The follow-up TRAILBLAZER-EXT and broader population TRAILBLAZER-ALZ 2 studies are currently ongoing.
Eli Lilly has announced results from its randomized, placebo-controlled, double-blind, multi-center phase 2 TRAILBLAZER-ALZ study (NCT03367403) investigating donanemab for slowing the progression of Alzheimer disease. When compared to placebo, patients treated with donanemab showed a significantly slower decline in cognition and daily function.1
Patients treated with donanemab declined 32% slower compared to placebo as assessed by the Integrated Alzheimer's Disease Rating Scale (iADRS) from baseline to 76 weeks. Donanemab also showed consistent improvements in secondary end points measuring cognition and function as compared to placebo, but not all of these endpoints reached statistical significance.
Lilly added that the full results of the trial will be presented at a future medical congress and published in a peer-reviewed clinical journal.
"We are extremely pleased about these positive findings for donanemab as a potential therapy for people living with Alzheimer's disease, the only leading cause of death without a treatment that slows disease progression,” Mark Mintun, MD, vice president, pain and neurodegeneration, Eli Lilly, said in a statement. “We look forward to discussing the TRAILBLAZER-ALZ study data and next steps with global regulators. In addition, we are committed to reproducing and extending these important findings in our second ongoing pivotal donanemab trial, TRAILBLAZER-ALZ 2."
The study enrolled 272 patients with early-stage Alzheimer disease, based on cognitive assessments, amyloid plaque imaging, and tau imaging. During the study, patients were assessed with iADRS, which is a composite tool combining the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog13) and the Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living (ADCS-iADL) for function.
The study’s secondary end points include changes from baseline to 76 weeks in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), ADCS-iADL, Mini-Mental State Exam (MMSE), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores. Biomarkers such as amyloid deposition and brain tau deposition were also assessed as secondary outcomes.
Investigators found that donanemab, by targeting N3pG beta amyloid, reduced amyloid plaque by an average of 78%, or an 84 centiloid reduction at 76 weeks compared to a baseline of 108 centiloids. Patients were switched to placebo when their plaque level was below 25 centiloids for 2 consecutive measures or below 11 centiloids in 1 measure, indicative of a negative amyloid scan.1,2
The safety profile of donanemab was consistent with what was observed in phase 1 data. Amyloid-related imaging abnormalities (ARIA) were observed as expected with amyloid plaque clearing antibodies. ARIA-edema (ARIA-E) occurred in 27% of patients treated with donanemab, 6% of which were symptomatic cases.
Daniel Skovronsky, MD, PhD, chief scientific officer and president, Lilly Research Laboratories, said in a statement that "this unique mechanism and antibody for clearing plaques, discovered at Lilly, has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing. In conjunction with our expertise in amyloid and tau imaging, this allowed us to conduct a trial to test if reducing amyloid plaques in Alzheimer's patients to levels seen in scans of healthy individuals could result in clinically meaningful slowing of cognitive decline. The positive results we have obtained today give us confidence in donanemab and support its rapid and deep plaque clearance for the potential treatment of Alzheimer's disease."
Patients assessed in TRAIBLAZER-ALZ are still participating in the ongoing follow-up trial TRAILBLAZER-EXT. The full results of TRAILBLAZER-ALZ will be presented at a future medical congress and submitted for publication in a peer-reviewed clinical journal. Eli Lilly noted it will seek to pursue next steps for regulatory approval of donanemab.
A second randomized, placebo-controlled, double-blind, multi-center phase 2 study, TRAILBLAZER-ALZ 2 (NCT04437511), was initiated in June 2020 to further evaluate the safety, tolerability, and efficacy of donanemab. TRAILBLAZER-ALZ 2 will also assess patients with high levels of tau, unlike TRAILBLAZER-ALZ, which only assessed early-stage Alzheimer patients with low-to-mid levels of tau. The primary endpoint for TRAILBLAZER-ALZ 2 is Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score at 18 months, and topline results are expected in March 2023.