FDA Grants Donanemab Breakthrough Designation for Alzheimer Disease

Eli Lilly plans on submitting a biologics license application for donanemab under the accelerated approval pathway based on data from the phase 2 TRAILBLAZER-ALZ study.

Eli Lilly has announced that the FDA has granted breakthrough therapy designation for donanemab, its investigational antibody therapy for the treatment of Alzheimer disease (AD). The company also noted that they intend to submit a biologics license application for donanemab under the accelerated approval pathway later this year based on data from the phase 2 TRAILBLAZER-ALZ study.1

The phase 2 trial, which evaluated the efficacy and safety of donanemab in 272 patients with early-stage, symptomatic AD, showed that when compared to placebo, the investigational agent slowed the progression of AD. Improvements in secondary end points measuring cognition and function were observed as well, but did not reach statistical significance.2

In March 2021, when the TRAILBLAZER data were originally announced, Daniel Skovronsky, MD, PhD, chief scientific officer, and president, Lilly Research Laboratories, Eli Lilly, expressed his confidence in the results in a statement from the company. "This is the first late-stage study in Alzheimer's disease to meet its primary endpoint at the primary analysis. Donanemab has the potential to become a very important treatment for Alzheimer's disease. We were pleased to see not only slowing of cognitive and functional decline, but also very substantial clearance of amyloid plaques and slowing of spread of tau pathology," he said at the time.3

Patients treated with donanemab declined 32% slower compared to placebo as assessed by the Integrated Alzheimer’s Disease Rating Scale (iADRS) from baseline to 76 weeks. iADRS is a composite tool combining the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living (ADCS-iADL) for function.

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The difference between the donanemab group and the placebo group in the change from baseline at 76 weeks was −0.36 (95% CI, −0.83 to 0.12) for Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score, −1.86 (95% CI, −3.63 to −0.09) for ADAS-Cog13 score, 1.21 (95% CI, −0.77 to 3.20) for ADCS-iADL score, and 0.64 (95% CI, −0.40 to 1.67) for Mini-Mental State Examination (MMSE) score.

Investigators found that donanemab, by targeting N3pG beta-amyloid, reduced amyloid plaque by an average of 78%, or an 84-centiloid reduction at 76 weeks compared to a baseline of 108 centiloids. Patients were switched to placebo when their plaque level was below 25 centiloids for 2 consecutive measures or below 11 centiloids in 1 measure, indicative of a negative amyloid scan.

In the safety population, 90.8% (n = 119) of the donanemab group and 90.4% (113 of 125) of the placebo group had at least 1 adverse event (AE) during the double-blind intervention period. The incidence of ARIA-E was significantly higher in the donanemab group (26.7%) than in the placebo group (0.8%; P <.001). Symptomatic ARIA-E was reported by 6.1% of all participants in the donanemab group (22% of those with ARIA-E), as compared with 0.8% of all participants in the placebo group.

Patients assessed in TRAILBLAZER-ALZ are still participating in the ongoing follow-up trial TRAILBLAZER-EXT. The safety, tolerability, and efficacy of donanemab are also being evaluated in the ongoing randomized, placebo-controlled, double-blind, multi-center phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511).1

This news follows a flurry of events in the AD therapeutic field in recent weeks, specifically the FDA approval of Biogen's aducanumab (Aduhelm) for the treatment of AD. Notably, the approval was granted through the same accelerated approval pathway that Eli Lilly has declared it intends to pursue for donanemab. The pathway allows the somewhat conditional approval of an agent, and as is the case for Biogen, requires phase 4 confirmatory trial(s) to be conducted to confirm any clinical benefit of the agent.

1. Lilly’s donanemab receives US FDA’s breakthrough therapy designation for treatment of Alzheimer disease. News release. Eli Lilly. June 24, 2021. Accessed June 25, 2021. https://www.prnewswire.com/news-releases/lillys-donanemab-receives-us-fdas-breakthrough-therapy-designation-for-treatment-of-alzheimers-disease-301318931.html
2. Mintun MA, Lo AC, Evans CD, et al. Donanemab in Early Alzheimer’s Disease. N J Med. Published online March 13, 2021. doi: 10.1056/NEJMoa2100708
3. Lilly's donanemab slowed Alzheimer's disease progression in Phase 2 trial: full data presented at AD/PD™ 2021 and published in NEJM. News release. March 13, 2021. Accessed June 25, 2021. https://www.prnewswire.com/news-releases/lillys-donanemab-slowed-alzheimers-disease-progression-in-phase-2-trial-full-data-presented-at-adpd-2021-and-published-in-nejm-301246745.html