Aducanumab:  “Coverage with evidence development”

Aducanumab received accelerated approval by the FDA on June 7, 2021, for the treatment of Alzheimer’s disease. As described below, Medicare coverage is limited to research settings that provide “evidence development.”

Aducanumab is a monoclonal antibody directed against amyloid, and it is administered as an intravenous infusion every 4 weeks. “Accelerated approval” differs from regular FDA approval. Accelerated approval can be based on a substitute endpoint — in this case, brain amyloid visualized with a PET brain scan — and accelerated approval does not require demonstration that the drug is clinically effective. Rather, accelerated approval reflected the view that there was an important unmet medical need when it comes to the treatment of Alzheimer’s disease and the drug reduces brain amyloid.

The accelerated approval of aducanumab followed on the heels of two, very large clinical trials (phase-3 trials), each lasting one and a half years. Both trials involved people with very mild forms of Alzheimer’s disease. The trials did not include people with moderate or severe dementia.

It is clear that aducanumab reduces amyloid plaque in the brain. Other monoclonal antibody treatments also reduce brain amyloid, but they failed to provide clinical benefit and failed to gain FDA approval. We are concerned that the average clinical effect of aducanumab in the first phase-3 clinical trial was too small to be noticed by patients or family members. Results from the second phase-3 trial failed to detect even this very small effect.

The principal side effect in these trials was ARIA (Amyloid-Related Imaging Abnormalities). ARIA represents swelling or bleeding in the brain, as detected by an MRI brain scan. This side effect can be serious but usually is not. ARIA can cause headache and confusion. Some Alzheimer’s disease specialists are concerned by a treatment that has not shown clinically meaningful benefit and is associated with some degree of potential harm.

On April 7, 2022, CMS (the Centers for Medicare and Medicaid Services) announced its national policy on coverage of aducanumab.  This policy also applies to any future, similar approved treatment (i.e., monoclonal antibodies directed against amyloid). Medicare, the primary insurer for most Americans aged 65 and over, will cover Medicare Part B prescription costs of aducanumab, but only with an important limitation referred to as “coverage with evidence development.”

Practically speaking, CMS coverage is available only for patients enrolled in a randomized clinical trial of aducanumab or in other aducanumab trials supported by the National Institutes of Health or CMS.  CMS coverage is not available in routine clinical practice. CMS “coverage with evidence development” pertains to to people with a diagnosis of mild cognitive impairment due to Alzheimer’s disease or a diagnosis of mild dementia, where amyloid plaque has been confirmed, for example, by an amyloid-PET brain scan.

We continue the search for better, more effective means of prevention and treatment through NIH-sponsored research in the Iqbal Farrukh and Asad Jamal, Stanford Alzheimer’s Disease Research Center. Further information on the aducanumab clinical trials is provided in the report of the Institute for Clinical and Economic Review (ICER) and its summary document.