NEW YORK – The US Food and Drug Administration on Monday will seek input from a panel of independent experts on whether Eli Lilly has provided enough evidence to support its application to market donanemab, the company's anti-amyloid drug candidate for Alzheimer's disease.
Specifically, the FDA is asking its Peripheral and Central Nervous System Drugs Advisory Committee to vote on whether there's sufficient evidence that the drug is an effective treatment against early Alzheimer's and whether clinical trial data support a favorable benefit-risk profile, according to documents agency staff released Thursday.
The advisory committee, whose recommendations are nonbinding, will review evidence that Lilly submitted as part of a biologics license application seeking traditional FDA approval for donanemab, a monoclonal antibody that targets beta-amyloid plaque in the brain. The company submitted data from a pivotal randomized-controlled Phase III trial, known as Study AACI or TRAILBLAZER-ALZ 2, in which more than 1,736 patients with early Alzheimer's and beta-amyloid pathology received either donanemab or a placebo.
Investigators observed significantly slower disease progression among patients in the Phase III clinical trial who were treated with donanemab when compared to those who received placebo, as measured by changes in scores on the integrated Alzheimer's Disease Rating Scale (iADRS) from baseline through 76 weeks later. This held true in the overall study population as well as in a subgroup of patients Lilly homed in on who had low or medium levels of tau, another protein biomarker associated with Alzheimer's that's typically seen after beta-amyloid accumulation.
Lilly required patients enrolled in the clinical trial to have signs of tau pathology in an effort to enrich its patient population for those who were likely to experience disease progression during the 18-month study period. The company believed progression would be less likely among patients without the tau biomarker.
Although Lilly opted to stratify patients by tau pathology in the pivotal trial, the firm has not proposed requiring physicians to confirm or quantify it when prescribing donanemab.
"While patients were prospectively characterized for tau levels in the context of the highly controlled, and rigorously conducted donanemab development program … tau levels were not designed to become a prospective patient selection factor in clinical practice," Lilly wrote in a briefing document it prepared for the FDA advisory committee. "There is no mechanistic basis to believe that with an amyloid-targeted therapy, such as donanemab, there is a specific tau level at which this mechanism of action would not be potentially beneficial."
Lilly prioritized analysis of the subgroup with low or medium levels of tau, rather than high levels, out of concern that patients with higher tau may be too advanced to show a treatment benefit. Ultimately, subjects with high levels of tau also experienced a slower rate of decline when treated with donanemab, though not to the same extent as the overall study population.
The FDA is asking advisory committee members to consider whether the available evidence supports efficacy across all tau subgroups, and weigh promising biomarker data from an open-label safety addendum alongside the fact that the drug's effect on patients with no or minimal tau has not been established.
Although patients with no or very low tau were not allowed to enroll in the randomized-controlled portion of the Phase III study, about 200 patients with these characteristics were eligible to join the clinical trial's open-label safety addendum, during which biomarker data was collected. Patients with no or very low levels of tau experienced reductions in beta-amyloid and plasma phosphorylated-tau 217 that were similar to those with higher levels of tau.
"The pharmacodynamic effect of the drug is expected to be similar in patients who are amyloid positive, regardless of tau status," FDA reviewers wrote in its briefing document. "It may be reasonable to generalize the efficacy results from the population studied in Study AACI across the spectrum of tau burden, including patients with very low or no tau."
The FDA has also asked the advisory committee to weigh in on Lilly's proposed dosing regimen, which would comprise an intravenous infusion of donanemab once every four weeks until patients reach a certain level of beta-amyloid plaque clearance as measured by amyloid PET.
That's different than the approach taken for Leqembi (lecanemab), another drug in this class that was codeveloped by Eisai and Biogen. Leqembi received accelerated approval from the FDA in January 2023, which was converted to a full approval in July 2023, although some experts still question its clinical benefit. Eisai currently is seeking FDA approval for Leqembi as an ongoing maintenance therapy that patients would continue to receive after initial beta-amyloid clearance.
The first Alzheimer's drug in this class to reach the market, Biogen and Eisai's Aduhelm (aducanumab), is being discontinued.
Subjects in Lilly's Phase III clinical trial were allowed to stop donanemab based on a threshold of beta-amyloid plaque, at which point they switched to placebo. However, FDA reviewers raised concerns about lack of evidence regarding the optimal threshold for when to stop dosing, a lack of a comparator group, and questions around whether patients may need to restart treatment in the future if beta-amyloid reaccumulates in the brain.
"Efficacy data from participants who had their dose switched to placebo during the study are inadequate to draw conclusions regarding persistence of clinical benefit due to the relatively short off-treatment period and the lack of an appropriate comparator group," FDA reviewers wrote. "The applicant assumed that cessation of donanemab dosing once brain amyloid on PET was reduced beyond a specific threshold would not adversely affect clinical outcomes. Although this assumption is reasonable, it was not verified by including an arm with continuous donanemab dosing."
Lilly in its briefing document argued that although the clinical trial does not "definitively quantify the effect of this intervention," the study's results, which were positive, support this approach.
Additionally, the FDA is requesting that the advisory committee vote on whether the benefits of donanemab outweigh the risks, and in particular consider the effects of amyloid-related imaging abnormalities (ARIA) and cerebral hemorrhage, which were consistent with other drugs approved in this class. Risk of ARIA was higher in patients who were APOE ε4 carriers, which was also true of Leqembi, for which the FDA required a boxed warning.
Overall, more patients who received donanemab died compared to those on placebo, 17 patients and 10 patients, respectively, or 2.2 percent of treated patients and 1.2 percent of patients in the placebo group. However, other than three ARIA-related mortalities, the deaths did not appear to be linked to the treatment, according to the FDA reviewers.
Lilly suggested recommending APOE testing prior to treatment initiation, MRI scans to monitor patients for ARIA events during early treatment, and providing guidance to physicians on potentially suspending treatment in response to ARIA in certain cases. The company also proposed three post-authorization studies to characterize safety risks associated with the treatment, including ARIA, intracerebral hemorrhage, and serious hypersensitivity reactions.
"With appropriate labeling and management, the potential risks are outweighed by the demonstrated benefits on the clinical endpoints in patients with AD," Lilly wrote.