Health

A Drug to Treat Alzheimer’s Was Approved. Now What?

Now that the FDA has approved Biogen’s aducanumab (Aduhelm), the controversial new drug for Alzheimer’s disease, what does this mean?

“I think this is good news for our patients with Alzheimer’s disease who now have a therapy that attacks one of the underlying causes of the disease,” said Ronald Petersen, MD, PhD, of Mayo Clinic in Rochester, Minnesota.

“A great deal of work lies ahead to choose which patients might be eligible for the treatment and to monitor safety,” Petersen added.

Aducanumab, a monoclonal antibody that selectively binds to aggregated forms of amyloid beta, raised considerable questions in the wake of findings from two identical phase III studies, EMERGE and ENGAGE. The trials were terminated in March 2019 when a futility analysis determined aducanumab was unlikely to outperform placebo at completion.

In October 2019, Biogen reversed its position, saying a review of previously unavailable data showed the drug actually reduced cognitive decline in EMERGE, but not in ENGAGE. In November 2020, an FDA advisory committee voted overwhelmingly against the data presented about the Alzheimer’s drug candidate, saying the positive results seen in one of the two trials could not be considered alone.

A Surrogate Endpoint

The FDA approval on Monday was made through the agency’s accelerated approval pathway, a way to approve drugs for serious conditions that fill an unmet medical need based on a surrogate endpoint. The approval assumes the drug is reasonably likely to produce a clinical benefit.

In this case, the surrogate endpoint was aducanumab’s ability to reduce beta-amyloid. That’s “reasonable, although it opens the door for companies with competing monoclonal antibodies — and there are several — to make a similar claim even without compelling clinical data,” noted Pierre Tariot, MD, director of the Banner Alzheimer’s Institute in Phoenix.

In past trials, a number of anti-amyloid drugs have reduced amyloid plaques in the brain but showed no clinical benefit on cognition. The FDA accelerated approval pathway will require Biogen to conduct a post-approval trial to show clinical benefit, and the agency can withdraw its approval if the trial doesn’t meet expectations.

Biogen has been laying the groundwork to launch the drug upon approval by helping clinics set up to treat patients. In April, the company said it had identified 600 U.S. sites to assess and treat people with Alzheimer’s disease.

Aducanumab will be administered as an infusion once every 4 weeks and will cost an average of $56,000 per year, Biogen said. That doesn’t include the cost of MRIs, which the FDA advised using to monitor patients on aducanumab for amyloid-related imaging abnormalities (ARIA), a temporary swelling in the brain that occurred in the aducanumab trials.

“In addition, it is not entirely clear whether testing for elevated brain amyloid is required, since it is not in the prescribing information approved by the FDA except for the description of the trial populations,” Tariot said. “Payers may require this, however, which would incur not only the costs of amyloid testing but disclosure of the amyloid results.”

Whether people need to have genetic testing for APOE4 is unclear, too, he added.

Importantly, the “FDA’s aducanumab label is broad,” noted Jason Karlawish, MD, co-director of the Penn Memory Center at the University of Pennsylvania in Philadelphia.

“The drug is for the treatment of Alzheimer’s without any of the criteria that defined the subjects of the trials,” Karlawish pointed out. “This when paired with the $50,000 per year cost passes the problem of aducanumab into the hands of Medicare to decide whether the drug is reasonable and necessary.”

The FDA approval was just a “step in the process to bring this drug to the clinic,” Tariot said. “We need to see the details of the phase IV plan and what that means for practice.”

Experts React

Many dementia experts expressed reservations about the approval, but others embraced the FDA’s decision enthusiastically.

“I feel that aducanumab is a great advancement for the field and a major win for patients living with Alzheimer’s disease and their families,” James Galvin, MD, MPH, of the University of Miami Miller School of Medicine in Florida, told MedPage Today.

“The first drug approval in any class is often not the best in class,” Galvin noted. “There has to be a first before there can be a second. I think this decision — and the decision by the FDA to use the accelerated approval — will do for Alzheimer’s what accelerated approval has done for cancer, which is spur investment and research and development back in the area of neuroscience and Alzheimer’s disease. That’s going to make a huge difference in the field as a whole.”

“Accelerated approval based on a biomarker and requiring a confirmatory trial is a common FDA strategy for cancer drugs and was a good approach for aducanumab,” said Jeffrey Cummings, MD, ScD, of the University of Nevada in Las Vegas. “Patients get the drug without waiting 5 more years, and additional data will help us understand the efficacy and safety of the treatment.”

The FDA’s approval of aducanumab was the first in the world, and whether regulators in the U.K. and Europe will take a similar view of the drug is unknown. Experts in other countries shared mixed reactions on social media this week; for many, hesitancy about aducanumab’s effectiveness persisted.

“The hopes of dementia sufferers and people who care for them for a treatment that can slow the progression of dementia should always be served by the best science,” noted Robert Howard, MD, MRCPsych, of University College London.

“Regrettably, the FDA has ignored high quality scientific evidence of non-efficacy provided by the large and carefully conducted phase III studies,” Howard told MedPage Today. “They’ve effectively approved an expensive placebo with unpleasant side effects on the basis of action against brain amyloid levels, an action that has already been shown to have little or no effect on cognitive and functional decline with this and earlier agents.”

“Happily, science generally finds a way of correcting itself when it goes astray,” Howard said. “It’s too early to know how this will happen with aducanumab.”

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow

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