2014年12月22日讯 /生物谷BIOON/ --阿尔茨海默氏症（AD）一直是新药研发的重灾区，该领域临床失败率高达99.6%。许多曾经极具潜力的药物最终都失败了，包括辉瑞（Pfizer）和强生（JNJ）的单抗bapineuzumab及礼来（Eli Lilly）的单抗solanezumab，这2种单抗投资均超过10亿美元，在早期临床表现出极大的潜力，但在III期临床均惨遭失败，在AD领域为公司带来了非常沉重的打击。这一回，瑞士制药巨头罗氏（Roche）不幸中招，该公司单抗药物gantenerumab在大型III期也以失败告终。可以说，阿尔茨海默氏症（AD）妥妥的就是个“巨坑”，各大巨头接连失足，景象简直惨不忍睹！！！
罗氏近日宣布，终止实验性单抗药物gantenerumab一项大型III期临床研究（SCarlet RoAD）。罗氏表示，该决定是根据独立数据监测委员会（IDMC）开展的一项既定分析结果及建议，研究中gantenerumab未表现出明显的疗效迹象，但也未出现新的安全性信号。罗氏表示，对此感到失望，将对SCarlet RoAD研究数据进行充分审查和分析，之后与医学界分享。该研究的结果将为阿尔茨海默氏症（AD）领域今后的临床项目、试验方法及设计提供参考。SCarlet RoAD研究的失败，也标志着罗氏合作伙伴MorphoSys公司遭受的大挫折。
值得一提的是，SCarlet RoAD研究是将治疗时机提前至“症状出现前(presymptomatic，即0期，又称前驱期，)”阿尔茨海默氏症（AD）的首个III期临床试验。之前，礼来、辉瑞和强生的2个单抗在轻度至中度AD患者III期临床的失败，使科学家相信，需要将干预时机提前至AD疾病的早期阶段（尚未对大脑造成不可挽回的损伤）。因此，罗氏SCarlet RoAD研究的失败，将在科学界再次引发关于β-淀粉样蛋白理论及AD可能病因的一场新辩论。
尽管已决定终止SCarlet RoAD研究，但罗氏表示，将会继续推进gantenerumab另一项III期研究Marguerite RoAD，评估用于轻度阿尔茨海默氏症（AD所致轻度痴呆）的治疗。然而业界认为，SCarlet RoAD研究的突然叫停可能已经为该项III期研究蒙上了厚厚的阴影。
阿尔茨海默氏症（AD）是罗氏神经科学研发的重点，其管线中拥有广泛的研究项目，专注于据认为在AD发生及发展中发挥关键作用的几个途径。罗氏的科学家正在开发和设计以多种方式靶向这些途径和疾病不同阶段的药物，其管线中还有2个实验性药物正处于II期临床开发，其中crenezumab是一种抗淀粉样蛋白单抗，在一项II期研究中针对轻度AD患者表现出了一些疗效迹象；RG1577则是一种单胺氧化酶-B抑制剂。
AD领域，不抛弃，不放弃!
gantenerumab（RG1450）是一种实验性全人源化单克隆抗体，旨在清除阿尔茨海默氏症（AD）患者大脑中的β-淀粉样蛋白斑块（损害可能已经发生），在2011年的一项I期临床试验中，gantenerumab减少了患者大脑中沉积的β-淀粉样蛋白斑块，当时的结果非常激动人心。β-淀粉样蛋白被认为在AD的发生和发展中发挥了关键作用。礼来的solanezumab则靶向可溶性单体β-淀粉样蛋白，百健艾迪的BIIB037似乎对可溶性低聚体β-淀粉样蛋白有作用，不过效果是否显著尚不清楚。
一直以来，业界分析师对阿尔茨海默氏症（AD）领域都表现出相当的谨慎态度。如果哪家公司能够在III期获得成功，必将赢得重磅回报。然而，过去十年中，该领域临床失败率高达99%，风险之高令人生畏。尽管前路艰难，但尚无迹象表明，生物医药行业将要放弃阿尔茨海默氏症（AD）领域的新药研发。礼来已启动了solanezumab一项新的III期研究，默沙东、阿斯利康及其他药企目前已转向BACE抑制剂的研发。
根据世界卫生组织（WHO），在全球范围内阿尔茨海默氏症（AD）患者总数高达3500万例，这一数字预计将每20年翻一番，在2030年达到6600万例。在美国，患者总数超过500万例。
英文原文：Roche scuttles PhIII Alzheimer's study in yet another setback for the field
Yet another big Phase III test of an experimental Alzheimer's drug has flopped. And this time it's Roche's turn to admit defeat.
The pharma giant ($RHHBY) has opted to discontinue a late-stage study of gantenerumab, another drug that targeted amyloid beta--toxic protein clusters in the brain which have been associated with the disease. Like solanezumab and bapineuzumab--two other big Phase III flops in the field--the antibody failed to register significant signs of efficacy.
But this study was one of the first to move upstream in the patient population, recruiting presymptomatic, or prodromal, patients. Failures at Eli Lilly ($LLY) and Johnson & Johnson ($JNJ) in mild to moderate patients persuaded scientists that they needed to move at an earlier stage of the disease, before it had done irreparable damage to the brain. The early termination of the study will once again trigger renewed debate over the amyloid beta theory and the likely cause of a disease that afflicts millions.
Despite the decision to terminate the study, Roche says it will continue studying patients in a separate Phase III trial for mild cases of Alzheimer's, even though any positive indications that could come of it would be heavily clouded by the sudden halt to the SCARLET-ROAD study.
The failure also marks a setback for MorphoSys, which partnered with Roche on the program.
Roche neuroscience chief Luca Santarelli was excited about gantenerumab's chances after researchers saw signs in 2011 that the antibody was clearing amyloid beta in a small group of patients. "The playing field has changed dramatically and gantenerumab is now the most advanced monoclonal antibody in early Alzheimer's and the next big news to read out in this space," Santarelli told Reuters in late 2012.
Roche also has another Alzheimer's program in play for crenezumab.
"In July, crenezumab showed some signs of efficacy when results from a Phase II trial were cut a certain way to look at "mild" patient specifically," notes Bernstein's Tim Anderson this morning. "While similar to gantenerumab, there are enough differences with this product that we suspect it will likely advance into Phase III development, primarily because of the encouraging July results."
In a follow-up note, Anderson went on to highlight some key differences between gantenerumab and two other drugs he follows. Gantenerumab is targeted against deposited amyloid beta (where damage may have already occurred) while Lilly's solanezumab goes after soluble monomeric AB and Biogen Idec's ($BIIB) BIIB037 appears to have an effect on soluble oligomeric AB. Just how significant that is, though, is uncertain.
All the analysts tend to view this field with considerable caution. A winner in Phase III would ignite a blockbuster market for any company that gets over the finish line. But the failure rate for these drugs over the last decade has run at about 99%, making the risk involved daunting. Lilly, though, mounted a new Phase III program for solanezumab, while Merck ($MRK), AstraZeneca ($AZN) and others have been focused on a BACE approach to amyloid beta by preventing the formation of the protein.
"We are disappointed with these study results because people with early stage Alzheimer's need new medicines that delay disease progression," said Sandra Horning, the head of global product development at Roche. "This is the first Phase III trial to evaluate a potential disease-modifying medicine in this early prodromal stage of Alzheimer's disease. We remain committed to investigating new medicines for this devastating illness."