2014年12月23日訊 /長春力太生物/ --阿爾茨海默氏癥（AD）一直是新藥研發的重災區，該領域臨床失敗率高達99.6%。許多曾經極具潛力的藥物最終都失敗了，包括輝瑞（Pfizer）和強生（JNJ）的單抗bapineuzumab及禮來（Eli Lilly）的單抗solanezumab，這2種單抗投資均超過10億美元，在早期臨床表現出極大的潛力，但在III期臨床均慘遭失敗，在AD領域為公司帶來了非常沉重的打擊。這一回，瑞士制藥巨頭羅氏（Roche）不幸中招，該公司單抗藥物gantenerumab在大型III期也以失敗告終?？梢哉f，阿爾茨海默氏癥（AD）妥妥的就是個“巨坑”，各大巨頭接連失足，景象簡直慘不忍睹?。?！
羅氏近日宣布，終止實驗性單抗藥物gantenerumab一項大型III期臨床研究（SCarlet RoAD）。羅氏表示，該決定是根據獨立數據監測委員會（IDMC）開展的一項既定分析結果及建議，研究中gantenerumab未表現出明顯的療效跡象，但也未出現新的安全性信號。羅氏表示，對此感到失望，將對SCarlet RoAD研究數據進行充分審查和分析，之后與醫學界分享。該研究的結果將為阿爾茨海默氏癥（AD）領域今后的臨床項目、試驗方法及設計提供參考。SCarlet RoAD研究的失敗，也標志著羅氏合作伙伴MorphoSys公司遭受的大挫折。
值得一提的是，SCarlet RoAD研究是將治療時機提前至“癥狀出現前(presymptomatic，即0期，又稱前驅期，)”阿爾茨海默氏癥（AD）的首個III期臨床試驗。之前，禮來、輝瑞和強生的2個單抗在輕度至中度AD患者III期臨床的失敗，使科學家相信，需要將干預時機提前至AD疾病的早期階段（尚未對大腦造成不可挽回的損傷）。因此，羅氏SCarlet RoAD研究的失敗，將在科學界再次引發關于β-淀粉樣蛋白理論及AD可能病因的一場新辯論。
盡管已決定終止SCarlet RoAD研究，但羅氏表示，將會繼續推進gantenerumab另一項III期研究Marguerite RoAD，評估用于輕度阿爾茨海默氏癥（AD所致輕度癡呆）的治療。然而業界認為，SCarlet RoAD研究的突然叫?？赡芤呀洖樵擁桰II期研究蒙上了厚厚的陰影。
阿爾茨海默氏癥（AD）是羅氏神經科學研發的重點，其管線中擁有廣泛的研究項目，專注于據認為在AD發生及發展中發揮關鍵作用的幾個途徑。羅氏的科學家正在開發和設計以多種方式靶向這些途徑和疾病不同階段的藥物，其管線中還有2個實驗性藥物正處于II期臨床開發，其中crenezumab是一種抗淀粉樣蛋白單抗，在一項II期研究中針對輕度AD患者表現出了一些療效跡象；RG1577則是一種單胺氧化酶-B抑制劑。
AD領域，不拋棄，不放棄!
gantenerumab（RG1450）是一種實驗性全人源化單克隆抗體，旨在清除阿爾茨海默氏癥（AD）患者大腦中的β-淀粉樣蛋白斑塊（損害可能已經發生），在2011年的一項I期臨床試驗中，gantenerumab減少了患者大腦中沉積的β-淀粉樣蛋白斑塊，當時的結果非常激動人心。β-淀粉樣蛋白被認為在AD的發生和發展中發揮了關鍵作用。禮來的solanezumab則靶向可溶性單體β-淀粉樣蛋白，百健艾迪的BIIB037似乎對可溶性低聚體β-淀粉樣蛋白有作用，不過效果是否顯著尚不清楚。
一直以來，業界分析師對阿爾茨海默氏癥（AD）領域都表現出相當的謹慎態度。如果哪家公司能夠在III期獲得成功，必將贏得重磅回報。然而，過去十年中，該領域臨床失敗率高達99%，風險之高令人生畏。盡管前路艱難，但尚無跡象表明，生物醫藥行業將要放棄阿爾茨海默氏癥（AD）領域的新藥研發。禮來已啟動了solanezumab一項新的III期研究，默沙東、阿斯利康及其他藥企目前已轉向BACE抑制劑的研發。
根據世界衛生組織（WHO），在全球范圍內阿爾茨海默氏癥（AD）患者總數高達3500萬例，這一數字預計將每20年翻一番，在2030年達到6600萬例。在美國，患者總數超過500萬例。（長春力太生物http://www.galasko.com）
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."
