May 3, 2023–Eli Lilly and company announced today (https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional) the positive topline results from their Phase 3 clinical trial of donanemab, a monoclonal antibody that rapidly lowers beta amyloid levels in the brain of people with Alzheimer’s disease. The release indicated that patients treated with donanemab experienced significantly slower cognitive and functional decline, compared to those receiving placebo, over 18 months. The primary outcome was a composite measure known as the integrated Alzheimer’s Disease Rating Scale (iADRS, a tool that borrows pieces of other instruments to look at elements key in early disease) and was reported as demonstrating a 35% slowing of decline for donanemab compared to placebo. The press release also indicated that benefit was observed on key secondary clinical outcome measures—strong indication that the observed benefit is real.
The release indicates that the sponsor will quickly submit for full FDA approval. The application for accelerated approval of donanemab was declined in January (https://mind.uci.edu/fda-decides-not-to-grant-accelerated-approval-to-donanemab/) but if the complete data adequately reflect the press release, the case should be compelling for full clinical approval. The FDA will convene an advisory panel in June to consider full approval of another monoclonal antibody, lecanemab, which was previously approved under the accelerated approval pathway (https://mind.uci.edu/fda-grants-accelerated-approval-to-lecanemab/).
As with other amyloid-lowing drugs, the main safety concern was amyloid-related imaging abnormalities. About a quarter (24%) of participants assigned to donanemab experienced ARIA-E (swelling in the brain) and 31% experienced evidence of microhemorrhage (ARIA-H). While most cases did not result in clinical symptoms for patients, some did and a small number were very serious. Learning more about these cases, and particularly whether specific patients are at greater risk for adverse safety issues will be essential, and will likely be a feature of the first public presentation of the trial data—which Lilly indicated will happen in July at the Alzheimer’s Association International Conference in Amsterdam.
There were several unique features of the TRAILBLAZER 3 trial that will have important implications to clinical practice. Rather than treating patients for the full 18-months of the trial, patients were treated only until their brain amyloid levels had been determined to be adequately reduced so as to no longer be considered “elevated.” Fifty-two percent of participants had achieved this goal by 12-months and 72% by 18 months. This approach was used in Lilly’s Phase 2 trial of donanemab (TRAILBLAZER 2) and was partly why the FDA declined to grant accelerated approval to the drug—citing an inadequate safety data since many patients had limited duration of treatment. Also, the TRAILBLAZER 3 study used measures of both amyloid plaques and neurofibrillary tangles as part of the inclusion criteria. The press release indicates that the benefit of therapy was reduced when the data included patients with greater neurofibrillary tangle burden, compared to when restricting analyses to those with less burden. If approved, the label for donanemab should reflect the eligibility criteria from the trial, and could limit the population of patients who are appropriate for therapy and introduce challenges in clinical practice for determining who should and who should not be treated.
It is nevertheless an exciting time. We can be increasingly convinced that at least some amyloid-lowering therapies will offer clinical benefits for at least some patients. But we must strive to bring additional, better, safer and more convenient therapies to the millions of patients and families who need them; and the millions more who will eventually. On Monday, I presented “Clinical Trial Design in the Era of Disease Modifying Therapies for Alzheimer’s Disease” to the meeting of the Directors of the NIA-funded Alzheimer’s Disease Research Centers (https://files.alz.washington.edu/spring-adrc-meeting/preliminary-agenda-2023.pdf). Our efforts to develop new treatments will incur new challenges, as well as new opportunities, but the mission to find meaningful treatments and treatment combinations that stop disease progression or better yet prevent the onset of cognitive impairment cannot be delayed.