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Donanemab FDA AdComm Hearing Scheduled for June 10, Eli Lilly Says
The AdComm plans to review data from the TRAILBLAZER-ALZ 2 phase 3 clinical trial that served as the foundation for Eli Lilly's original BLA submission to the FDA.
Months after the original announcement of a pending meeting, Eli Lilly has announced that the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee (PCNS) will convene on June 10, 2024, to discuss the new drug application of donanemab, an investigational antiamyloid therapy in development for early-stage Alzheimer disease (AD).1
The committee will review data from the supportive phase 3 TRAILBLAZER-ALZ 2 trial (NCT04437511) to determine whether there is sufficient evidence to warrant recommendation for approval. TRAILBLAZER-ALZ 2, a double-blind, placebo-controlled trial led by Daniel M. Skovronsky, MD, PhD, executive vice president of science and technology at Eli Lilly, enrolled 1736 participants across 8 countries to assess the efficacy and safety of donanemab in participants age 60-85 with early symptomatic AD.
TRAILBLAZER-ALZ 2 follows the phase 2 TRAILBLAZER-ALZ study (NCT03367403), which served as the basis for the original biologics license application of donanemab. In January 2023, the FDA issued a complete response letter to Eli Lilly for its submission of donanemab, stating that the company needed to provide data from at least 100 patients who received a minimum of 12 months of continuous treatment with donanemab. At the time, the agency indicated that the data to meet the exposure expectation would likely need to include unblinded safety data from TRAILBLAZER-ALZ 2 upon completion.
Eli Lilly was originally supposed to hear a decision on donanemab in the first quarter of 2024; however, announcement of the AdComm meeting has delayed timing of the decision. To date, the PDUFA action date has not been rescheduled for a decision on donanemab, although typically decisions are made 1 or 2 months following an AdComm meeting.
If approved, donanemab, a humanized IgG1 monoclonal antibody, would be the third antiamyloid therapy to gain FDA greenlight, following aducanumab (Aduhelm; Biogen) in 2021, and lecanemab (Leqembi; Eisai) in 2023. Of note, earlier this year, aducanumab was pulled from market. Since its controversial approval, there had been concerns with access to the drug and with its true therapeutic efficacy and safety for treatment of patients with AD.2 Antiamyloid therapies, considered disease-modifying in nature, work by attaching to and removing amyloid-ß, a protein that accumulates into plaques, from the brain. Each drug works differently and targets amyloid-ß at a different stage of plaque formulation.
TRAILBLAZER-ALZ-2
In TRAILBLAZER-ALZ 2, among 1736 participants randomly assigned to donanemab or placebo, 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. Overall, the least-squares mean (LSM) change in integrated Alzheimer’s Disease Rating Scale score, the primary end point, at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population.
At 76 weeks, the LSM change in Clinical Dementia Rating-Sum of Boxes score was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population.
Amyloid-related imaging abnormalities (ARIA), a concern for antiamyloid therapies, occurred in 205 participants (24.0%; 52 symptomatic during the study) in the donanemab group and 18 (2.1%; 0 symptomatic) in the placebo group and infusion related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were also considered treatment related.
