By Emily Largent
On June 7, the U.S. Food and Drug Administration (FDA) used the Accelerated Approval pathway to approve aducanumab, which will go by the brand name Aduhelm, to treat patients with Alzheimer’s disease (AD). Aducanumab, developed by Biogen, is the first novel therapy approved for AD since 2003. This news has left many experts stunned.
I have at least one colleague, Dr. Jason Karlawish, who has publicly stated that he will not prescribe aducanumab. Other clinicians have said they will only prescribe it reluctantly. These are individuals who have dedicated decades of their lives to treating patients with AD, to conducting path-breaking research and serving as investigators in clinical trials, and to advocating for public policies that will better serve AD patients and their families. Many have also seen their own families affected by AD. My colleagues are hardly indifferent to the suffering wrought by AD and would like to have a meaningful treatment to offer to patients and their families. But, they have concluded, aducanumab is not it.
It is, in many ways, surprising that we have even arrived at this moment. On March 21, 2019 Biogen discontinued a pair of Phase III clinical trials of aducanumab after a futility analysis indicated the trials were unlikely to meet their primary endpoint. In October 2019, Biogen reversed course and announced that—after reviewing a larger dataset and conducting new analyses — it had changed its mind and planned to pursue regulatory approval for aducanumab.
Biogen’s application to the FDA was polarizing. At a November 2020 meeting, the director of FDA’s Office of Neuroscience spoke in favor of aducanumab’s approval, but members of the advisory committee reviewing the application were openly skeptical. Committee members overwhelmingly concluded that Biogen had failed to prove aducanumab is an effective treatment for AD. Then, in January 2021, Biogen announced that it had submitted a response to an FDA information request, that the application would require additional time for review, and that a decision was expected June 7, 2021.
As we now know, the FDA ultimately decided to approve aducanumab using the Accelerated Approval pathway, which had not been discussed with the advisory committee. Biogen will be required to conduct a Phase IV confirmatory trial, which may take nearly a decade to complete. Additionally, aducanumab’s FDA-approved label is for AD broadly, with no mention of limiting its indication to any particular subset of patients.
What now? Here are a few of my initial thoughts and concerns.
Aducanumab is, at best, marginally effective. It can clear amyloid plaques, which are a biological marker of AD, but there is evidence that amyloid plaques do not, themselves, cause AD. It is not clear that the benefit claimed by Biogen — 22% less cognitive and functional decline than placebo — is clinically meaningful. Moreover, aducanumab is not without risks for those who take it, including brain swelling and bleeding. Still, given the lack of alternatives, it is expected many patients and families will want to try it, and clinicians will doubtlessly face substantial pressure to prescribe it.
The Institute for Clinical and Economic Review (ICER) — accepting the benefit claimed by Biogen for purposes of its analysis — concluded that aducanumab would need to be priced between $2,500 and $8,300 per year to meet ICER’s thresholds for cost-effectiveness. But aducanumab, which is a monthly intravenous infusion, will have a wholesale price of $56,000 per year and may be taken indefinitely. Additional costs are likely to accrue for diagnostic testing and patient monitoring. Further, these costs must be multiplied over the millions of patients eligible to take aducanumab. Biogen stands to make, and our health care system to spend, billions.
There are open questions about whether insurers will place limits on reimbursement. The Centers for Medicare and Medicaid Services (CMS) will have an important role to play in such determinations. If insurers do limit coverage, wealthy patients may pay out of pocket and exacerbate already existing disparities in AD care. Regardless of coverage decisions, disparities may be heightened given that our memory care system is already strained, and it has been suggested that only specialists should prescribe aducanumab and people will need to come in regularly for infusions.
Patients may now be reluctant to participate in clinical trials to find more effective drugs for AD if they can, instead, be certain of receiving a prescription for aducanumab from their clinician. This may compound ongoing difficulties recruiting sufficient numbers of participants for AD clinical trials, a challenge that reflects features of trial design.
Finally, the FDA has placed itself in a difficult position. One advisory committee member has resigned in protest, and another has spoken out against the “dangerous precedent” the FDA set by approving aducanumab. Already, patients with other fatal diseases for which there are limited treatment options are wondering why the FDA hasn’t approved drugs with similar safety and efficacy profiles for them. Patients are understandably desperate, but their needs are best served by following the science, rather than lowering the standards for future drugs.