Aducanumab Fails to Produce Efficacy Results Yet Obtains US Food and Drug Administration Approval

The US Food and Drug Administration (FDA) recently approved use of the first new drug for the treatment of Alzheimer's dementia in almost 2 decades. This infusion from Biogen, Aduhelm (R) (aducanumab) is a monoclonal antibody, administered monthly, that targets amyloid-beta oligomers and fibrils in the brain that are considered pathognomonic to neurodegeneration in Alzheimer's disease. ¹ Although some have hailed this drug as a breakthrough treatment, many others strongly assert that the drug was approved without proper investigation or proof of efficacy and is associated with potentially significant clinical side effects as well as high cost.

Some of the controversy derives from the FDA's own advisory committee, along with an independent think tank and several prominent experts who worked on the aducanumab clinical trials. ² Although the FDA formally approved the drug on June 6th after an accelerated approval process, the FDA's expert advisory committee, whose recommendation is usually followed by the FDA, unanimously objected (zero yeses, 10 noes, and 1 uncertain) to the approval of the drug last November.^{3(pg 318)} This committee was presented with only 2 studies, together representing less than 4000 patients, to determine their decision whether to approve the drug. Both of these Phase III trials were halted early by the independent data monitoring committee overseeing them because of lack of efficacy, though subsequent analyses showed a potential marginal benefit in one trial. ^1,4 Additionally, the infusion was associated with amyloid related imaging abnormalities with swelling or hemosiderin deposition of the brain in as much as 41% of trial participants taking the drug as compared to 10% in the placebo group. ⁵ Despite these cautionary findings, Biogen decided to continue its pursuit of FDA approval.

The FDA advisory committee also questioned the use of the drug for anything but early stages of disease. The 2 trials only examined the use of aducanumab in participants with early-stage dementia. ¹ Despite there being no evidence to support use in advanced or even moderate disease, the FDA ultimately approved aducanumab for all stages of disease severity. In response, at the time of this writing, 3 experts from the FDA advisory committee have since resigned in protest, and the FDA has commissioned an inspector general to review the approval process for the drug. It also should be noted that the FDA did not grant the medication full approval. Instead, the agency granted conditional approval and ordered Biogen to conduct a Phase IV post-approval study confirming that the medicine slows cognitive deterioration. If the medication does not provide such a clinical benefit, the FDA's approval could be withdrawn. ^6,7 It is expected that this additional study may take years to complete.

There are currently approximately 6 million individuals in the United States with Alzheimer's disease, a number projected to more than double by 2060 without interventions to prevent, slow, or cure the disorder. ⁸ Medicare, the largest payer for Alzheimer's care in the United States, has yet to commit to coverage of aducanumab. However, it is estimated that for the drug to be cost-effective, aducanumab should be priced at $2500 to $8000 per year per patient. ² Unfortunately, Biogen has tentatively priced the drug at $56,000 annually.

There also are expected to be tens of thousands of dollars in additional costs for diagnostic testing and brain imaging required both before the drug can be given as well as during specified intervals during therapy. Given that Medicare pays 80% of the costs of an infusion or testing, at that price, and with the expected high demand from an aging population fearful of developing dementia, aducanumab is certain to cause profound stress on Medicare funding of Part B and/or Part D benefits. Patients without a supplement or Medicare Advantage plan would be responsible for more than $10,000 per year, even after Medicare pays its expected share. This cost sharing will precipitate issues of access and health inequities in communities where funds may be limited. Because Medicare Parts B and D are funded through beneficiary premium funds, the Centers for Medicare & Medicaid Services will require higher premiums to be paid by all seniors for this type of Medicare coverage. ⁹

Further, aducanumab will push the management of dementia out of the hands of the primary provider team who likely has the established relationship with the individual and can understand the complexities and caregiver dynamics that require attention. Moving dementia care to the infusion unit changes the focus from a comprehensive care approach to plaque management. Patients may lose out on the opportunity for the comprehensive management necessary to improve stability and quality of life.

In closing, the care of the individual with Alzheimer's disease is complex and overdue for scientific breakthrough. We look forward to new technology to improve the management of this population with proven efficacy, cost-effectiveness, and safety standards that has been properly vetted through thorough and expert consensus. Unfortunately, aducanumab fails to fulfil these important criteria.