First new Alzheimer’s drug in decades receives controversial FDA approval

A new Alzheimer’s disease treatment has been controversially approved for use in the United States despite an independent Food and Drug Administration (FDA) advisory panel reporting last year the drug’s Phase 3 trial results were inconclusive. The approval marks the first new treatment for Alzheimer’s in almost 20 years.

The ongoing story of aducanumab is turning into a twisty tale worthy of a Hollywood screenplay. Early clinical trials for this novel treatment were promising, removing accumulations of the toxic amyloid proteins thought to be one of the major damaging factors behind Alzheimer’s disease.

In early 2019 pharmaceutical company Biogen unexpectedly announced it was discontinuing its two large Phase 3 trials for aducanumab. An independent data monitoring committee had looked at the early results and concluded the drug didn’t seem to be working. The failure of these aducanumab trials followed the failure of a number of other anti-amyloid Alzheimer’s drugs, raising doubts over the veracity of the one hypothesis that dominated Alzheimer’s research for decades.

Then, later in 2019, something strange happened. Biogen suddenly revealed it had re-analyzed the aducanumab trial data and discovered the prior analysis was premature. It was claimed further investigations revealed significantly positive results from patients exposed to higher doses of the drug for longer periods of time. So, despite one of the two large Phase 3 trials finding no difference between aducanumab and placebo, the drug still potentially slowed cognitive decline in some patients.

The company claimed it was entering discussions with the FDA for market approval but many experts were concerned the evidence was simply not there to justify broad clinical use. An independent advisory committee convened by the FDA overwhelmingly recommended against the market approval of aducanumab in late 2020, claiming the clinical trials did not deliver clear evidence for the drug’s efficacy.

Now, in a rare instance of the FDA going against the advice of its own advisory panel, aducanumab has been conditionally approved for use in the United States. The FDA’s approval was granted under what is called Accelerated Approval, which means the drug meets such a serious unmet need it can be allowed to be administered to patients while Biogen undertakes another large clinical trial to confirm efficacy. Biogen has been given until 2030 to complete this additional trial.

“Currently available therapies only treat symptoms of the disease; this treatment option is the first therapy to target and affect the underlying disease process of Alzheimer’s,” says Patrizia Cavazzoni, from the FDA’s Center for Drug Evaluation and Research. “As we have learned from the fight against cancer, the accelerated approval pathway can bring therapies to patients faster while spurring more research and innovation.”

The approval of aducanumab is broad, authorizing its use for all Alzheimer’s patients from mild to severe. In approving aducanumab, the FDA has focused solely on the drug’s apparent ability to reduce the build-up of amyloid plaques in the brain. Whether this slows cognitive decline in late-stage Alzheimer’s or is more effective at preventing neurodegeneration in early-stage patients is yet to be determined.

However, what does seem clear is how unusual this particular approval is, considering the clinical data presented is below what would usually be necessary for FDA authorization. Caleb Alexander, a scientist on the FDA advisory panel who recommended against aducanumab’s approval, says he is surprised the drug has been authorized.

“The most compelling argument for approval was the unmet need but that cannot, or should not, trump regulatory standards,” Alexander said to StatNews. “It’s hard to find any scientist who thinks the data are persuasive. Unmet need is an important contextual factor but it’s not an evidentiary threshold.”

Robert Howard, a dementia researcher from University College London went even further, claiming the FDA has ignored the data, meaning it will take a decade of high healthcare costs before questions of efficacy can be resolved by the extra confirmatory trial.

“I consider the approval of aducanumab represents a grave error that will have only negative impact on patients and their families and that could derail the ongoing search for meaningful dementia treatments for a decade,” says Howard.

Biogen has priced the drug at US$56,000 per year, under the name Aduhelm, vowing to not increase the cost for at least four years. It is administered via monthly intravenous infusions and it’s unclear how much of the cost health insurers will cover.

“Price and access are sensitive matters for all groundbreaking innovations,” says Michel Vounatsos, CEO of Biogen. “We have engaged extensively with health economists, public health experts, and payers about Aduhelm – and we have examined other recent biologic drug innovations. Consistent with our pricing principles, we have established a price for Aduhelm that reflects the overall value this treatment brings to patients, caregivers and society – and one that will enable continuous innovation.”

Source: FDA