Lilly's Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer's Disease
Nearly half (47%) of the participants on donanemab (compared to 29% on placebo) had no clinical progression at 1 year (defined as no decline in CDR-SB)
Phase 3 trial met primary endpoint and all secondary endpoints measuring cognitive and functional decline
Donanemab treatment slowed clinical decline by 35% compared to placebo, and resulted in 40% less decline on the ability to perform activities of daily living
Over half of all participants completed their course of treatment by 12 months
TRAILBLAZER-ALZ 2, a randomized, double-blind, placebo-controlled study, evaluated the safety and efficacy of donanemab, an investigational amyloid plaque targeting therapy. The study enrolled people with early symptomatic Alzheimer's disease (AD), which includes mild cognitive impairment (MCI) and the mild dementia stage of disease, with the confirmed presence of AD neuropathology, and participants completed their course of treatment with donanemab once they reached a prespecified level of amyloid plaque clearance.
Participants in TRAILBLAZER-ALZ 2 were stratified by their level of the brain protein tau, a predictive biomarker for Alzheimer's disease progression. The primary analysis population (n=1182) for which the study was powered was comprised of people with an intermediate level of tau and clinical symptoms of Alzheimer's disease. In this population, the primary endpoint (iADRS) showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months. Additional prespecified secondary analyses showed:
- 47% of participants on donanemab showed no decline on CDR-SB, a key measure of disease severity at 1 year (compared to 29% of participants on placebo, p<0.001).
- 52% of participants completed their course of treatment by 1 year and 72% completed by 18 months as a result of achieving plaque clearance.
- Participants on donanemab had 40% less decline in ability to perform activities of daily living at 18 months [as measured by Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (ADCS-iADL), p<0.0001].
- Participants on donanemab experienced a 39% lower risk of progressing to the next stage of disease compared to placebo (CDR-Global Score, HR=0.61; p<0.001).
"Over the last 20 years,
The study also enrolled a smaller number of people with high levels of tau at baseline (n=552), representing a later stage of disease progression. Because these participants were predicted to progress more quickly and be less responsive to therapy, the target population for the study was the intermediate tau population. The high tau participants were combined with the intermediate tau population in an additional primary analysis of all participants enrolled (n=1736). In this combined population, donanemab also demonstrated meaningful positive results across all clinical endpoints (p<0.001), with CDR-SB and iADRS showing 29% and 22% slowing of decline, respectively.
The incidence of amyloid-related imaging abnormalities (ARIA) was consistent with the TRAILBLAZER-ALZ Phase 2 study. ARIA is observed with the amyloid plaque clearing antibody class of therapies and is most commonly observed as temporary swelling in an area or areas of the brain (ARIA-E) or as microhemorrhages or superficial siderosis (ARIA-H), in either case detected by MRI. In the overall donanemab treatment group, ARIA-E occurred in 24.0% of treated participants, with 6.1% experiencing symptomatic
"We are encouraged by the potential clinical benefits that donanemab may provide, although like many effective treatments for debilitating and fatal diseases, there are associated risks that may be serious and life-threatening," said
In addition to slowing cognitive and functional decline in TRAILBLAZER-ALZ 2, donanemab produced significant reductions in brain amyloid plaque levels as early as 6 months after initiating treatment, as observed using amyloid positron emission tomography (PET) brain scan, with many patients reaching amyloid levels considered negative for pathology1 (34% of participants in the intermediate tau population achieved amyloid clearance at 6 months and 71% achieved clearance at 12 months).
"Amyloid plaque is a defining pathophysiological feature of Alzheimer's disease," said Dr.
"These Phase 3 data confirm the benefit observed in our TRAILBLAZER-ALZ study and show that donanemab, if approved, may represent a significant step forward for people with early symptomatic Alzheimer's disease, and allow them to continue to participate in activities that are meaningful to them," said
Topline study results:
In the intermediate tau population, the baseline characteristics were similar to other contemporary early symptomatic AD studies (e.g., MMSE score was 22.9). Accordingly, the placebo arm progressed as expected (decline on iADRS and CDR-SB of 9.3 and 1.9 points respectively over 18 months). Prespecified analyses used standard statistical methods including the mixed model for repeated measures (MMRM) and natural cubic spline (NCS) analyses, with similar results across both methods. The following efficacy measures were obtained at 18 months comparing decline in donanemab to placebo treated participants:
Intermediate tau |
MMRM statistical analysis |
NCS statistical analysis |
||
Relative % slowing |
p-value |
Relative % slowing |
p-value |
|
iADRS |
40 % |
p<0.0000004 |
35 % |
p<0.000004* |
CDR-SB |
36 % |
p<0.000002* |
37 % |
p<0.0000005 |
ADCS-iADL |
43 % |
p<0.00005 |
40 % |
p<0.0001* |
ADAS-Cog13 |
35 % |
p<0.00003 |
32 % |
p<0.00005* |
*indicates alpha-controlled analyses; iADRS= Alzheimer's Disease Rating Scale; CDR-SB= Clinical Dementia Rating-Sum of Boxes; ADCS-iADL = Alzheimer's Disease Cooperative Study – instrumental Activities of Daily Living Inventory (iADL); ADAS-Cog13 = the 13-item Alzheimer's Disease Assessment Scale – Cognitive |
In the combined intermediate and high tau population the baseline MMSE score was 22.3 and the placebo arm showed a greater decline compared to the intermediate tau population (worsening on iADRS and CDR-SB of 13.1 and 2.4 points respectively over 18 months). Study results at 18 months showed:
Combined intermediate |
MMRM statistical analysis |
NCS statistical analysis |
||
Relative % slowing |
p-value |
Relative % slowing |
p-value |
|
iADRS |
23 % |
p<0.00004 |
22 % |
p<0.00006* |
CDR-SB |
29 % |
p<0.00000005* |
29 % |
p<0.00000007 |
ADCS-iADL |
28 % |
p<0.0002 |
28 % |
p<0.0002* |
ADAS-Cog13 |
19 % |
p<0.0008 |
20 % |
p<0.0007* |
*indicates alpha-controlled analyses |
Full results of the TRAILBLAZER-ALZ 2 study will be presented at the Alzheimer's
About TRAILBLAZER-ALZ 2 Study and the TRAILBLAZER-ALZ program
TRAILBLAZER-ALZ 2 (NCT04437511) is a Phase 3, double-blind, placebo-controlled study to evaluate the safety and efficacy of donanemab in participants ages 60-85 years with early symptomatic Alzheimer's disease (MCI or mild dementia due to Alzheimer's disease) with the presence of confirmed Alzheimer's disease neuropathology. The trial enrolled 1736 participants selected based on cognitive assessments in conjunction with amyloid plaque imaging and tau staging by PET imaging.
About
© Lilly
Cautionary Statement Regarding Forward-Looking Statements
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about donanemab as a potential treatment for people with early symptomatic Alzheimer's disease and the timeline for future readouts, presentations, and other milestones relating to donanemab and its clinical trials and reflects
1. JAMA. 2011;305(3):275-283
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