阿尔茨海默病免疫治疗新药4项研究均失败

2种阿尔茨海默病免疫治疗药物在一系列Ⅲ期临床试验的4,000多例患者中未能显示出任何获益。《新英格兰医学杂志》1月23日发表的报告显示，不论是靶向作用于可溶性和聚合性β淀粉样蛋白(Abeta)的bapineuzumab，还是靶向作用于可溶性Abeta的solanezumab，均未能在总体队列中达到主要终点。

在主要终点(阿尔茨海默病评估量表11项或14项认知分量表评分变化，痴呆与阿尔茨海默病残疾评估协作研究-日常生活能力量表评分变化)方面，这2种药物均未显示出临床益处。

2项失败的bapineuzumab研究均为期78周，均在2012年完成。该药的研发者辉瑞公司与杨森阿尔茨海默免疫治疗部在2012年7月发布了头条新闻，数周后，辉瑞公司取消了整个bapineuzumab研发计划。

本次新发布的bapineuzumab研究包含所有的最终数据，包括数项旨在梳理任何可能的治疗效应的先验亚组分析(N. Engl. J. Med. 2014;370:322-33)。尽管bapineuzumab并未显示出任何临床益处，但该药的确到达了其主要靶点：由聚合性Abeta构成的脑部斑块。

在一项涉及携带高危载脂蛋白Eε-4等位基因(APOE-ε-4)患者的临床试验中，采用匹兹堡化合物B(PiB)进行正电子发射断层显像(PET)脑部扫描的结果显示，接受bapineuzumab 治疗的患者的Abeta斑块负荷并未增加，而注射安慰剂的患者的斑块负荷增加。

APOE-ε-4携带者还显示出2种斑块分解生物标志物的明显改变。血清和脑脊液(CSF)中的磷酸化tau(神经损伤的一种标志物)浓度下降。CSF中的Abeta增多，提示这种蛋白被从斑块中解离出来。在另一项临床试验中，非携带者未显示出任何改变。

多达27%(具体取决于接合性)的APOE-ε-4携带者发生了淀粉样蛋白相关影像学水肿异常(与针对斑块的免疫应答相关的一种不良事件)。非携带者中也有多达14%发生此异常，这种关联具有剂量依赖性。

由礼来公司资助的2项solanezumab研究也同样令人失望(N. Engl. J. Med. 2014;370:311-21)。EXPEDITION 1和EXPEDITION 2分别进行了18个月，纳入了大约2,000例患者。研究结果最初在2013年阿尔茨海默病学会国际会议上发布。

本次发表的新数据更加具体，并且包含了大量生物标志物结果。Solanezumab增加了血浆和CSF中的Abeta，提示这种蛋白已不再在大脑中聚集。但这些发现在这2项研究中均缺乏一致性。

Solanezumab未对斑块负荷或大脑病理生理产生任何明显影响。由于该药的设计目的是阻止斑块形成，因此研究者并未期待它会攻击已存在的斑块。

与bapineuzumab不同的是，solanezumab在轻度疾病患者中显示出了有益的迹象，这促使礼来公司计划开展EXPEDITION 3研究。这项研究目前正在招募有符合阿尔茨海默病特点的认知改变且18F- florbetapir Abeta成像发现脑部斑块的患者。

这种更严格的招募标准应当能确保获得一个更单纯的队列。前2项EXPEDITION研究的科研人员表示，多达25%的轻度疾病受试者实际上并未罹患阿尔茨海默病，这类受试者的存在可能稀释甚至掩盖了治疗效应。

纽约Icahn医学院阿尔茨海默病研究所的Samuel E. Gandy博士在接受采访时表示，假如EXPEDITION 3能够使潜在阳性生物标志物数据与有说服力的临床获益相一致，solanezumab就仍有成为预防药物的可能性。Gandy博士并未参与这4项研究。

“最令人失望的结果可能是在生物标志物与获益迹象之间未观察到明显的关联。目前有两种途径向FDA申请注册新型阿尔茨海默病药物，一是证明认知和功能获益，但鉴于solanezumab在多项研究中都未能达到这一目标，就只剩下另一个途径了——同时证明生物标志物和神经精神获益。除非我们认为生物标志物获益与临床获益无关，否则这个途径似乎是目前最有吸引力的。不过如果二者不能齐头并进，很难想象FDA会支持。”

