Two new exploratory analyses from the phase 2 TRAILBLAZER-ALZ study have suggested a relationship between reduced amyloid plaque in the brain and slowed cognitive decline among patients with Alzheimer disease receiving the investigational drug donanemab.
According to a press release from Eli Lilly and Co, donanemab is an 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 new presentations at the Alzheimer’s Association International Conference suggest more encouraging results, according to an Eli Lilly press release.
Participants in the TRAILBLAZER-ALZ study received donanemab 700 mg every 4 weeks for the first 3 doses, followed by 1400 mg every 4 weeks for up to 76 weeks. Planned blinded dose reduction evaluations occurred at 24 and 52 weeks.
In the first presentation, donanemab induced rapid amyloid plaque reduction at 24 weeks in patients with early symptomatic Alzheimer disease, with the most rapid clearance in patients with the most severe plaque burden at baseline. Participants who achieved complete amyloid plaque clearance at 24 weeks were able to stop or reduce donanemab dosing earlier than other patients.
Among participants who achieved complete amyloid plaque clearance at 24 weeks and had a blinded switch to placebo, researchers observed minimal amyloid re-accumulation over the next year. Furthermore, among patients who reached early complete amyloid plaque clearance status at 24 weeks, brain scans at 76 weeks showed a significant decrease of tau spread—a predictive biomarker for Alzheimer’s disease progression—over 76 weeks in the frontal, parietal, and temporal brain regions.
Patients with greater amyloid plaque change at 24 weeks also saw improved scores on the Integrated Alzheimer’s Disease Rating Scale (iADRS), which is used to assess cognition and daily function. Pharmacokinetic and pharmacodynamic modeling also showed that greater relative amyloid plaque clearance was associated with a greater clinical benefit.
“We are excited by these promising results, which provide further evidence on the potential for donanemab to slow disease progression for people with early symptomatic Alzheimer’s disease,” said Mark Mintun, MD, vice president of pain and neurodegeneration at Lilly, in the press release. “Importantly, these data link the mechanism of action of donanemab, plaque clearance, with positive effects on both clinical outcomes and brain tau pathology.”
The second oral presentation discussed plasma tau phosphorylated at threonine 217 (P-tau217), which is a research blood biomarker associated with amyloid and tau pathology and diagnosis of Alzheimer disease. According to the press release, planned analyses found that treatment with donanemab resulted in early reduction of P-tau217 and showed significant reduction by the 3-month timepoint compared to individuals receiving the placebo. Decreased P-tau217 was significantly associated with amyloid change at all timepoints, at 24 weeks, and at 76 weeks.
“Notably, these data support the amyloid cascade hypothesis and suggest that amyloid-related tauopathy can be altered with donanemab’s impact on plaque clearance,” said John Sims, MD, senior medical director of neurodegeneration at Lilly and co-author of the analysis, in the press release. “Furthermore, the data support that early and profound amyloid clearance may translate into clinical benefit for patients.”
Donanemab is also being investigated for patients with early, symptomatic Alzheimer disease in the TRAILBLAZER-ALZ 2 study, whereas the TRAILBLAZER-ALZ 3 study is planned to investigate whether donanemab can prevent the clinical progression of Alzheimer disease before clinical impairment begins.
Lilly releases donanemab data that demonstrated relationship between reduction of amyloid plaque and slowing of cognitive decline. News release. Eli Lilly and Co; July 29, 2021. Accessed August 3, 2021. http://lilly.mediaroom.com/2021-07-29-Lilly-releases-donanemab-data-that-demonstrated-relationship-between-reduction-of-amyloid-plaque-and-slowing-of-cognitive-decline