Donanemab significantly slows cognitive decline in Phase 3 trial

Eli Lilly set to ask FDA to approve therapy for early Alzheimer’s

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Donanemab significantly slowed the decline of cognitive and functional abilities in people with early Alzheimer’s disease, according to top-line data from a Phase 3 clinical trial.

Based on these findings, Eli Lilly, its developer, plans to ask the U.S. Food and Drug Administration (FDA) to approve it within the next months.

“These Phase 3 data … 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 of Eli Lilly, said in a company press release.

The findings came from a Phase 3 trial, called TRAILBLAZER-ALZ 2 (NCT04437511) that tested donanemab against a placebo in patients with early Alzheimer’s disease. Its primary aim was to assess the impact of treatment on the Integrated Alzheimer’s Disease Rating Scale (iADRS) score, a measure of cognitive and functional abilities, after about 18 months.

The main analysis included 1,182 patients with intermediate levels of the Alzheimer’s protein biomarker tau. In this group, the rate of iADRS decline was significantly lower — by 35% — in those given donanemab over a placebo.

“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 Eli Lilly.

Scores on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a measure of cognitive functioning, also declined at a significantly slower rate — by 36% — with donanemab. After a year, nearly half (47%) of the patients on donanemab had no worsening in CDR-SB scores compared to less than a third (29%) on a placebo.

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Donanemab with high tau levels, on other measures of ability

The study also enrolled 552 people with higher tau levels, who, according to Eli Lilly, are expected to have faster disease progression and show a poorer response to anti-amyloid treatment.

In analyses of all 1,736 patients, the rate of decline on iADRS was significantly lower, by 22%, with donanemab. Similarly, the CDR-SB decline was 29% slower in those on donanemab than a placebo.

Other standardized measures of functional ability, including the Alzheimer’s Disease Cooperative Study- instrumental Activities of Daily Living Inventory (ADCS-iADL) and the 13-item Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog13), also showed a statistically significant progression slowdown with donanemab.

These differences were generally more heightened in the primary analysis group with intermediate tau compared with the overall population, but the difference between donanemab and a placebo was statistically significant for all these outcomes in the primary analysis group and the total population.

This is the first Phase 3 trial of any investigational medicine for Alzheimer’s disease to deliver 35% slowing of clinical and functional decline.

“We are extremely pleased that donanemab yielded positive clinical results with compelling statistical significance for people with Alzheimer’s disease in this trial,” Skovronsky said.

Donanemab and therapies in its class are known to cause a potential side effect called amyloid-related imaging abnormalities (ARIA), which are marked by swelling (ARIA-E) and/or bleeding (ARIA-H) in the brain.

Safety data from the Phase 3 study were consistent with earlier trials, with 24% of patients given the experimental therapy having ARIA-E, and 31.4% ARIA-H. Most cases were mild to moderate and were managed without serious issues.

ARIA usually doesn’t cause symptoms, but in some cases it can be severe. Severe ARIA occurred in 1.6% of patients on donanemab. Two patients died as a result of this side effect and a third died after a serious ARIA incident.

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Reactions from Alzheimer’s community

The findings were met with excitement by the Alzheimer’s community.

“These are the strongest phase 3 data for an Alzheimer’s treatment to date,” Maria Carrillo, PhD, chief science officer of the Alzheimer’s Association, said in a statement.

Donanemab is an antibody-based therapy designed to clear amyloid plaques, a type of toxic protein clump that’s thought to drive the disease.

Biomarker data from the study suggest donanemab cleared amyloid plaques, as designed. In the primary analysis group, 71% of the patients given donanemab showed signs of amyloid clearance after a year on it.

“These data are another proof point that amyloid-targeting drugs are a first step to slowing cognitive and functional decline, providing a clinically meaningful benefit to patients,” Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation (ADDF), said in a separate press release.

Two other amyloid-targeting therapies — Leqembi (lecanemab) and Aduhelm (aducanumab), both developed by Eisai and Biogen — have received accelerated approval from the FDA. Accelerated approval lets the FDA give conditional marketing authorization based on early clinical data that suggests a therapy is likely to be effective. Leqembi is being considered for traditional approval, with a decision expected in July.

These are the strongest phase 3 data for an Alzheimer’s treatment to date.

The FDA rejected an application for donanemab’s accelerated approval earlier this year on the basis that early clinical data didn’t cover the expected number of patients.

Although Aduhelm and Leqembi are already FDA-approved under the accelerated pathway, Medicare — the government-funded program that insures elderly people in the U.S. — has adopted a policy that narrowly provides coverage for amyloid-targeting therapies for people in clinical trials. This decision has been met with outrage in the Alzheimer’s community and advocates are looking at how this could affect donanemab, if it’s approved.

“The progress we’ve seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease. Yet, Medicare stubbornly continues to block access for the people who could benefit,” Carrillo said.

“We believe our data meets the ‘high level of evidence’ the Centers for Medicare & Medicaid Services has described as the trigger for reconsideration of its National Coverage Determination. People with early Alzheimer’s disease need and deserve full coverage and access for approved therapies,” White said.

The full results from TRAILBLAZER-ALZ 2 will be presented at a conference this year and submitted for publication in a peer-reviewed journal, according to Eli Lilly.

“We look forward to additional data from the TRAILBLAZER-ALZ2 trial … including data on participant safety and representation. If those data are consistent with what we saw today regarding efficacy and safety, we strongly support FDA approval and, if approved, we expect CMS and other private insurance coverage,” Carrillo said.