Donanemab Significantly Slows Cognitive, Functional Decline in Early Alzheimer Disease

Donanemab, an investigational amyloid plaque-targeting therapy in development by Eli Lilly and Company (Lilly), significantly slowed cognitive and functional decline in a phase 3 study of early symptomatic Alzheimer disease, meeting the study’s primary endpoint, according to a Lilly news release.

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Nearly half (47%) of participants in the TRAILBLAZER-ALZ 2 study treated with donanemab displayed no clinical disease progression at the 1-year follow-up compared with 29% of those treated with placebo.

Further, treatment with donanemab slowed participants’ clinical decline by 35% over 18 months compared to placebo and was associated with a 40% less decline in participants’ ability to perform activities of daily living (ADL), Lilly stated. Moreover, donanemab-treated participants had a 39% lower risk of progressing to the next stage of disease.

“This is the first phase 3 trial of any investigational medicine for Alzheimer's disease to deliver 35% slowing of clinical and functional decline," said Daniel Skovronsky, MD, PhD, chief scientific and medical officer at Lilly, and president of Lilly Research Laboratories.

Based on these findings, a new drug application submission to the US Food and Drug Administration may come as early as this quarter, the company said.

The TRAILBLAZER-ALZ 2 primary endpoint was change from baseline until 18 months on the integrated Alzheimer Disease Rating Scale (iARDS), a measure of cognition and ADL such as driving, managing finances, and conversing about current events. The randomized, placebo-controlled TRAILBLAZER-ALZ 2 also met all secondary endpoints of cognitive and functional decline, with statistically significant clinical benefits of similar magnitude, according to the release.

TRAILBLAZER-ALZ 2

The primary analysis population in TRAILBLAZER-ALZ 2 numbered 1182 and was comprised of participants with an intermediate level of the predictive biomarker tau and clinical symptoms of the disease. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (P<.001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes) showed 36% slowing of decline (P<.001) over 18 months.

When investigators evaluated a cohort that combined participants with high tau levels and the original group with intermediate tau levels, meaningful positive results persisted with donanemab across all clinical endpoints (P<.001).

Donanemab also was associated with significant reductions in levels of brain amyloid plaque and as early as 6 months after treatment began, Lilly’s release noted. Specifically, many donanemab-treated participants achieved amyloid levels considered negative for pathology with 34% of the intermediate tau population reaching amyloid clearance at 6 months and 71% reaching the mark at 12 months.

-- Anne White, Lilly EVP

These findings, according to Lilly head of neuroscience R&D Mark Mintun, “suggest that people in the early pathological stage of disease could be the most responsive to therapeutics targeting amyloid."

"Amyloid plaque is a defining pathophysiological feature of Alzheimer's disease," said Dr. Eric Reiman, CEO of Banner Research, one of the research sites for the TRAILBLAZER-ALZ 2 trial. "This study's topline results provide compelling support for the relationship between amyloid plaque removal and a clinical benefit in people with this disease."

Safety results

Regarding safety, Lilly reported the incidence of amyloid-related imaging abnormalities was consistent with the previous TRAILBLAZER study, citing ARIA-E, related to brain swelling in 24% of treated participants, with 6.1% experiencing symptoms. ARIA-H, associated with microhemorrhages, was observed in 31.4% of treated patients and 13.6% of those who got placebo. Lilly notes that while typically asymptomatic ARIA can be serious and life-threatening. Serious ARIAs occurred in 1.6% of the study population, including 2 participants whose death was attributed to ARIA and a third participant who died after an incident of serious ARIA.

"These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them,” Anne White, executive vice president, Eli Lilly, and president of Lilly Neuroscience, said in the Lilly statement.

Lilly said that it will present the full results of the study at the Alzheimer’s Association International Conference in July and submit the data to a peer-reviewed publication.