Is Aducanumab (Aduhelm) effective for Alzheimer's disease patients?

From a highly experienced neurologist who contributes to the HealthTap doctor network: Bennett I. Machanic, MD, FAAN, sends this description of the issues surrounding the recent FDA approval of a new, potentially disease-modifying agent for treating Alzheimer's disease.

There are no data demonstrating clinical effectiveness

On June 7, 2021, the FDA granted "accelerated approval" for Biogen's Aduhelm as the first new treatment approved for Alzheimer's disease since 2003, despite the absence of clear-cut evidence of any long-term benefit to anyone, other than a small number of mild early cases.

The approval generated substantial controversy, and to date, three resignations by members of the Neurological Drugs Advisory Panel. Approval was based solely on ability to remove beta-amyloid plaques, which "is reasonably likely to predict clinical benefit". The FDA appeared to address the conundrum of two Phase 3 studies coming up with conflicting evidence by stating "the product has an effect on a surrogate endpoint".

The FDA Neurological Drugs Advisory Panel had strongly advised against approval, voting 10-1, and 3 members subsequently resigned to protest a far broader use than intended. One former member expressed "probably the worst drug approval decision in recent U.S. history". Compounding all of this was the intent of Biogen to charge $56,000 per year. Although Biogen has promised to cover lumbar puncture costs, there is no plan to include blood studies (APOE typing), neurofilament light measures, PET scanning, infusion center costs, or administrative costs for practices, and there appears to be no protocol to clearly assess efficacy versus failure on an ongoing basis.

Adverse event possibilities are troublesome. ARIA (amyloid related imaging abnormalities), such as brain swelling and bleeding did occur infrequently in the research studies, but the prescribing information label does not reveal that Aduhelm was stopped after 10 microbleeds were imaged on MRI studies.

Neurofilament light measures would be helpful to assess efficacy of this monoclonal antibody, but Biogen has so far not revealed these outcomes.

Additional issues of pathogenesis are salient. First, it is not fully clear whether the amyloid plaque really affects clinical deterioration, or is merely a marker in the disease progression. It is no accident that the neurofibrillary tangles appear early within the peri-rhinal and trans-rhinal cortices, and affect short-term memory by disrupting the perforant pathway to the hippocampus. Amyloid plaques do not seem to be playing a role anatomically in these locations. Another challenge involves the most toxic amyloid oligomer, a process that cannot be detected in the living brain. Furthermore, several neurotransmitters appear involved in Alzheimer's disease, including acetylcholine and glutamine, and the older "memory-enhancing agents" focus on this, but the interventions have been only modestly helpful. For years, many investigators have embraced the Amyloid Cascade hypothesis, and this explains the focus on the plaques. Incidentally, if a neurofibrillary tangle drug were to be successful, one would have to uncover an appropriate receptor, and perhaps employ a Polyclonal Antibody approach (such as IVIG).

Therefore, in my opinion, I would be very reluctant to recommend Aduhelm to anyone other than young, mild, early Alzheimer's patients who are at least APOE epsilon-4 homozygotes, have high burden of amyloid on PET imaging or significant changes in spinal fluid, high levels of NFl (which drop with therapy), and show clinical benefits on MOCA office tests.

Alternatively, we have convincing data that shows both rivastigmine and galantamine can prevent Alzheimer's patients from declining below moderate levels. Perhaps we now could modify combination therapy, which is the current state of the art, and combine one or the other with memantine, instead of donepezil.