FDA Scrutinizes ARIA, Tau, Dosing for Lilly's Alzheimer's Drug

Eli Lilly's pursuit of approval for its experimental Alzheimer's drug, donanemab, is entering a critical phase next week. The pharmaceutical company will present its case to a panel of external advisors at the FDA, aiming to make donanemab the third amyloid-targeting treatment approved for Alzheimer's since 2021.

In preparation for the June 10 meeting, FDA staff released briefing documents, highlighting safety concerns despite no efficacy issues. One primary concern is the risk of amyloid-related imaging abnormalities (ARIA), a side effect associated with amyloid-targeting therapies.

The TRAILBLAZER-ALZ 2 study, which lasted 18 months, showed that 24% of patients on donanemab experienced cerebral edema (ARIA-E) and 31.4% had cerebral microhemorrhages (ARIA-H). These rates are higher than those observed with Leqembi (12.6% and 17.3%, respectively), another Alzheimer's drug approved last July. Most ARIA cases in the study were asymptomatic, but there were serious incidents, including two deaths directly linked to the condition and another subsequent death.

Leqembi already carries a warning about brain swelling and bleeding risks, recommending regular MRIs for patient monitoring. Stifel analyst Paul Matteis pointed out that the key issue for donanemab could be whether more frequent MRIs are needed compared to Leqembi.

FDA reviewers also observed an "imbalance" in mortality rates, with 17 deaths among donanemab users versus 10 for placebo. After providing additional data, Eli Lilly showed 19 deaths in the donanemab group (2.3%) compared to 16 in the placebo group (1.9%) within 76 weeks of starting the treatment. Despite this adjustment, around 10% of participants still lacked vital status information. Apart from ARIA-related deaths, other fatalities did not seem to be directly related to donanemab, according to FDA staff.

Another noteworthy point is the inclusion criteria regarding tau protein. Unlike Leqembi's study, donanemab's trial required participants to show positive tau levels on PET scans. Two subgroups were analyzed based on tau imaging: those with low/medium tau levels and the broader group including patients with high tau levels. Despite this, Lilly did not propose confirming tau pathology in its prescribing information, leading the FDA to question if efficacy should be limited to the tested population.

The FDA also seeks guidance on Lilly's dosing strategy, which permits stopping donanemab once amyloid plaques reduce to a certain level on PET scans. Lilly suggested that further dosing might not be necessary to sustain clinical benefits after reaching this reduction. However, the FDA wants the advisory panel to deliberate if scientific or clinical evidence supports continued or discontinued dosing after amyloid reduction.

Efficacy-wise, donanemab showed a 29% reduction in cognitive and functional decline in the TRAILBLAZER-ALZ 2 study, comparable to Leqembi's 27% reduction. RBC Capital Markets analyst Brian Abrahams noted that while FDA comments might lean slightly in favor of Leqembi due to fewer side effects, the agency still seems inclined to approve donanemab.

The upcoming FDA advisory panel meeting will be crucial for Eli Lilly's donanemab, potentially paving the way for its approval as a new Alzheimer's treatment.