辉瑞和杨森阿尔茨海默免疫治疗部资助了上述bapineuzumab研究。礼来资助了上述solanezumab研究。Gandy博士是多家药企(包括辉瑞和礼来)的顾问或接受其研究支持。

随刊述评：还不是免疫治疗的终审判决

Eric Karran博士和John Hardy博士在随刊述评中指出，尽管上述4项研究提供了有价值的见解，但它们并未充分检验“清除淀粉样蛋白(无论是通过溶解斑块还是通过防止进一步聚集)对阿尔茨海默病患者有益”的理论(N. Engl. J. Med. 2014;370:377-8)。

在第一项bapineuzumab研究中，该药的剂量范围受到了大剂量相关性脑水肿(有时为微出血)的限制。“轻度阿尔茨海默病”患者(很可能为非阿尔茨海默病痴呆)的入组，可能“污染”了这两项研究的样本和随后的结果。

Bapineuzumab和solanezumab的试验有一个共同点，即大约25%的轻度阿尔茨海默病患者的PET淀粉样蛋白成像结果为阴性，这意味着他们很可能并未罹患阿尔茨海默病。在EXPEDITION 3中，PET淀粉样蛋白成像结果为阳性被列为一项入组标准，这将在很大程度上增加显示出疗效的可能性。

尽管bapineuzumab研究失败了，但对solanezumab的研究仍在继续。基于在轻度疾病患者中显示出的获益迹象，EXPEDITION 3将单纯关注这类患者。研究者希望解决该药的矛盾——有临床获益迹象而缺乏生物标志物证据。

“Solanezumab有可能在轻度阿尔茨海默病患者中遏制进行中的Abeta聚集，而且可能正是Abeta聚集而非已存在的斑块促发下游的病理变化过程，而后者就不再与Abeta相关了……我们建议继续研究调节脑中Abeta水平的方法，同时也要意识到我们对于不同形式Abeta在该病中的角色缺乏清晰的认识。”

Karran博士是英国阿尔茨海默病研究所所长，曾担任杨森制药的首席科学官。他没有利益冲突披露。Hardy博士是英国伦敦大学学院的遗传学和分子生物学专家。他首先提出了“阿尔茨海默病理生理学的淀粉样蛋白级联理论”。他因担任礼来的讲者和为卫材提供咨询而获得了酬金。

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By: MICHELE G. SULLIVAN, Internal Medicine News Digital Network

Two investigational Alzheimer’s immunotherapies failed to show any benefit in a series of phase III trials comprising more than 4,000 patients.

Neither bapineuzumab, which targets soluble and aggregated amyloid-beta (Abeta), nor solanezumab, which targets soluble Abeta, achieved the primary endpoints in their overall cohorts, investigators wrote Jan. 23 in the New England Journal of Medicine.

No clinical gains were detected with either drug on the primary endpoints of change in the 11- or 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale, as well as the Disability Assessment for Dementia and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale.

The two failed bapineuzumab studies were each 78 weeks long and were completed in 2012. Pfizer, which was developing the drug in collaboration with Janssen Alzheimer Immunotherapy, released top-line results in July 2012. A few weeks later, the company canceled the entire bapineuzumab development program.

The newly published bapineuzumab studies contain all the final data, including several a priori subanalyses that were designed to tease out any possible treatment effect (N. Engl. J. Med. 2014;370:322-33). Although bapineuzumab didn’t show any clinical benefits, it did apparently engage its main target: brain plaques composed of aggregated Abeta.

In one trial involving patients who carried the high-risk apolipoprotein E epsilon-4 allele (APOE-epsilon-4), positron emission tomography (PET) brain scans with Pittsburgh compound B (PiB) showed no increase in Abeta plaque burden in bapineuzumab-treated patients, compared with increases seen among those who had placebo infusions.

APOE-epsilon-4 carriers also showed significant changes in two biomarkers of plaque dissolution. Phosphorylated tau, a marker of neuronal damage, decreased in serum and cerebrospinal fluid (CSF). Abeta in CSF increased, suggesting that the protein bound in plaques was being freed. In the other trial, noncarriers didn’t show these changes.

Amyloid-related imaging abnormalities with edema (an adverse event associated with immune response directed toward plaques) occurred in up to 27% of APOE-epsilon-4 carriers, depending on their zygosity. It also appeared in up to 14% of noncarriers; the relationship was dose dependent.

The picture was similarly bleak in the two solanezumab studies sponsored by Eli Lilly (N. Engl. J. Med. 2014;370:311-21). EXPEDITION 1 and EXPEDITION 2 each lasted 18 months and comprised about 2,000 patients. They were initially reported at the 2013 Alzheimer’s Association International Conference.

