Drug development for Alzheimer’s disease is a graveyard for clinical trials, with more than 120 failures over the past 20 years. The handful of approved treatments only provide modest and temporary relief for symptoms such as memory loss; none halt the disease's progress.
Against that gloomy backdrop come provocative results from two high-profile clinical trials, presented today at the Alzheimer's Association International Conference in Washington, D.C. Both trials tested antibodies that latch onto β amyloid, a protein that forms sticky masses in the brains of people with Alzheimer's. One reported that the treatment slowed cognitive decline; the other found that the antibody lowered brain levels of amyloid, which many scientists have argued is at the heart of Alzheimer’s.
The findings, presented at the meeting by biotech companies Biogen and Eli Lilly, provide some of the first "clear-cut" evidence that targeting the β amyloid protein is a promising approach to Alzheimer's treatment, says Dennis Selkoe, a neuroscientist at Harvard University and a major proponent of the so-called amyloid hypothesis. But the small cognitive benefits and the fact that one trial didn’t show any reduction in the amyloid in people’s brains left plenty of room for skepticism.
Eli Lilly's antibody, solanezumab, had failed to show any benefit over placebo in a previous trial in people with mild-to-moderate Alzheimer's, as well as Lilly's own study in 2012. Today, however, the company reported that the drug seemed to slow cognitive decline in one standard measure by roughly 34% in a subset of patients with mild Alzheimer's, which Lilly allowed to continue taking the drug after the 2012 trial ended. A control group in the original trial that then was started on the drug later showed similar improvements.
Still, the Lilly study didn't actually measure amyloid decline, Selkoe notes: "It might go down, but we don't know that." Participants in the Lilly trial also failed to show significant benefit in two other important cognitive tests—a result which "warrants some caution in drawing firm conclusions from these analyses," the company acknowledged in a statement. In hopes of seeing clearer benefits, the company is currently running a much larger, phase III trial, slated to end in October 2016, only in people with mild Alzheimer’s disease.
Biogen’s antibody, adumanucab, also has a mixed record. It had set the Alzheimer's community abuzz when the company announced positive results from an early stage study. After administering several different doses of the drug to 166 patients who had been diagnosed with early stage Alzheimer's, the company reported that 27 people who had received the highest dose of 10 mg per kilogram showed significant cognitive benefits over controls, as well as reduced levels of protein.
But that dose caused brain swelling and microscopic hemorrhages in some cases, so the company decided to try a smaller, 6 mg dose. Today, the company reported deflating results from a follow-up trial: Over 54 weeks, the 6 mg dose failed to show any significant effects on cognition, although it did reduce levels of amyloid in the brain. The stock market, for one, judged the results harshly, initially sending the price of Biogen’s shares down after the data came out. Despite the setback, this year the company will launch a 18-month phase III trial with 2700 participants in the United States, company representative Jeff Sevigny says.
Much rides on the success of these follow-up trials, says neurologist Rakez Kayed of the University of Texas Medical Branch in Galveston, Texas. "If they fail later and we get another black eye, that will be tough."
Selkoe argues that the new Biogen data still suggest that other approaches to reducing amyloid, such as drugs that block the production and transport of molecules that contribute to amyloid buildup as well as vaccines that prime the immune system to break down plaques, should be "vigorously" pursued.
But Kayed cautions that the tantalizing results shouldn't overshadow other approaches to Alzheimer's treatment. Though many researchers now agree that β amyloid is an important trigger for Alzheimer's, most also believe that secondary processes, such as the buildup of another protein called tau, drive the disease in its later stages. "If we go all in on β amyloid and ignore other therapeutic approaches, that will be devastating," he says.