The earlier Alzheimer’s disease is treated, the better. Maybe even before symptoms arise. That’s the idea behind experimental drugs designed to remove plaques from the brain and prevent cognitive changes.
Today in Washington, both Eli Lilly and Biogen presented new data suggesting that antibodies designed to break up or clear the beta-amyloid plaques can slow the advancement of Alzheimer’s, particularly in patients with the mildest form of the disease.
The drugs are based on the “amyloid hypothesis,” that the buildup of starchy amyloid in the brain is the cause of Alzheimer’s. The “peculiar material” was first described in 1907 by the doctor Alois Alzheimer, after whom the disease is named.
There’s still debate about the real cause of Alzheimer’s, and the best way to stop it. But major drug efforts like those of Biogen and Lilly are now coalescing around a common strategy, say experts: patients are being treated earlier and also getting new brain-imaging tests to confirm they have the plaques.
Based on preliminary data gathered over the last few years, Lilly is midway through a third large study of its antibody, named solanezumab, and Biogen is about to launch its own Phase 3 studies of aducanumab. Unlike earlier studies, these require that patients undergo imaging tests and also favor patients with very limited symptoms.
The brain scans are a key innovation, and a recent one. In 2012, the U.S. Food and Drug Administration approved a fluorescent imaging dye made by Lilly that sticks to the plaques and makes them light up in a PET scanner (see “Brain Scan for Alzheimer’s”). Before that, Alzheimer’s plaques were usually diagnosed with certainty after death, during an autopsy.
That has meant as many as 25 percent of patients in drug studies haven’t actually had Alzheimer’s, but instead a different form of dementia. What’s more, scientists have discovered that the plaques start building up 10 to 20 years before outward symptoms arise, suggesting that drugs ought to be given much sooner.
Some academic studies are even treating people with no outward symptoms all. For instance, one study is following some 300 people from an extended family in Colombia suffering from a rare genetic mutation that causes Alzheimer’s by age 45, and some will get Genentech’s experimental plaque-clearing antibody, crenezumab. The goal of the study is to see if the onset of Alzheimer’s disease is postponed.
Another prevention study, called A4, is recruiting 1,000 people over 65 who don’t yet have any memory problems, but who did test positive for plaques in a PET scan. In that study, which lasts three years, some will get Lilly’s drug and others will get a placebo.
So far, only five drugs are approved in the U.S. to treat Alzheimer’s disease—with no new ones since 2003, according to a study last year by the Cleveland Clinic. None of the existing drugs helps very much, and developing new ones has proved difficult. Over a decade, more than 99 percent of Alzheimer’s drug studies failed to move forward, the Cleveland Clinic found.
The anti-amyloid drugs are not yet home runs either. In 2012, large studies by Lilly failed to show a statistically significant effect for its antibody drug. Despite doubts, the company decided to press ahead with another large Phase III trial in mildly affected patients, which should have results next year. At the meeting of the Alzheimer’s Association in Washington, Lilly presented a reanalysis of its earlier data supporting the idea that it might work in these types of patients.
Biogen’s results have been by far the most promising. Last March, it found in a small study that patients taking the highest dose of its antibody underwent cognitive declines about a fifth as great as patients getting a placebo. The mental declines were measured using exams with questions like “What is the year?” and “Where are we now?” and “Count backwards from 100 by 7s.” They also had less plaque in their brains.
The higher doses of Biogen’s drug did have side effects, including headaches and water buildup on the brain. In Washington today, Biogen presented new data on an additional 30 patients who received an intermediate dose of the drug. The results were largely consistent with its previous findings: both the degree of side effects and improvements seem to track to the dose of its drug.
Biogen says its drug is the first ever to show a statistically significant reduction in plaques and a slowdown in symptoms. Based on that, Biogen decided to advance directly to “pivotal” Phase 3 studies of the drug. It is now launching two studies, each involving about 1,000 patients. (To win FDA approval, it’s often necessary to show positive results in two independent studies.) Like Lilly, Biogen will be looking for patients with early-stage symptoms and will screen them with imaging tests, according to the description of the studies.
Another thing these antibody tests have in common is their staggering cost. Earlier this year, Biogen’s CEO, George Scangos, estimated the cost of its Alzheimer’s program at $2.5 billion, including the expense of manufacturing the drug. About 40 or 50 million people worldwide have Alzheimer’s, and any drug able to slow the disease could become the drug industry’s largest blockbuster.