The newly published data are more detailed, and include numerous biomarker findings. Solanezumab increased Abeta in plasma and CSF, a sign that the protein had stopped clumping in the brain. These findings, however, were not consistently significant in either of the two studies.

Solanezumab didn’t have any significant effect on plaque burden or brain pathophysiology. Because it’s designed to prevent plaques from forming, investigators didn’t expect that it would attack existing plaques.

The drug was a bust in terms of cognitive and functional gains. Unlike with bapineuzumab, a signal of benefit with solanezumab in patients with mild disease prompted Eli Lilly to launch EXPEDITION 3. The study is now recruiting patients who have both cognitive changes consistent with Alzheimer’s and brain plaques detected with 18F-florbetapir Abeta imaging.

These more stringent entry requirements should ensure a purer cohort. Investigators on prior EXPEDITION studies said that up to 25% of the mild participants didn’t actually have Alzheimer’s, which they said could have diluted or negated any treatment effect.

If EXPEDITION 3 can reconcile its potentially positive biomarker data with solidly positive clinical benefit, it might have some future as a preventive agent, Dr. Samuel E. Gandy said in an interview.

"Perhaps the most discouraging bottom line here is the absence of an obvious relationship between biomarker trends and hints at benefit," said Dr. Gandy, professor of Alzheimer’s disease research at the Icahn School of Medicine at Mount Sinai, New York. He was not involved in the four studies.

"There are currently two pathways to FDA [Food and Drug Administration] registration of a new Alzheimer’s drug," he said. The first is proof of cognitive and functional benefit. "Since solanezumab has failed to meet that bar in multiple studies, that avenue is extremely unlikely."

That leaves the potential for approval as a preventive agent, which means providing both biomarker and neuropsychological benefit.

"This seems the most attractive pathway, until we consider the dissociation between biomarker benefit and clinical benefit. If the two do not go hand in hand, it is hard to imagine that the Food and Drug Administration would be supportive."

Pfizer and Janssen Alzheimer Immunotherapy sponsored the bapineuzumab studies. Eli Lilly sponsored the solanezumab studies. Dr. Gandy has been an adviser to or received research support from several pharmaceutical companies, including Pfizer and Lilly.

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Not the final word on immunotherapy

Although they provided valuable insight, the four failed immunotherapy trials didn’t adequately test the theory that clearing amyloid – whether by dissolving plaques or preventing further aggregation – could benefit Alzheimer’s patients, Eric Karran, Ph.D., and John Hardy, Ph.D., wrote in an accompanying editorial (N. Engl. J. Med. 2014;370:377-8).

During the first bapineuzumab study, its upper dosing range was limited by the occurrence of brain edema, and sometimes microhemorrhages, associated with higher doses, the authors said. And the inclusion of patients with "mild Alzheimer’s," who probably had non-Alzheimer’s dementia, may have tainted the study pool and subsequent results of both trials.

"A common finding in the trials of bapineuzumab and solanezumab was that approximately 25% of patients with mild Alzheimer’s disease tested negative by means of PET amyloid imaging; they most probably did not have Alzheimer’s disease. In EXPEDITION 3, positivity on PET amyloid imaging is an inclusion criterion, and this will greatly increase the potential to show efficacy," they wrote.

Although bapineuzumab research is dead, work on solanezumab continues. Building on a signal of possible benefit in patients with mild disease, EXPEDITION 3 will focus solely on those patients. Investigators hope to reconcile the drug’s dichotomy – a hint of clinical effect in the absence of biomarker evidence.

"Possibly, in mild Alzheimer’s disease, solanezumab reduces the process of ongoing Abeta aggregation, and it is this – rather than the presence of plaques – that triggers downstream pathologic processes that later become Abeta-independent ... . We advocate continuing to investigate ways to modulate Abeta levels in the brain while accepting that we lack clarity on the roles that different forms of Abeta play in the disease," the authors wrote.

Dr. Karran is the director of research at Alzheimer’s Research UK, the country’s leading dementia research charity. He was previously chief scientific officer at Janssen Pharmaceuticals in Belgium. He had nothing to disclose. Dr. Hardy is a geneticist and molecular biologist at University College London. He first posited the amyloid cascade theory of Alzheimer’s pathophysiology. He has received fees for serving on a speakers bureau for Eli Lilly and consulting for Eisai.