Eli Lilly Initiates Rolling Submission for Donanemab in Early Alzheimer Disease


The company is planning to enroll patients in a phase 3 head-to-head study comparing donanemab to aducanumab (Aduhelm; Biogen) to assess superiority of brain amyloid clearance.

Daniel Skovronsky, MD, PhD

Daniel Skovronsky, MD, PhD

According to a company-wide update, Eli Lilly has announced that they have initiated rolling submission of a biologics license application (BLA) for donanemab, an investigational antibody therapy, to the FDA for accelerated approval in early Alzheimer disease (AD). Additionally, the company announced plans to conduct TRAILBLAZER-ALZ 4, a phase 3 head-to-head trial comparing donanemab to aducanumab (Aduhelm; Biogen), the most recently approved disease-modifying therapy (DMT) for patients with early AD.1

In June, the company announced that the FDA had granted breakthrough therapy designation for donanemab, along with the idea that they were planning of submitting a BLA.2 The basis for the decision was data from the phase 2 TRAILBLAZER-ALZ study, which showed that when compared to placebo, donanemab slowed the progression of AD.

At the time of the original data announcement, 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.3 "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."

The phase 2 trial, which evaluated the efficacy and safety of the investigational agent in 272 patients with early-stage, symptomatic AD, showed a 32% slower decline on the Integrated Alzheimer’s Disease Rating Scale (iADRS) compared to placebo from baseline to 76 weeks. Furthermore, 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.4

READ MORE: Aducanumab’s Clinical Use in Alzheimer Disease Appears Limited Post-Approval

The difference between donanemab and placebo in the change from baseline in Clinical Dementia Rating Scale–Sum of Boxes score was –0.36 (95% CI, –0.83 to 0.12). Additionally, the difference between groups was –1.86 (95% CI, –3.63 to –0.09) on Alzheimer’s Disease Assessment Scale–Cognitive subscale, 1.21 (95% CI, –0.77 to 3.20) for Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living, and 0.64 (95% CI, –0.40 to 1.67) for Mini-Mental State Examination score.

Lilly seeks to have donanemab approved under the same accelerated pathway that Biogen’s aducanumab was greenlit. Aducanumab’s approval in June represented a major step for the AD community, as it became the first novel DMT approved for the treatment of this disease since 2003. Under the Accelerated Approval pathway, Biogen is required to conduct post-approval phase 4 studies to confirm the benefit of the drug, for which some have already been announced.

Enrollment for TRAILBLAZER-ALZ 4, which will compare donanemab’s ability to clear brain amyloid plaque to aducanumab, is expected to begin this year. The company has not released any information on the specifics of the trial, including target enrollment and when updates may become available.1

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, multicenter phase 3 TRAILBLAZER-ALZ 2 study (NCT04437511).

1. Lilly reports robust third-quarter 2021 financial results as pipeline success strengthens future growth potential. News release. October 26, 2021. Accessed October 26, 2021. https://investor.lilly.com/news-releases/news-release-details/lilly-reports-robust-third-quarter-2021-financial-results
2. 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
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
4. 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
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