The Battle Over an Alzheimer’s Treatment

The Food and Drug Administration is under scrutiny for overweighting the risks versus the benefits of recommending a break

Johnson & Johnson‘s

Covid19 vaccination. This compromise is also at the center of another heated debate over whether the FDA should approve the first drug shown to slow the progression of Alzheimer’s disease.

The FDA has long been plagued by a culture of bureaucratic overcautiousness. But it showed more flexibility and accelerated new drugs during the late Obama and Trump presidencies. However, doctors who advocate stronger government scrutiny than European health systems say the agency approves too many high-priced drugs.

Biogenic‘s

The Alzheimer’s drug aducanumab is now caught in this battle.

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Alzheimer’s disease is more than six million Americans, and the number is expected to increase as the US population ages. The tragic symptoms of the disease are well known – progressive memory loss, abnormal behavior, and inability to perform everyday tasks.

Brain scans reveal the build-up of amyloid plaque and entanglements of tau proteins, which typically begins decades before patients experience cognitive problems. High blood pressure, obesity, diabetes, smoking, sleep disorders, and the APOE4 gene variant put people at higher risk. Scientists have yet to identify the cause of Alzheimer’s disease, however.

This has thwarted the search for treatments, especially since Alzheimer’s is usually diagnosed after irreversible brain loss. Some drugs can temporarily improve memory, alertness, or mood, but none will slow neurological and cognitive degeneration.

Since 2008, 10 to 20 clinical trials of Alzheimer’s drugs have been initiated each year. Aducanumab, a monoclonal antibody drug, is the first disease-modifying drug to show effectiveness. It works by targeting specific molecules on the amyloid to remove plaque. While more than 25 studies of drugs using this strategy have failed, Biogen has learned from its mistakes.

The company used PET scans to examine study participants to make sure they had Alzheimer’s – rather than other forms of dementia – and weren’t in advanced stages of the disease. This filtered out patients who would not benefit from the drug.

A late-stage study showed that high-dose treatment removed 71% of plaque buildup after 18 months and also had a significant impact on disease progression. After 78 weeks of treatment, patients who received a high dose were 84% less stressful for caregivers than controls. They showed a 91% smaller decrease in the ability to prepare a meal and a 39% smaller decrease in the ability to discuss current events.

In short, patients treated with high doses of the Biogen drug were much more independent and capable. Given the long history of failed Alzheimer’s drugs, skeptics say Biogen’s promising result is false positive. They cite a second, simultaneous, late-stage study by Biogen which indicated that aducanumab had no statistically significant benefit on symptoms.

However, in a post hoc review, Biogen found the likely reason for the inconsistent results. The two studies had nearly identical designs, but patients in one study received the high dose for longer and the benefits increased over time. A peculiarity of randomization also meant that twice as many “fast advanced users” – people who walk downhill quickly – were assigned to the high-dose arm than the control arm in the study, which showed no benefit. The positive effects for many patients receiving the drug were partially offset in the data by these rapid advances.

Biogen worked with FDA scientists to analyze the discrepancies between the two studies. The FDA stated in June 2019 that the evidence from the positive study “can be considered extremely compelling”. Biogen filed for drug approval in July. Doctors and groups working with Alzheimer’s patients have asked the agency to approve the drug.

An external panel of scientists convened by the FDA in November to advise them – none of whom specialize in treating Alzheimer’s patients – has condemned Biogen for massaging the data. They said the positive results from one study could be a fluke and urged the FDA to force Biogen to do another – which could take five or more years.

Three panelists wrote in the Journal of the American Medical Association that the FDA’s “unusual level of collaboration” with Biogen may have “potentially compromised” their objectivity. However, this type of “collaboration” between drug manufacturers and the FDA is one reason for the rapid development of Covid vaccines.

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The FDA does not need to heed its advisory boards, but rarely rejects its recommendations. Acting FDA Commissioner Janet Woodcock has been criticized for this, particularly for making correct decisions in the cases of Sareptas Duchenne Muscular dystrophy drug and an extended-release opioid

Zogenix.

Ms. Woodcock, who is running as FDA commissioner, is under political pressure from the left to reject Biogen’s drug.

This could hold back Alzheimer’s drug development for years and discourage investment in a disease that is causing terrible trouble. It would send the signal that the FDA will ignore the complexities – and that they care more about their own reputations than about patients with certain medical elites.

Studies are rarely conclusive, so FDA scientists need to interpret and analyze evidence holistically. The risk of approval is that some Alzheimer’s patients will not benefit from the drug and US taxpayers will pay the costs through Medicare.

But Biogen’s drug could extend Americans’ independence even in the early stages of the disease, saving the healthcare system hundreds of billions of dollars. Older people could recognize grandchildren longer. And with the advent of blood tests that can help identify people who are at risk for Alzheimer’s before symptoms appear, it could ultimately benefit millions more Americans.

The US may be close to the Alzheimer’s breakthrough, and the FDA’s first duty is to patients.

Journal Editorial Report: Paul Gigot interviews Dr. Marty Makary. Image: Michael Ciaglo / Getty Images

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