Did the FDA Err by Approving the New Alzheimer’s Drug?

For the past 45 years, I have been conducting pre-clinical research on Alzheimer’s disease (AD). I have seen more than 30 clinical trials of new drugs that completely failed to slow cognitive decline. This explains why families of AD patients are eager for a new treatment that actually benefits their loved ones with dementia. The FDA felt this pressure and recently responded by making a terrible decision to approve a new treatment. This is the first treatment approved by the FDA for the treatment of AD since 2003 when it approved Namenda (memantine).

This week, the FDA approved Aduhelm for the treatment of Alzheimer's Disease.

Does it improve cognition? No, not significantly as compared to the placebo group.

Is it expensive? Yes, very. One year’s treatment will cost $56,000. It’s unknown whether Medicare will cover the cost of treatment.

Is it safe? No.

The FDA usually requires that all drugs, before being approved for use, are both safe and effective. Unfortunately, Aduhelm appears to be neither. During Phase III of its clinical testing, the study was discontinued because Aduhelm showed no clinical benefits. Like so many similar drugs that are anti-bodies against the protein amyloid, Aduhelm had no future. For some reason, its manufacturer, BIOGEN, decided to pursue FDA approval using very limited safety and efficacy data.

The FDA approved Aduhelm based on its ability to partially clear beta-amyloid from the brain. Indeed, this is the first drug that targets amyloid directly that has been approved by the FDA. None of the other drugs designed to clear amyloid ever made it this far in the approval process. Amyloid deposits were once believed to underlie the etiology and progression of Alzheimer’s. The problem is that this theory, related to the critical role of amyloid, has been tested extensively by hundreds of laboratories all over the world, including mine, and has been found sorely lacking. The amyloid hypothesis posits that the deposition of amyloid in the brain causes the pathology of Alzheimer’s disease. If this is true, then drugs that selectively and effectively remove amyloid from the brain should significantly improve the cognitive function of patients with Alzheimer’s disease. Unfortunately, every single attempt to translate that prediction derived from the amyloid hypothesis into a beneficial clinical effect has failed completely and miserably.

The dangers of removing amyloid from the brain:

The removal of amyloid causes negative consequences in the brain that can be seen using standard MRI scanning methods. These changes have been observed during the testing of amyloid-modifying therapies, such as Aduhelm. When monoclonal antibodies against amyloid are infused into humans, MRI scans see evidence of vasogenic edema and cerebral microhemorrhages. The occurrence of these negative brain changes is so common that it has been given its own acronym, ARIA, for Amyloid-related imaging abnormalities. ARIA is a common, dose-dependent effect of therapies such as Aduhelm.

The problem with the FDA’s ruling for Aduhelm is that doctors can give it to any AD patients. Most patients with AD (up to 75 percent) have a specific gene, called apolipoprotein E (APOE) ε4 allele; having this particular gene places a person at great risk of developing Alzheimer’s disease. Unfortunately, when AD patients with the APOE4 gene are given drugs like Aduhelm they are much more likely to develop brain edema and cerebral microhemorrhages. Indeed, in the BIOGEN trials, almost 50 percent of the APOE4 patients developed brain edema and hemorrhaging. In addition, these symptoms were accompanied by malignant hypertension and epileptic seizures.

There are simply so many valid reasons that Aduhelm should never have been approved by the FDA. It is not safe and it is not effective. Drug safety and effectiveness are the cornerstones on which the FDA has based all of its previous decisions. Finally, the underlying scientific rationale, the amyloid hypothesis, is completely flawed. The targeting of amyloid deposits produces more harm than benefit.