Eli Lilly’s experimental drug donanemab slowed the progression of Alzheimer’s by 60% for patients in the earliest stages of the brain-wasting disease, according to the latest trial data presented this week, nearly twice the rate reported in May for the trial’s overall group. However, side effects – like swelling of the brain – were still a worry.
The full analysis of the trial, known as Trailblazer ALZ-2, showed results were less robust for older, later-stage patients, as well as those with higher levels of a protein called tau that has been linked to Alzheimer’s disease progression.
The study also showed brain swelling, a known side effect of drugs such as donanemab, occurred in more than 40% of patients with a genetic predisposition to develop Alzheimer’s, reports BusinessLIVE.
The company had previously reported that 24% of the overall donanemab treatment group had brain swelling. Brain bleeding occurred in 31% of the donanemab group and about 14% of the placebo group.
The deaths of three trial patients had been linked to the treatment, researchers reported.
“These side effects should not be taken lightly but most cases were manageable by monitoring with magnetic resonance imaging (MRI) or stopping the drug,” said study investigator Dr Liana Apostolova, professor in Alzheimer’s Disease research at Indiana University School of Medicine.
Doctors are likely to use “very stringent MRI safety screening while we treat these patients”, she said.
Donanemab, like Eisai and Biogen’s recently approved Leqembi, is an intravenous antibody designed to remove deposits of a protein called beta amyloid from the brains of Alzheimer’s patients.
Lilly said donanemab’s treatment effect continued to increase relative to placebo over the course of the 18-month trial, even for participants who had been taken off the drug after their levels of amyloid deposits fell significantly.
“At the end of the trial, the average patient had been without the drug for seven months and yet continued to benefit,” said Anne White, an executive vice-president at Eli Lilly and president of Lilly Neuroscience.
She said the findings support the idea that donanemab can be stopped once amyloid is cleared from the brain.
Lilly said in May that the study had met all of its goals, showing that donanemab slowed cognitive decline by 29% compared with a placebo in 1 182 people with mild cognitive impairment or mild dementia whose brains had deposits of two key Alzheimer’s proteins, beta amyloid and tau.
For high tau patients, donanemab was shown to slow disease progression by about 17%, while the benefit was 35% for those with low-to-intermediate tau levels.
The full study results were presented at the Alzheimer’s Association International Conference in Amsterdam and published in JAMA.
Lilly expects the US Food and Drug Administration to decide by year-end whether to approve donanemab. It said submissions to other global regulators are under way, and most would be completed by within six months.
This month the FDA granted standard approval to Leqembi, the first Alzheimer’s disease-modifying treatment to achieve that goal, clearing the way for wider insurance coverage of the drug.
Health leaders have hailed the arrival of the drugs as a turning point in the fight against Alzheimer’s, through which the disease could become just as manageable as conditions like diabetes or asthma.
Dr Susan Kohlhaas, the executive director of research and partnerships at Alzheimer’s Research UK, said it was critical for regulators to act promptly to avoid patients experiencing frustrating waits for clinically effective treatments.
“We now have two potentially life-changing Alzheimer’s treatments on the horizon and we need to see rapid regulatory decisions so people who could benefit from these treatments aren’t left in limbo,” she said.
The health spending watchdog in England, the National Institute for Health and Care Excellence, said this week it had already begun assessing whether donanemab could be used in the NHS, reports The Guardian.
Before Nice can give the drug the green light for NHS use, Eli Lilly must also gain approval from the UK medicines regulator, the Medicines and Healthcare products Regulatory Agency.
Alzheimer’s, the most common cause of dementia, is one of the world’s biggest health threats. The number of people living with dementia globally is forecast to nearly triple to 153m million by 2050.
Study details
Donanemab in Early Symptomatic Alzheimer Disease:The TRAILBLAZER-ALZ 2 Randomized Clinical Trial
John Sims, Jennifer Zimmer, Daniel Skovronsky, et al for the TRAILBLAZER-ALZ 2 Investigators
Published in JAMA Network on 17 July 2023
Key Points
Question Does donanemab, a monoclonal antibody designed to clear brain amyloid plaque, provide clinical benefit in early symptomatic Alzheimer disease?
Findings In this randomised clinical trial that included 1736 participants with early symptomatic Alzheimer disease and amyloid and tau pathology, the least-squares mean change in the integrated Alzheimer Disease Rating Scale score (range, 0-144; lower score indicates greater impairment) at 76 weeks was −6.02 in the donanemab group and −9.27 in the placebo group for the low/medium tau population and −10.19 in the donanemab group and −13.11 in the placebo group in the combined study population, both of which were significant differences.
Meaning Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab treatment significantly slowed clinical progression at 76 weeks.
Abstract
Importance
There are limited efficacious treatments for Alzheimer disease.
Objective
To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.
Design, Setting, and Participants
Multicentre (277 medical research centres/hospitals in 8 countries), randomised, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).
Interventions
Participants were randomised in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.
Main Outcomes and Measures
The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.
Results
Among 1736 randomised participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.
Conclusions and Relevance
Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.
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