http://www.scientificamerican.com/article/pharma-watch-the-promise-of-alzheimer-s-drugs-revived/
With millions of baby boomers fast approaching old age, Alzheimer’s disease diagnoses are set to spike—and the hunt is on to find medications that can slow or halt the progression of this most common form of dementia. Many pharmaceutical companies pinned high hopes on monoclonal antibodies, drugs designed to latch onto a toxic protein that builds up in the brain of sufferers and triggers the immune system to break it down. In preliminary studies during the past decade, however, these drugs often failed to outperform placebos. Now several new analyses may have resurrected their original promise.

In July three research teams presented data at the Alzheimer’s Association International Conference in Washington, D.C., suggesting that monoclonal antibodies could potentially stall Alzheimer’s relentless progression—provided they could be given early enough and at high-enough doses. These experimental drugs all target beta-amyloid, a protein fragment at the heart of a widely accepted theory about how Alzheimer’s destroys memory. Every cell in the body produces beta-amyloid, but if the brain cannot clear it fast enough, it starts to clump together, gumming up synapses and amassing into neuron-killing plaques. Antiamyloid monoclonal antibodies are designed to bind to the fragments and flag them for removal by the immune system.

At the meeting, pharmaceutical company Biogen presented new findings from an ongoing study of its monoclonal candidate, aducanumab. Biogen had announced with much fanfare in March that the drug significantly reduced beta-amyloid plaques seen on PET scans and slowed cognitive impairment in 166 patients with mild Alzheimer’s. Patients on the top dose tested—10 milligrams per kilogram of body weight—maintained the highest memory scores but also experienced more localized brain swelling, a side effect linked to leaky blood vessels. So midtrial they introduced what they hoped would be a Goldilocks dose—not too much, not too little. But it was not just right. Biogen’s researchers revealed that six milligrams produced even less benefit than three milligrams on one measure of cognitive function. The search for the perfect dose, and definitive proof of the drug’s potency, will continue during an upcoming five-year study.

In the meantime, researchers at Eli Lilly described potentially encouraging results from an extension of a large failed trial of solanezumab. To highlight this monoclonal antibody’s efficacy, they focused only on patients with early disease and used a so-called delayed-start analysis—the first ever for an Alzheimer’s drug. At the start of the 3.5-year trial, they randomly assigned 1,322 patients to either placebo or active treatment. After 80 weeks, everyone in the placebo group began taking solanezumab as well.

Both groups continued to show worsening symptoms, but treatment seemed to slow the pace by about one third. Of significance, the placebo group never caught up to the cognitive scores of patients who received solanezumab from the start. The researchers interpret this finding as tantalizing evidence that the drug is mopping up beta-amyloid in the brain and tempering its toxicity. If it were simply treating symptoms, the delayed-start control group should have made the same gains as the first group—just later on. A confirmation study is under way.

And scientists at Hoffmann–La Roche have described new findings about yet another antiamyloid drug, gantenerumab. A large trial of this monoclonal antibody was canceled in December 2014, when it failed to show any measurable effects. Yet when the researchers reanalyzed the data, considering only patients with very early and rapidly progressing disease, they found that gantenerumab had reduced beta-amyloid on PET scans for that group. It also reduced levels of tau—another protein that builds up inside neurons as Alzheimer’s advances, forming tangles that fritz normal cell function.

All three reports underscore the importance of early intervention. At a certain point, it may be too late to stem the amyloid tide. Several other trials are now probing whether antiamyloid drugs might be even more powerful when used preventively. The so-called A4 study, a joint effort of the National Institutes of Health, Eli Lilly and several nonprofit organizations, is testing solanezumab in patients who do not yet display memory deficits but have increased levels of beta-amyloid on PET scans. Two more investigations are exploring solanezumab’s effect on healthy people who carry genetic mutations that put them at high risk for inheriting Alzheimer’s.

For all the rekindled hope around monoclonal antibodies, other classes of drugs in earlier stages of testing may wind up doing as much or more to help Alzheimer’s patients. “Some of the most advanced stages of development are in drugs targeting beta-amyloid,” says Heather Snyder, director of medical and scientific operations at the Alzheimer’s Association, “but there are other clinical trials targeting insulin, tau, inflammation, and mechanisms behind neuron growth and health. We will need to identify all the biological changes taking place and intervene with all the treatments we have available—both medications and lifestyle changes—if we are going to reduce the risk or stop or slow the progression of Alzheimer’s.”