Recently, the FDA made a historic decision to approve the anti-amyloid antibody, ADUHELM (aducanumab), for the treatment of Alzheimer’s disease using the Accelerated Approval pathway. The FDA approves a drug under this pathway for a serious or life-threatening illness that may provide meaningful therapeutic benefit over existing treatments when the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients and there remains some uncertainty about the drug’s clinical benefit.
The late-stage development program for ADUHELM consisted of two phase 3 clinical trials:
- One study met the primary endpoint (the clinical dementia rating – CDR- scale sum of boxes), showing a 22% reduction in clinical decline, but only for the participants at the highest dose of the antibody given.
- The second trial did not meet the primary clinical endpoint.
In all studies in which ADUHELM was evaluated, it consistently and clearly reduced the level of amyloid plaques in the brain (as assessed by amyloid PET) in a dose- and time-dependent fashion. The FDA concluded that it is expected that the reduction in amyloid plaque will result in a reduction in clinical decline.
The Peripheral and Central Nervous System Drugs Advisory Committee, convened in November 2020 and reviewed the clinical trial data to discuss the evidence supporting the ADUHELM application. The committee recommended that based on the clinical evidence from the 2 trials that ADUHELM should not be approved. The ANA Executive Committee is in agreement with the original recommendation of the Peripheral and Central Nervous System Drugs Advisory Committee. Namely, that based on the clinical evidence, ADUHELM should not have been approved at this time.
The option of the accelerated approval process was not discussed with the FDA advisory committee. In the FDA’s decision to approve ADUHELM for treatment via this process, their decision was based on the fact that all trials with the antibody were shown to substantially reduce amyloid beta plaques. They concluded that this reduction in plaques is reasonably likely to result in clinical benefit.
In the current FDA label for the antibody, it states that “treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease than were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM.”
Our recommendation is that patients who are considered for treatment with ADUHELM, should meet the same or very similar criteria that were utilized in the clinical trials for ADUHELM. Namely, they should meet clinical criteria for mild cognitive impairment or have very mild or mild dementia with a syndrome consistent with that seen due to underlying AD pathology. Further, they should have evidence of having amyloid in the brain by appropriate imaging or fluid-based biomarker testing. In addition, because of the risk of side effects including amyloid-related imaging abnormalities (ARIA)-edema (E) and ARIA- hemorrhage (H), appropriate MRI monitoring is required as well as careful assessment for risk factors that may put them at higher risk for complications of ARIA such as being on anti-coagulants. We also urge the FDA to ensure that Biogen complete a phase 4 confirmatory study as soon as possible, preferably within 3 years, to confirm or not whether clinical efficacy is observed.
Executive Committee: American Neurological Association
Justin C. McArthur, MBBS, MPH, President
Frances E. Jensen, MD, President Elect
David M. Holtzman, MD, Past President
M. Elizabeth Ross, MD, PhD, Vice President
Clifton Gooch, MD, Treasurer