Monday, July 19, 2021

Should the FDA have approved aducanumab?

- Jennifer Middleton, MD, MPH

The US Food and Drug Administration (FDA) recently approved  aducanumab (Aduhelm), "a first-of-its-kind treatment....that targets the fundamental pathophysiology" of Alzheimer's disease. Pharmacologic treatment options for Alzheimer's disease have previously only targeted symptoms, but aducanumab purports to attack the amyloid plaques "that result in loss of neurons and their connections." Aducanumab's approval, however, has been met with criticism from both the medical community and members of the FDA themselves.

The FDA approved aducanumab via its accelerated approval pathway, intended for "drugs for serious conditions that fill an unmet medical need." The accelerated approval pathway permits drug makers to present less rigorous (and less time consuming) outcomes than the traditional approval process:

A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).

The two phase III trials that aducanumab's manufacturers presented to the FDA had identical study designs; each enrolled adults worldwide aged 50-85 with symptoms consistent with early Alzheimer's disease and randomized them into 3 groups: placebo, low-dose aducanumab, and high-dose aducanumab (all administered every 4 weeks intravenously). Their primary endpoint was the Clinical Dementia Rating - Sum of Boxes (CDR-SB), administered at participant enrollment and again after 78 weeks of treatment.  Neither study found benefit for low-dose aducanumab; one study's results suggested potential for high-dose aducanumab, while the other study did not.

Perhaps not unsurprisingly, 10 of the 11 FDA advisory committee members voted against aducanumab's approval in November of 2020 after reviewing the results of these 2 studies. Yet on June 7, 2021, the FDA approved aducanumab, citing trial data demonstrating that "[p]atients receiving the treatment had significant dose-and time-dependent reduction of amyloid beta plaque, while patients in the control arm of the studies had no reduction of amyloid beta plaque." It's notable that the FDA justified its decision using one of the trials' secondary outcome measures and not the primary outcome measure, CDR-SB, that had inconsistent results. Three physicians resigned from the FDA advisory committee in protest, including Dr. Aaron Kesselheim, who has since publicly aired his concerns regarding the drug's questionable safety, unproven efficacy, monitoring requirements, and steep price tag ($56,000/year). Allegations of improper communications between aducanumab's manufacturers and the FDA have also emerged, casting more doubt on the propriety of aducanumab's approval.

Patient advocacy groups are cheering aducanumab's approval, though, and understandably so; the devastation Alzheimer's disease wreaks on patients and families is profound, and the potential to ameliorate that suffering with a completely new drug is tantalizing. The FDA is requiring aducanumab's manufacturers to continue gathering data regarding its safety and efficacy, so time will tell whether the FDA's approval decision will prove to be a rash or sound one.

You can read more about Alzheimer's disease, and other dementia disorders, at the AFP By Topic on Dementia, which includes this 2017 AFP overview of "Alzheimer Disease: Pharmacologic and Nonpharmacologic Therapies for Cognitive and Functional Symptoms."