The U.S. Food and Drug Administration.
Today, the FDA convened its Peripheral and Central Nervous System Drugs Advisory Committee to review the data from pivotal clinical trials of donanemab, a monoclonal antibody against the beta amyloid protein that accumulates in the brain of people with Alzheimer’s disease. One of these trials was conducted at UCI MIND.
The efficacy of donanemab in treating early Alzheimer’s disease in people with Mild Cognitive Impairment and mild dementia due to Alzheimer’s disease is largely agreed to have been demonstrated. The bulk of the discussion at the meeting emphasized other aspects, such as the safety of the treatment, particularly in some subgroups of patients, and especially what an eventual approved label for the drug should say. In particular, the trials of donanemab included two PET scans to assess participant eligibility: an amyloid PET to ensure that plaques were present in the brain, and a tau PET to stage disease severity based on neurofibrillary tangles. The broad consensus is that an approved label for donanemab would require demonstration of the presence of amyloid plaques prior to treatment—by amyloid PET, cerebrospinal fluid, or perhaps by plasma biomarker. But how the label will handle tau PET remains uncertain. In the trials, participants had to have “enough” signal on tau PET to qualify, so a minimum signal could similarly be required in the clinical use of the drug. But in some analyses, those with the least tau PET burden seemed to benefit the most from treatment. Alternatively, those with too “much” tau were also excluded from the trials, but here too, benefit was still observed in those with the most severe tau burden, albeit reduced compared to those with less severity.
Another point of discussion was whether the label should specifically address treatment in people who are APOE e4 homozygotes. This population is at increased risk to develop the most important side effect of treatment, amyloid-related imaging abnormalities (ARIA, bleeding or swelling in the brain) and may have had smaller benefits in the trials. The number of these participants, however, was quite small, and the clinical presenter on behalf of the sponsor, Dr. Reisa Sperling from Harvard Medical School, made a strong case that these individuals and their families should have the opportunity to discuss the potential risks and benefits of treatment and arrive at their own decisions.
Other important topics included whether the FDA was considering potential adjustments based on race and ethnicity or for individuals with Down syndrome. The FDA indicated that their stance was that individuals with amyloid in the brain as a cause of their cognitive impairment should all be equally likely to benefit from treatment with donanemab, regardless of their race and ethnicity. For their part, Eli Lilly—the maker of donanemab—showed safety data among Black and Hispanic participants; the safety profile of the drug did not appear different in these groups compared to larger trial population.
For individuals with Down syndrome, the FDA stance was that while it is reasonable to expect treatment to lower brain amyloid levels in this population as it does in non-Down syndrome patients, whether the treatment is similar in safety is a critical unknown. Eli Lilly indicated that studies in people with Down syndrome were planned to address this very issue.
The public open comment session included a series of vociferous 3-minute testimonials, approximately half in favor and half against approval of donanemab.
In the end, the panel seemed quite supportive of the conclusion that donanemab has adequate efficacy to support approval. Most of the committee members also seemed to support approval without contingencies based on tau PET, though this opinion was not unanimous. This opinion seemed largely due not to demonstration of efficacy in high and low tau populations, but because of the practical challenges in securing tau PET clinically, and the ramifications such a decision would have on access to a potential new treatment option for people living with Alzheimer’s disease.
Question 2, Vote 1. Do the available data show that donanemab is effective for the treatment of Alzheimer’s disease in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?
11 yes, 0 no, 0 abstain.
Question 5, Vote 2: Do the benefits outweigh the risks of donanemab in the treatment of AD in the population enrolled in the clinical trials with mild cognitive impairment and mild dementia?
11 yes, 0 no, 0 abstain.
