧，阿尔茨海默病药物的研发已迫在眉睫。 但是神经退行性疾病药物的研发一直属于最难研发的那一类，自2003年各医药巨头纷纷踏足阿尔茨海默病领域，至今已有20余年的时间，却只有Aducanumab、Lecanemab以及Rexulti获批上市，而这三款药物的获批也充满着争议。可以说阿尔茨海默病药物是全球临床研发失败率最高的新药，据统计，阿尔茨海默病药物的研发成功率不足0.4%。 那么当前AD新药全球在研状态如何？ 全球在研AD新药盘点 重磅产品即将获批？ 据药渡数据显示，当前全球AD新药在研超700项，下表2为部分处于临床3期及以上阶段在研药物，其中有哪些值得我们重点关注？ 表2.全球在研AD新药 Remternetug Donanemab的“升级款” 首先需要注意的一种新药是Remternetug，该药物同为礼来开发的一种治疗AD药物。该药物为新一代N3pG的淀粉样抗体类药物，也就是Donanemab升级版。 在2023年阿尔茨海默病与帕金森疾病国际学术研讨会上，礼来也发布了该药物的部分临床研究成果。数据表明，Remternetug能够迅速清除斑块，效果值得期待。 Blarcamesine 可减少45%的认知衰退 Blarcamesine是一款靶向Sigma-1的口服小分子药物，可有效改善神经炎症。 临床数据显示，在接受Blarcamesine治疗的受试者中： （1）超过84%的受试者ADAS-Cog评分下降0.5分以上； （2）经过Blarcamesine治疗的受试者，ADAS-Cog认知评分平均下降4.03分； （3）经过Blarcamesine的治疗，改善功能的可能性提高167%，ADCS-ADL评分增加3.5分以上； （4）Blarcamesine组受试者可减少45%的认知衰退； 该药物目前已提交NDA申请，距离获批上市指日可待。 小结 AD新药Donanemab如今迎来反转，FDA外周和中枢神经系统药物咨询委员会成员均认为Donanemab对早期AD患者的收益大于风险，经此一役，Donanemab距离正式获批已经指日可待。 而礼来已经在阿尔茨海默病药物领域历经三十几年风风雨雨，尤其2016年Solanezumab的临床3期失败对礼来造成巨大的打击，但礼来如今依靠Donanemab呈崛起之势，不知今后礼来可否借助Donanemab的获批从而突破万亿美元市值大关？敬请期待。 参考文献 [1]10.1001/jama.2023.13239 [2] https://investor.lilly.com/news-releases/news-release-details/results-lillys-landmark-phase-3-trial-donanemab-presented [3] 药渡数据 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！ 点击下方“药渡“，关注更多精彩内容 NK细胞疗法：优势与挑战并存，能否精准施治扬长避短？ 国内即将迎来AI制药第一股？AI药物研发前景和价值获认可 新型药物模态：共价生物制剂 点击蓝字 关注我们

An experimental and closely watched medicine for Alzheimers disease is one step closer to approval, after receiving support from a panel of experts who advise the Food and Drug Administration.On Monday, the panel unanimously voted that the medicine, developed by Eli Lilly and known as donanemab, appears to be an effective treatment for certain Alzheimers patients. The experts also concluded, by an 11-0 vote, that the drugs benefits outweigh its risks, despite some safety concerns.I thought the evidence is very strong and the trials [show] the effectiveness of the drug, said Dean Follman, a panelist and assistant director of biostatistics at the National Institute of Allergy and Infectious Diseases.Though the FDA isnt required to follow the recommendations of its advisory committees, it typically does. Should the agency grant approval, donanemab would be the third Alzheimers therapy of its kind cleared for the U.S. market. These medicines work by breaking up sticky, toxic collections of amyloid beta, a protein many researchers believe to be a root cause of the memory-robbing disease.Whether Lillys drug can avoid the obstacles that have held back its predecessors remains unclear. The first product in this class, Biogen and Eisais Aduhelm, was mired in controversy and eventually withdrawn from market. A second, newer option from those companies called Leqembi is faring better commercially. But both Biogen and Eisai acknowledge Leqembis launch has been more challenging than they anticipated.Lilly built its approval application around a placebo-controlled clinical trial that enrolled nearly 1,700 people in early stages of Alzheimers disease. The trial found participants who were given donanemab declined 22% slower than those who were in the control group, as measured by a rating scale that combines two well-known scoring systems for evaluating the severity of Alzheimers symptoms.FDA advisers acknowledged the positive results, yet questioned how applicable they would be to the broader Alzheimers population. All study participants were in earlier stages of the disease, and most were white.Additionally, Lillys study had unique design elements that made evaluating the results trickier. For example, in order to enroll, participants had to test positive not only for amyloid, but also for another protein tied to the development of Alzheimers. The trial found the disease progressed even slower among donanemab-treated patients with low to medium levels of this tau protein.FDA advisers therefore wanted more clarity about the role tau would play in prescribing the drug if it were approved especially since testing for tau requires PET scans, which can be costly and time-consuming.Inclusion of