FDA Expresses Concerns Over Lilly’s Donanemab Alzheimer’s Drug Before Advisory Committee

Before the upcoming FDA advisory committee meeting, internal reviewers at the agency have voiced multiple safety and efficacy concerns regarding Eli Lilly's investigational anti-amyloid antibody, donanemab, which is being considered for the treatment of Alzheimer’s disease.

One primary issue highlighted by the FDA reviewers is Lilly's use of the integrated Alzheimer’s Disease Rating Scale (iADRS) as the primary endpoint in their pivotal trial. The iADRS, developed by Lilly, amalgamates two existing Alzheimer’s clinical scales: 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). It aims to increase sensitivity to treatment effects in early-stage patients. However, the FDA reviewers noted that the agency did not endorse the iADRS over the more widely accepted Clinical Dementia Rating-Sum of Boxes (CDR-SB), typically used as the primary efficacy metric in Alzheimer’s trials.

The FDA briefing document states, “We 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,” referencing minutes from a March 2021 Type C meeting with Lilly. Nonetheless, Lilly’s Phase III data did show a significant improvement in CDR-SB with donanemab treatment.

Another point of contention for the FDA reviewers is Lilly’s criterion for study inclusion based on tau protein levels. Individuals exhibiting none to very low levels of tau protein were excluded from the study, directing the trial’s focus mainly on those with low-to-medium tau levels. The FDA has requested the advisory committee to evaluate the effectiveness of donanemab across subgroups identified by tau PET imaging during Monday’s meeting.

Additionally, the FDA reviewers raised concerns about Lilly’s decision to halt donanemab treatment in patients whose brain amyloid levels fell below a certain pre-defined 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,” the reviewers remarked.

The safety profile of donanemab was also scrutinized. An “imbalance in deaths” among patients treated with donanemab was noted, which could not be fully explained by amyloid-related imaging abnormalities (ARIA) and cerebral hemorrhage. However, the reviewers acknowledged that there was no unusual clustering of deaths indicative of a causal relationship.

The FDA’s Peripheral and Central Nervous System Advisory Committee will gather on Monday to deliberate on these concerns and determine whether the overall risk-benefit profile of donanemab supports its approval.

Despite these issues, William Blair analyst Myles Minter expressed a degree of optimism. In a note to investors, he wrote, “We believe the documents appear bullish on approval with only a low probability of a tau-restricted label.”

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