More than half of patients with Alzheimer disease administered donanemab showed a significantly reduced cognitive and functional decline.
Eli Lilly announced that donanemab stopped the clinical progression of Alzheimer disease (AD) at 1 year in 47% of participants in the phase 3, double-blind, placebo-controlled TRAILBLAZER-ALZ 2 study. In the trial, donanemab met the primary endpoint of change from baseline until 18 months on the integrated Alzheimer's Disease Rating Scale (iADRS) and secondary endpoints of cognitive and functional decline, measured in Clinical Dementia Rating-Sum of Boxes (CDR-SB).
"Amyloid plaque is a defining pathophysiological feature of Alzheimer's disease," said Eric Reiman, CEO, Banner Research, in a press release. "This study's topline results provide compelling support for the relationship between amyloid plaque removal and a clinical benefit in people with this disease."
Donanemab is an investigational antibody that targets a modified form of beta amyloid plaque called N3pG. It was granted FDA Breakthrough Therapy designation in June 2021 based on phase 2 trial data, and 2 presentations at the Alzheimer’s Association International Conference suggest more encouraging results, according to an Eli Lilly press release.
Investigators conducted TRAILBLAZER-ALZ 2 (NCT04437511) to evaluate the safety and efficacy of donanemab in 1736 patients aged 60 to 85 years with confirmed AD neuropathology and who are experiencing mild cognitive impairment (MCI) or mild dementia (early symptomatic AD).
Patients with amyloid plaque and an intermediate level of brain protein tau— a predictive biomarker of AD progression—and clinical AD symptoms were in the primary analysis group. They completed donanemab treatment once achieving a prespecified level of amyloid plaque clearance.
Amyloid positron emission tomography (PET) brain scans showed that donanemab significantly decreased brain amyloid plaque levels at 6 months of treatment. After 12 months of treatment, a prespecified secondary analysis showed that 71% of patients with intermediate tau levels had no amyloid plaque, 52% of patients completed treatment, and 47% of participants had no clinical progression compared to 29% of placebo.
At 18 months, 72% had completed treatment because of plaque clearance, 40% had a slower decline in ability to perform daily living activities (as measured by iARDS), and 36% had slower decline on the CDR-SB scale.
In an analysis of amyloid-related imaging abnormalities (ARIA), which can include temporary swelling in an area or areas of the brain (ARIA-E) or microhemorrhages or superficial siderosis (ARIA-H), most were mild to moderate and appropriately managed. In TRAILBLAZER-ALZ 2, 24% of treated participants experienced ARIA-E and 31.4% experienced ARIA-H; serious incidence occurred in 1.6% of treated patients.
Lilly plans to submit donanemab for FDA regulation during this quarter. They are working with other regulators for fast global approval as well.
"We are encouraged by the potential clinical benefits that donanemab may provide," said Mark Mintun, MD, group vice president Neuroscience Research & Development at Lilly, and president of Avid Radiopharmaceuticals, in the press release. “These results suggest that people in the early pathological stage of disease could be the most responsive to therapeutics targeting amyloid.”
Eli Lilly and Company. Lilly's Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer's Disease. News Release. May 3, 2023. Accessed on May 3, 2023. https://investor.lilly.com/news-releases/news-release-details/lillys-donanemab-significantly-slowed-cognitive-and-functional