requirements for [tau testing] will further limit the number of patients who can have access to these types of medications, said Cynthia Carlsson, a panelist and a professor of medicine at the University of Wisconsin School of Medicine and Public Health.So it's a nuanced situation where, on the one hand, we do need to have additional data on the no and very low tau population. And on the other hand, we should not require having [tau testing] for access to this medication.Teresa Burrachio, the director of FDAs neuroscience office, noted early on in the meeting that tau burden wouldnt necessarily affect the agencys approval decision, but could potentially be a consideration for labeling.Another distinctive choice Lilly made in running its study was to have participants discontinue donanemab if amyloid levels dropped below a certain threshold. While some panelists described this design as innovative, they still questioned how it would translate to real-world treatment. What would happen, they asked, if amyloid began accumulating again in patients brains?I love the idea of being able to stop the treatment, said Colette Johnston, the panels patient representative. But I am concerned about what happens if we're not following up, and we're not getting that information once we discontinue the dosing.Both FDA staff and panelists were also focused on a type of brain swelling and bleeding, known as ARIA, that occurred in people treated with donanemab and other drugs like it. ARIA is quite often asymptomatic and is only identified via magnetic resonance imagingBut at least two donanemab-treated participants, and possibly a third, died as a result of ARIA episodes, raising questions about the drugs safety if approved for general use.Lilly executives said that, later in the trial, they were able to better identify asymptomatic cases by having patients undergo more frequent MRIs. In these people, the company delayed additional drug infusions until brain swelling subsided to prevent it from becoming more serious.For people at high risk of ARIA, such as those with a genetic marker named APOE4, Lilly executives said they would recommend closer monitoring.Patients, caregivers and physicians testified at the hearing, almost all of whom asked the committee to recommend an approval. One, a 75-year-old man who participated in Lillys trial, said he had an infusion-related side effect that ended with an emergency room visit. Even so, he said he concluded donanemabs benefits still counterbalanced its risks and decided to remain in the study.“The community understands that donanemab is not curative, but has shown in promising clinical trials it can delay progression of disease,“ Sue Peschin, CEO of the Alliance for Aging Research, said. “This is of key importance to people living with early Alzheimer's where quality of life outcomes such as cognition, personality, and the ability to care for oneself are the ones that matter most.Estimates hold that roughly 6 million to 7 million people in the U.S. have Alzheimers. The disease is a leading cause of death, and inflicts an immense physical, mental and emotional toll on patients and their caregivers. It is also extremely expensive. Research published in the American Journal of Managed Care noted how, in 2022, the estimated healthcare costs associated with Alzheimers treatment were $321 billion.For Lilly, approval would cap off a decades-long mission to get an Alzheimers medication on the market. The company came somewhat close years ago with a similar drug called solanezumab, though clinical failures led to the therapy getting scrapped.On Wall Street, analysts expect an approval would add another blockbuster product to Lillys portfolio, which has been buoyed by the success of the companys GLP-1 drug for obesity. As of early March, the average analyst estimate had donanemab generating close to $3 billion in annual sales at its peak, according to the investment firm Jefferies.Editors note: This story has been updated with additional detail from the meeting. '