The FDA raises hopes for Alzheimer’s drugs with a new set of draft rules. But are they going too far?

The view from John Carroll

For years now the gold standard for R&D in Alzheimer’s has focused on generating convincing evidence that any new therapy being studied could slow the cognitive decline of patients and help preserve their ability to perform the kind of daily functions that can keep a patient independent for a longer period of time.

That’s a hurdle no one has managed to clear for well over a decade. So now, with late-stage clinical failures piling up, the FDA has set off down a path to adapt those standards as researchers are pushed inexorably into earlier and earlier forms of the disease, ahead of the brain damage inflicted by Alzheimer’s.

In a set of draft guidances, the agency essentially proposed to offer an approval pathway for new drugs that could prevent the onset of the devastating symptoms of Alzheimer’s if drug developers could hit acceptable biomarkers that indicate the drug is working. And they’re likely going to continue with a new gold standard that will focus on long-term cognition alone, lowering the bar for drugs for an enormous and growing market.

David Miller

David Miller, the clinical vice president of Bracket, a tech provider which specializes in Alzheimer’s studies, tells me the draft guidance hit just after a meeting of the Alzheimer’s Association research group, which was discussing how you might be able to use a mix of markers for amyloid beta and tau — two toxic proteins frequently cited as likely triggers — alongside  neurodegenerative markers to identify patients who could be enrolled at a very early point in the disease.

“It’s ahead of where it was,” Miller says about their understanding of pre-symptomatic biomarkers. “There’s been an improvement in our understanding of how these biomarkers work together, where there might be improvement. That doesn’t mean we are where we need to be, but we are getting closer.”

“We need to figure out ways to do measurements better, sensitive to earlier stages of the disease, looking at cognition and function for more sensitive ways of doing it,” says Miller.

One of the big challenges, he adds, will be to set up criteria for new studies that allow developers to accurately track biomarkers with a consistent focus on a clearly defined group of patients enrolled in studies around the world. And perhaps one way is to rely on more patient reported outcomes, where the patient themselves track their condition.

The move “is a big deal to companies,” Maria Carrillo, chief science officer for the Alzheimer’s Association, told Bloomberg. “It is a clear statement that the FDA understands that the science of Alzheimer’s has evolved.”

What’s driving the shift?

These draft guidances, which will have to be formally reviewed with time to gather more feedback from patients, physicians and developers, come after a drumbeat of late-stage failures is raising questions about what scientists actually know about this disease. Eli Lilly tried three times to produce pivotal evidence that solanezumab could influence the course of the disease by clearing amyloid beta, and failed. The company now has sola in a study to see if it can prevent the disease in at-risk patients.

Earlier this week Merck flagged a clear failure for its BACE drug verubecestat, which moves upstream in the biology of developing amyloid beta. It has now failed in both mild-to-moderate as well as prodromal patients. Axovant took a failed drug from GlaxoSmithKline and smashed into a subgroup flop recently, leaving the biotech badly wounded. And Pfizer added to the latest series of setbacks with its decision to dump its entire neurosciences effort and move on in other areas — following the exits of big players like AstraZeneca and GlaxoSmithKline over the years.

That doesn’t mean that R&D has stopped. Any new drug that can help patients, or patients at risk, is likely to be a blockbuster winner, and that has helped fill the cash reserves of new biotechs like Denali, lining up with longterm players like Takeda, which had its own recent setback.

The march to studying drugs at an earlier and earlier stage of the disease has been underway now for at least 5 years, so the move toward pre-symptomatic groups is a natural step in that evolution. However, shifting away from gold standard endpoints toward an evolving set of biomarkers also raises the prospect that the FDA will approve new drugs that eventually prove that they don’t actually do anything to affect the course of the disease, raising hopes and costing billions without any real benefit.

Standing still, though, is no longer an option.

The emphasis at the FDA now is to encourage successful drug development by recognized experts. If they start toeing the line on professional standards for efficacy and safety, you can expect to see the pendulum swing back again sometime in the future.

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