TORONTO – Eli Lilly and Company presented full results from the Phase 3 TRAILBLAZER-ALZ 2 study showing that donanemab significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease (AD). The data were shared at the 2023 Alzheimer’s Association International Conference (AAIC) as a featured symposium and simultaneously published in the Journal of the American Medical Association (JAMA).
“The positive TRAILBLAZER-ALZ 2 data bring hope to people with Alzheimer’s disease who urgently need new treatment options. This is the first Phase 3 study of a disease-modifying therapy to replicate the positive clinical results observed in a previous study” said Anne White, executive vice president of Eli Lilly and Company and president of Lilly Neuroscience. “If approved, we believe donanemab can provide clinically meaningful benefits for people with this disease and the possibility of completing their course of treatment as early as 6 months once their amyloid plaque is cleared. We must continue to remove any barriers in access to amyloid-targeting therapies and diagnostics in an already complex healthcare ecosystem for Alzheimer’s disease.”
Lilly previously announced that donanemab met the primary and all cognitive and functional secondary endpoints in the Phase 3 study. Submission to the U.S. FDA for traditional approval was completed last quarter with regulatory action expected by the end of the year. Submissions to other global regulators are currently underway, and the majority will be completed by year end.
The TRAILBLAZER-ALZ 2 results support Lilly’s application for regulatory approval to treat people with amyloid-positive early symptomatic Alzheimer’s disease (either mild cognitive impairment or mild dementia), regardless of their baseline level of tau. TRAILBLAZER-ALZ 2 enrolled participants with a broader range of cognitive scores and amyloid levels than other recent trials of amyloid plaque-targeting therapies. Participants in TRAILBLAZER-ALZ 2 were stratified by their level of tau, a predictive biomarker for disease progression, into either a low-medium tau group (sometimes referred to as intermediate tau) or a high tau group, which represented a later pathological stage of disease progression. All participants were then assessed over 18 months using scales that measure both cognition and function, including the integrated Alzheimer’s Disease Rating Scale (iADRS) and the Clinical Dementia Rating-Sum of Boxes (CDR-SB).
As previously reported, among participants with low-medium levels of tau (n=1182), donanemab treatment significantly slowed decline by 35 per cent on iADRS and 36 per cent on CDR-SB. Among all amyloid-positive early symptomatic AD study participants (n=1736), treatment with donanemab significantly slowed decline by 22 per cent on iADRS and 29 per cent on CDR-SB. Additional data presented at AAIC reinforced that regardless of baseline clinical or pathological stage of disease, treatment with donanemab resulted in cognitive and functional benefits relative to placebo:
- A pre-specified subpopulation analysis of low-medium tau participants based on clinical stage showed greater benefit of donanemab in those at earlier stage of disease:
- In participants with mild cognitive impairment (n=214), donanemab slowed decline by 60 per cent on iADRS and 46 per cent on CDR-SB (for those with mild dementia due to AD, n=534, donanemab slowed decline by 30 per cent on iADRS and 38 per cent on CDR-SB, respectively).
- Similarly, a post-hoc subgroup analysis of low-medium tau participants based on age showed greater benefit of donanemab in patients under the age of 75:
- In participants under the age of 75 (n=267), donanemab slowed decline by 48 per cent on iADRS and 45 per cent on CDR-SB.
- In participants aged 75 or greater (n=266), donanemab slowed decline by 25 per cent on iADRS and 29 per cent on CDR-SB.
- Results were similar across other subgroups, including participants who carried or did not carry an ApoE4 allele.
- The overall treatment effect of donanemab continued to grow throughout the trial, with the largest differences versus placebo seen at 18 months.
“The data presented here at AAIC gives us a full picture, reinforcing the preliminary results from earlier this spring that showed donanemab significantly slowed cognitive and functional decline in patients with early Alzheimer’s disease,” says Dr Ziad Nasreddine, Cognitive Neurologist, Principal Investigator and Director of the MoCA Clinic, Montreal. “This is great news for Canadian patients and their families who now have hope that treatment can slow the progression of this devastating disease when diagnosed and treated early, this is such an important step forward.”
“This is a very exciting time in Alzheimer’s disease, following years of disappointment as promising molecules failed to reach their endpoints in clinical studies,” says Dr. Sharon Cohen, Neurologist and Medical Director of Toronto Memory Program. “Today’s donanemab presentation at AAIC is what we have been striving for. Slowing decline of cognition and function at an early stage of disease allows patients to remain mild and to preserve their quality of life.”
Donanemab specifically targets deposited amyloid plaque and has been shown to lead to plaque clearance in treated patients. Treatment with donanemab significantly reduced amyloid plaque levels regardless of baseline pathological stage of disease. Among all participants, treatment with donanemab reduced amyloid plaque on average by 84 per cent at 18 months, compared with a 1 per cent decrease for participants on placebo. Participants were able to stop taking donanemab once they achieved pre-defined criteria of amyloid plaque clearance.* Approximately half of participants met this threshold at 12 months and approximately seven of every ten participants reached it at 18 months
In the earlier pathological stage of disease in participants with low-medium tau, treatment with donanemab resulted in 47 per cent of participants with no progression at one year on the CDR-SB assessment, versus 29 per cent on placebo. Those participants treated with donanemab also had a 39 per cent lower risk of progressing to the next clinical stage of disease over the 18-month trial. This delay in progression meant that, on average, participants treated with donanemab had an additional 7.5 months before they reached the same level of cognitive and functional decline on CDR-SB compared to those on placebo.