In advance of an advisory committee meeting on Monday, the FDA’s internal reviewers have raised issues regarding Eli Lilly’s Alzheimer’s disease candidate donanemab, flagging problems with its study design and safety outcomes.
In a briefing document ahead of Monday’s FDA advisory committee meeting, the agency’s internal reviewers have raised several safety and efficacy questions that the agency has surrounding Eli Lilly’s investigational anti-amyloid antibody donanemab, which the pharma is proposing as a treatment for Alzheimer’s disease.
Among the issues of concern, the regulator’s staffers flagged Lilly’s use of the integrated Alzheimer’s Disease Rating Scale (iADRS) as the primary endpoint in its pivotal trial.
Developed by Lilly, the iADRS combines two existing clinical scales for Alzheimer’s—the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog 13) and the Alzheimer’s Disease Cooperative Study-instrumental Activities of Daily Living Subscale (ADCS-iADL)—and is designed to be more sensitive to treatment effect in patients with early-stage disease.
However, the FDA’s reviewers noted that the agency did not sign off on the use of iADRS in place of Clinical Dementia Rating-Sum of Boxes (CDR-SB), which is the more accepted standard primary efficacy metric used in Alzheimer’s trials.
“’[W]e do not agree that a statistically significant treatment effect on the iADRS, unaccompanied by a valid statistically significant treatment effect on its two components, is acceptable for use as a primary efficacy assessment,’” the FDA briefing document states, citing the minutes of a March 2021 Type C meeting with Lilly.
Still, Lilly’s Phase III data showed that donanemab treatment led to a significant improvement in CDR-SB.
The FDA’s reviewers in the briefing document also took issue with Lilly’s use of tau protein levels to decide study inclusion. Patients with none to very low levels of tau were excluded from Lilly’s study, with the pharma’s trial focusing mainly on those with low-to-medium levels.
In consideration of the study’s patient population, the FDA is asking the advisory committee in Monday’s meeting to assess Lilly’s data to back donanemab’s “effectiveness across the subgroups based on tau PET imaging.”
The FDA’s briefing document also flagged Lilly’s decision to stop donanemab treatment in patients whose brain amyloid levels dropped past a certain, pre-specified threshold.
“Although participants appeared to show benefit compared to the overall placebo arm after dosing was stopped, there is not an adequate comparator group and there is no information on outcomes in similar participants if they had continued dosing,” according to the FDA reviewers.
In addition to efficacy concerns, the FDA’s briefing document also pointed to an “imbalance in deaths” in patients treated with donanemab. This excess mortality “cannot be completely explained” by amyloid-related imaging abnormalities (ARIA) and cerebral hemorrhage, though the agency’s reviewers conceded that “there was no unusual grouping of deaths that would suggest a causal relationship.”
The FDA’s Peripheral and Central Nervous System Advisory Committee will convene on Monday to discuss these issues and decide whether donanemab’s overall risk-benefit profile is favorable.
Despite the FDA’s concerns, William Blair analyst Myles Minter found reason for optimism in a note to investors. “We believe the documents appear bullish on approval with only a low probability of a tau-restricted label,” he wrote.
Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.
