Alzheimer's Disease: Amyloid 'Proponents' Soldier On
Posted Jan 01 2013 12:00am
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Year in Review
By John Gever, Senior Editor, MedPage Today
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As part of the Year in Review series,MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news on the topic. Here's what's happened with drug development for Alzheimer's disease since we published the first 2012 piece on what appeared to be the demise of beta-amyloid as a drug target for symptomatic disease.When drug giant Eli Lilly announced in August that both EXPEDITION trials of its anti-amyloid drug solanezumab had failed to show a significant benefit, many in the field thought that would be the end of the line for such agents, at least for patients showing clear signs of cognitive impairment.The failure followed a string of other disappointing results with a variety of agents targeting the rogue protein.Another monoclonal antibody drug, bapineuzumab, had also shown no clinical benefit in a large trial. Likewise, compounds aimed at inhibiting secretase enzymes responsible for producing beta-amyloid in vivo were disappointing.And before that, an immunotherapy intended to mobilize the body's own immune system against beta-amyloid plaques had also failed.Even staunch advocates of the so-called amyloid hypothesis in Alzheimer's disease -- which holds that beta-amyloid protein plaques are a key causative factor in the neurodegeneration that underlies the condition -- had changed their thinking.People like John Morris, MD, of Washington University in St. Louis, were saying that, by the time symptoms appear, beta-amyloid has already done its damage. Instead, anti-amyloid drugs would be effective only if introduced much earlier in the disease process, before plaques have become extensive and before neurodegeneration has really taken hold.But a funny thing happened -- Lilly didn't get the message that the drug was a dud. The company still believes that solanezumab has a future in treating symptomatic Alzheimer's disease.And the company is not alone. Merck recently announced that it was taking a secretase inhibitor into a large trial in patients with symptomatic disease.SolanezumabThe drug is a monoclonal antibody that binds to solitary, soluble strands of beta-amyloid protein, causing it to be eliminated by the body's waste-clearance mechanisms before they aggregate into insoluble plaques.In announcing that the EXPEDITION studies had failed to meet their primary endpoints, Lilly indicated that they nevertheless had suggested a hint of benefit in some patients."A pre-specified secondary analysis of pooled data across both trials showed statistically significant slowing of cognitive decline in the overall study population of patients with mild-to-moderate Alzheimer's disease," the company said."In addition, pre-specified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer's disease, but not in patients with moderate Alzheimer's disease."And, in October, Lilly reported that another set of analyses conducted by the Alzheimer's Disease Cooperative Study consortium had backed up the firm's own interpretation of the data.Encouraged by these findings, Lilly announced earlier this month that it would initiate another phase III study of solanezumab in patients with mild Alzheimer's disease. It had not set important details on the design and duration, but indicated that it would start by September of 2013.MK-8931This is Merck's oral inhibitor of beta secretase or BACE, one of the enzymes (the other principal one is gamma secretase) that cleaves beta-amyloid protein from a larger precursor molecule.By blocking this enzyme, beta-amyloid production should be greatly diminished. As with solanezumab, the idea is that formation of insoluble plaques will be diminished as well.A phase I study showed that MK-8931 reduced beta-amyloid protein levels in cerebrospinal fluid by more than 90% in healthy individuals.With Merck's announcement that it was commencing a phase II/III trial with MK-8931, it is the most advanced of several BACE inhibitors in development.The 78-week trial, dubbed EPOCH, will initially test three doses of the drug against placebo, to be followed with a larger efficacy study in up to 1,700 patients.Notably, EPOCH will enroll patients with symptomatic, mild-to-moderate Alzheimer's disease.Is Amyloid a Useful Target at All?John Morris told MedPage Today that the evidence from past anti-amyloid drug trials had shown convincingly that, when symptoms have developed, it's too late to reverse them by shutting down further production of beta-amyloid protein.The time to intervene, he has come to believe, is when plaque formation is under way -- and this can now be detected in PET scans -- but before they are so extensive as to cause irreversible neuron loss.Morris stressed that the solanezumab and MK-8931 trials could provide much useful data, but he is most excited about other studies set to get under way soon that will test anti-amyloid agents in this "preclinical" Alzheimer's disease population."These trials could be the best test yet of the beta-amyloid hypothesis," he said.And what if it fails in this setting too?"It would be extremely disappointing and also, I think, would be a major reason to reconsider" the amyloid hypothesis, Morris said.Another researcher who has been more skeptical of the hypothesis all along is Sanjay Pimplikar, PhD, of the Cleveland Clinic in Cleveland.In an interview with MedPage Today, he said that beta-amyloid is undoubtedly a factor in the pathology of Alzheimer's disease. But there are too many other factors that also play a role in the disease to justify singling out beta-amyloid as the point of therapeutic attack.Morris said that the field would certainly look at tau protein -- hyperphosphorylated versions of which form toxic structures in the brain in Alzheimer's disease -- as an alternative target if the next trials of anti-amyloid drugs fail.Pimplikar said that, in addition to tau, inflammatory processes within the brain are also clearly a factor in neurodegeneration and may be susceptible to drug therapies. The relative importance of the various contributors to Alzheimer's disease may even vary from one patient to the next."Let's not think of Alzheimer's as one disease, but as many diseases, like breast cancer," he toldMedPage Today. "When you have a breast cancer patient, you ask the question, is she HER2-positive? Then you treat her with Herceptin. Is she ER-positive? Then you use tamoxifen. You don't treat all the breast cancer patients the same way."Alzheimer's disease also is not likely to respond to any given single drug in all patients -- or perhaps even in any patients."A monotherapy is most likely not going to work," Pimplikar said.He added that lifestyle changes -- which recent studies have shown can be effective in reducing Alzheimer's disease risk and perhaps in reversing some symptoms -- will certainly be a component of future treatment strategies."Look at the cardiovascular diseases," Pimplikar said. "Of course, you can put [patients] on Lipitor. But you tell them, you must lose weight, you must control your cholesterol [intake] and your sodium.""Similarly, for Alzheimer's disease, hopefully we'll have a drug in the next 5 years. Maybe immunotherapy will work, maybe anti-tau will work. But that particular pharmaceutical has to be supported by lifestyle changes."