Drug regulators want to let drugmakers test Alzheimer’s disease treatments on patients years before the disease shows outward signs, and could approve the therapies based on subtle biological signals rather than proof they alleviate symptoms.
The Food and Drug Administration proposal will open new paths for drugmakers after repeated failures from companies that include Pfizer, Eli Lilly and Merck.
It also poses a scientific challenge. Researchers don’t fully understand the biological progression of Alzheimer’s disease, leaving the industry without a clear finish line or target.
While the FDA acknowledges the lack of an agreed-upon target, it loosened the standard for drugmakers to move ahead. The proposal cuts a line from a 2013 policy calling for “widespread evidence-based agreement in the research community” about the right biological signal.
The new guidance “is a big deal to companies,” said Maria Carrillo, chief science officer for the Alzheimer’s Association. “It is a clear statement that the FDA understands that the science of Alzheimer’s has evolved.”
In the proposal, the FDA said it quickly could approve a drug for people who haven’t shown outward signs of Alzheimer’s, if the therapy affects a biological marker of the disease — similar to how lowering blood pressure reduces the risk of a heart attack.
Nothing like that currently exists for the disorder, which is the sixth-leading cause of death in the United States.
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With a drug on the market under the fast-track process, a company then would have to conduct further trials to confirm that the biological change lead to a meaningful benefit, such as slowing patients’ initial decline in mental function, known as mild cognitive impairment.
“This guideline says they are willing to entertain a cognition-only endpoint and that is big change” from the way most trials have been run in the past, Carrillo said.
There also are implications for health insurers and the government, which will face pressure to pay for new treatments for the millions of Americans who suffer from the disease, said Craig Garthwaite, a professor at Northwestern University’s Kellogg School of Management.
Alzheimer’s disease “is filled with high-profile misses by pharmaceutical companies,” he said.
“There could be a massive waste of resources” if drugs are approved based on biomarkers that turn out not to predict Alzheimer’s progression, he said.
The draft guidance on Alzheimer’s disease is one of five proposals the FDA released Thursday to spur development of treatments for neurological diseases, including ALS, or amyotrophic lateral sclerosis.
“The brain, in many respects, is the last organ system where many aspects of our understanding of the underlying biology of disease remain uncertain,” FDA Commissioner Scott Gottlieb said in a statement.
“Symptoms and progression of neurological diseases can also vary significantly across patients, and even within patients, and across organ systems.”
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While the changes could reinvigorate research efforts for Alzheimer’s drugs, they also would ask patients and doctors to take a risk on new products that don’t have the same scientific proof behind them that comes from a trial measuring symptoms such as memory and function loss.
There are no approved Alzheimer’s treatments that slow progression of the disease, while almost 200 drugs have failed.
Merck said this week that its trial of a drug in early stage patients was being halted, and it was considering its next steps for the compound, called verubecestat.
This past Wednesday, Biogen said it was adding more patients to its study of another drug after the trial wasn’t producing a clear enough signal of the therapy’s effectiveness.
Investors took it as a sign the trial — the last remaining late-stage effort by a major drugmaker — might fail.
Alzheimer’s is thought to build for years in the brain before outward symptoms show themselves, at which point some researchers believe it may be too late.
By focusing on patients with the earliest biological stages of the disease, it may be possible to intervene before serious damage is done.
Those people — with no symptoms, no medical complaints and no detectable abnormalities — will be categorized as stage 1 patients.
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Patients with stage 2 disease have subtle abnormalities, but haven’t begun to lose ability to perform basic functions.
Stage 3 patients have signs of disease, including mild functional impairment.
It’s not until stage 4 that patients are classified with mild dementia.
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