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Thursday, December 7, 2023
Dr. Brown: New drugs and the ongoing battle against Alzheimer’s

Like Oliver Sachs, I eagerly look forward to the weekly arrival of the next issue of the journal Nature.

Last week a piece written by Paul Nurse caught my eye. He quoted his Nobel Prize-winning friend Sidney Brenner, who stated 20 years ago that, “we are drowning in a sea of data and starving for knowledge.”

Brenner’s observation, recycled by Nurse to apply to some science these days, hit home. Because that’s been the case for research into Alzheimer’s disease – a lot of data and a several-decade fixation on the “amyloid hypothesis,” which claims that Alzheimer's is caused by the accumulation of beta-amyloid (and tau) protein in the brain.

That fixation led to the development of several drugs, including vaccines and monoclonal antibody (mab) drugs designed to rid the brains of patients with Alzheimer's of their accumulations of beta-amyloid.

In every instance, except for the latest controversial evidence favouring aducanumab (Aduhelm), the vaccines and monoclonal antibody treatments failed to significantly slow progression of the cognitive impairment, even if they reduced the beta-amyloid load in the brain. Unfortunately, some of those same drugs provoked troublesome adverse side effects.

That was the situation until aducanumab came along several years ago. Like many of its predecessor anti-amyloid drugs, aducanumab successfully cleared the brain of much of its beta-amyloid load. However, that wasn’t the primary issue. The issue was whether aducanumab slowed progression of the cognitive impairment and other clinical markers.

One phase 3 trial said no, as did the other phase 3 trial – until Biogen, the pharmaceutical company that developed the drug, reassessed the data and claimed that at the highest dose level, aducanumab, did indeed slow the progression of cognitive impairment.

The claim divided the experts, many of whom felt the data favouring a clinically significant benefit was too weak to justify approval by the U.S. Food and Drug Administration, while other experts and Biogen claimed there was some clinical evidence to support their claim.

The FDA then made an unprecedented decision: the agency based its approval on what was obvious evidence that aducanumab cleared the brain of much of its beta amyloid load while turning a blind eye to the drug’s less-than-stellar clinical impact.

Many experts felt betrayed and that the FDA had lowered the bar for approval of this drug. Many felt this opened the door to other similar drugs in development in the face of a questionable clinical benefit and evidence that many patients suffered from adverse side effects such as swellings and tiny hemorrhages in the brain.

Did the FDA make a mistake? Yes, and a qualified No. Yes, for not demanding more convincing evidence that the rate of decline in cognitive impairment was slowed.

But a qualified No for two reasons. Even in the earliest clinical stages of Alzheimer's, it may be too late for drugs like aducanumab to have much, if any, clinical effect, because too many nerve cells and especially connections may be lost or dysfunctional beyond repair.

The real challenge would be to treat as-yet asymptomatic patients with progressive PET scan evidence of beta-amyloid accumulation. That’s a tricky step to take given the potential for adverse side effects of this and other similar drugs and uncertainty about whether the patient will actually develop clinically symptomatic Alzheimer's, and whether other factors such as co-existing vascular dementia might be playing role for which those drugs would not be expected to help.

Given the risk of those adverse side effects, a better bet for testing the amyloid hypothesis would be to prophylactically treat patients with the autosomal dominant variant of Alzheimer's.

These patients will for certain develop the disease and earlier by a decade or so before vascular dementia might fudge the study. As a result, it would be easier to justify taking the drug a decade or more before the anticipated onset of symptoms in the hope of delaying, or hopefully preventing the disease.

When I last wrote about the amyloid hypothesis and aducanumab in The Lake Report that was the state of affairs. Since then, the chasm between the approvers and non-approvers has widened with several high-profile health care organizations and experts in Alzheimer's distancing themselves from support for the drug, citing weak clinical evidence and high costs for the drug (more than $50,000 U.S. a year, exclusive of expensive PET scans and other costs).

Given the FDA’s approval for aducanumab, other similar drugs such as the more recent donanemab, will probably find their path to approval much easier.

You can access more information on the subject later this week by going the YouTube site below or the Niagara-on-the-Lake Public Library's website and following the leads.

See the video at youtube.com/watch?v=88B_OHUAQ9Y 

Dr. William Brown is a professor of neurology at McMaster University and co-founder of the InfoHealth series at the Niagara-on-the-Lake Public Library.  


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