Donanemab’s benefits greater for patients in early disease: Trial

Benefits more pronounced in those younger, with mild cognitive impairment

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Eli Lilly’s anti-amyloid therapy donanemab significantly slowed cognitive decline for most people with early Alzheimer’s disease in the Phase 3 TRAILBLAZER-ALZ 2 clinical trial.

The benefits were more pronounced among patients younger than 75 years and among those with mild cognitive impairment (MCI) relative to those with early dementia, according to subgroup analyses of the trial.

Full trial results were reported in the study “Donanemab in Early Symptomatic Alzheimer Disease The TRAILBLAZER-ALZ 2 Randomized Clinical Trial,” which was published in the Journal of the American Medical Association (JAMA).

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Donanemab significantly slows cognitive decline in Phase 3 trial

FDA decision on donanemab expected by year’s end

The data were used by Eli Lilly as the basis for an application asking the U.S. Food and Drug Administration (FDA) to approve the therapy. A regulatory decision is expected by the end of the year, according to the company.

“The positive TRAILBLAZER-ALZ 2 data bring hope to people with Alzheimer’s disease who urgently need new treatment options,” Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience, said in a company press release.

“If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease,” she said.

Alzheimer’s is characterized by toxic clumps of proteins, particularly amyloid-beta and tau, that form in the brain and are thought to play a central role in driving disease.

Donanemab is an antibody-based therapy that’s designed to break up amyloid-beta clumps. Another therapy that targets amyloid-beta, Biogen and Eisai’s Leqembi (lecanemab), became the first-in-class therapy to win full FDA approval to treat Alzheimer’s earlier this month.

The TRAILBLAZER-ALZ 2 trial (NCT04437511) tested donanemab against a placebo in 1,736 people with early Alzheimer’s.

These results demonstrate that diagnosing and treating people earlier in the course of Alzheimer’s disease may lead to greater clinical benefit. The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them.

At the study’s start, all patients either had MCI — meaning they showed Alzheimer’s symptoms, but were still able to function independently in daily life — or early dementia, meaning they needed some day-to-day help but could still perform basic self-care independently.

All participants were positive for amyloid-beta clumps. They were divided into two groups based on tau clump levels: 1,182 patients had low or medium levels of tau, while the remaining 552 had high levels.

The study’s main goal was to assess the treatment’s effects on cognitive and functional ability, as measured by the Integrated Alzheimer’s Disease Rating Scale (iADRS), after about 1.5 years in the group with low to medium tau levels. A number of other standardized measures of cognition were also evaluated as secondary outcomes.

A notable part of the study’s design was that brain amyloid-beta levels were measured at six months and one year. If patients on donanemab were found to have negligible levels, they were switched to a placebo for the remainder of the study.

Little over half (52%) of patients on donanemab stopped active treatment early in this way. According to White, this suggests that some patients on donanemab might be able to stop treatment after as little as six months once clumps are cleared, while still maintaining a clinical benefit.

“Given the high patient burden and anticipated costs of [amyloid-targeting] monoclonal antibodies, a limited duration of therapy might greatly enhance the feasibility of treatment for patients, clinicians, insurers, and health systems,” a pair of scientists at the University of California San Francisco wrote in an editorial published alongside the study in JAMA.

Significantly slower rate of cognitive worsening with donanemab

As announced earlier this year by Eli Lilly, the TRAILBLAZER-ALZ 2 trial met its main and secondary goals. In the subset of patients with low-to-medium tau levels, the rate of cognitive worsening on iADRS was significantly slower with donanemab than with a placebo, by 35.1%.

Donanemab’s superiority was also seen in other cognitive measures and in terms of disease progression — with fewer patients progressing from MCI to mild dementia, or from mild dementia to moderate dementia where patients require help with basic self-care tasks.

However, analyses of patients with high tau showed no notable differences between donanemab and placebo in iADRS or other measures, suggesting that these patients “received little to no clinical benefit [with donanemab] compared with placebo,” the editorial authors wrote.

“These results suggest that, in addition to clinical criteria and [amyloid-beta] biomarker positivity, staging of tau may be critical for identifying patients who would most benefit from [amyloid-beta]-targeting monoclonal antibody therapy,” the scientists added, though they noted that testing for tau might pose a logistical challenge, since many clinics don’t have access to the advanced imaging equipment needed for these tests.

Further subgroup analyses among low-medium tau participants showed that donanemab resulted in slower cognitive decline, by nearly twofold, among patients with mild cognitive impairment relative to those with early dementia. Similar differences were seen between those younger than 75 years and those 75 and older, favoring the younger group.

“These results demonstrate that diagnosing and treating people earlier in the course of Alzheimer’s disease may lead to greater clinical benefit,” said Liana Apostolova, MD, one of the study’s authors and a professor at Indiana University School of Medicine. “The delay of disease progression over the course of the trial is significant and will give people more time to do such things that are meaningful to them.”

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Side effects include brain swelling, bleeding

The most common side effects of donanemab were brain swelling and brain bleeding, which occurred in just over a third (36.8%) of patients. These amyloid-related imaging abnormalities (ARIAs) usually didn’t cause overt problems, but in rare cases they were serious — including three patients who died after developing these complications.

ARIA’s rate was notably higher among patients carrying APOE4, the strongest genetic risk factor of Alzheimer’s. Increased risk of ARIA events among APOE4 carriers also has been reported for other amyloid-targeting therapies.

“While ARIA has generally been managed safely in clinical trials, caution will be needed as [amyloid-beta]-targeting monoclonal antibody treatments are translated into clinical practice,” the editorial authors wrote, emphasizing the need for monitoring and risk-mitigation strategies.

They also noted that “clinical APOE genotyping is recommended to assess the risk of ARIA prior to [amyloid-beta]-targeting monoclonal antibody treatment.”

Collectively, these findings represent “an important start, and may be deemed clinically meaningful for some patients,” the editorial authors wrote, emphasizing, however, that “development of more impactful and safer treatments is still needed.”

“Despite these caveats, the field is making steady progress and gaining momentum in the fight against [Alzheimer’s],” they wrote. “The emergence of [amyloid-beta]-targeting monoclonal antibodies may prove to be just the opening chapter in a new era of molecular therapies for [Alzheimer’s] and related neurodegenerative disorders.”