The experts weigh in on Aduhelm

In the September 14 issue of the journal Neurology, Alzheimer’s experts have offered their opinions in one editorial and two viewpoint papers, one pro and one against, concerning the FDA approval of aducanumab, now known as Aduhelm, the anti-amyloid monoclonal antibody treatment for early-stage Alzheimer’s disease. Nobody disputes the fact that Aduhelm is very effective at removing beta-amyloid plaques from the brain. The disagreement arises about whether this results in any significant slowing of cognitive deterioration.  In one of two identical trials, the EMERGE trial, those receiving the highest dose of Aduhelm, 10 mg/kg, had a 22% drug-placebo difference on one cognitive measure, the Clinical Dementia Rating Scale sum of boxes. The other trial (ENGAGE) showed no benefit. After the two trials were under way, the highest dose of Aduhelm was raised in APOE-4 carriers to 10 mg/kg after it was determined that it was safe to do so, and in the EMERGE trial that started later, the APOE-4 carriers received that higher dose for a longer period of time than those that were in the ENGAGE trial that began earlier. Therefore, the trials were not really identical. A requirement for an additional trial might seem logical, and indeed the FDA has mandated a third, post-approval trial and has given Biogen nine years to complete it.  The FDA has really approved Aduhelm not because of any demonstrated cognitive benefit as there is little to support that.  Instead, the FDA has opted to approve it based on a surrogate outcome, the successful lowering of brain amyloid. Whether this surrogate marker predicts clinical benefit is still open to question.

Now that Aduhelm has been approved and can be prescribed, the authors of the three papers in Neurology are generally in agreement with the following recommendations listed in the editorial: “First, this drug is intended only for those who are in the mild cognitive impairment or mild dementia stage of Alzheimer’s disease…. Second, verifying the presence of amyloid pathology in the brain with an amyloid PET scan is recommended…. Third, APOE-4 screening, baseline MRI, and follow-up MRI are all important for predicting the risk of ARIA adverse events…. Fourth, the price of aducanumab [Aduhelm] is considerable (wholesale costs are currently $4,312 per monthly infusion for a 75-kg patient at the 10 mg/kg dose). Fifth, no stopping rules are currently provided in the drug label, but the American Academy of Neurology recommended that an ‘outcomes-based payment arrangement’ should be worked out in the future with third-party payers…. Finally, patients and their caregivers need to understand that the clinical benefits of aducanumab are small and that more data will be needed in the future to determine whether these benefits are clinically meaningful.” (L.A. Hershey and R. Tatawneh. Clinical efficacy, drug safety, and surrogate endpoints: has aducanumab met all of its expectations? Neurology 2021;97:517-518)