Until now, it was unclear as to whether drugs that clear amyloid, which accumulate in the brain during aging and accompany diseases such as Alzheimer’s, have any influence over cognitive decline.
Previous studies have aimed to find this out, but results have been inconclusive due to study designs, hard-to-interpret data, and other issues that muddy the waters. March 10-14th saw the 15th International Conference on Alzheimer’s and Parkinson’s Diseases being held (virtually of course), where Dr. Mark Mintun of Eli Lilly presented data that, at least somewhat, affirmatively answers the question [1].
Anti-amyloid drug donanemab clears amyloids and slows cognitive decline
Eli Lilly’s Phase 2 clinical trial data for its anti-amyloid antibody donanemab successfully reached its endpoint. While patients did not get better, the administration of donanemab appeared to slow decline by an average of 32 percent in a combined assessment of cognitive and functional decline.
The results show that donanemab was able to remove the plaques associated with Alzheimer’s in the majority of trial participants while also reducing the accumulation rate of neurofibrillary tangles in the frontal cortex and other regions.
This is the first disease-modifying Alzheimer’s drug to meet its clinical endpoint in a Phase 2 trial, an impressive feat given the graveyard of failed Alzheimer’s drugs.
Does this confirm the amyloid hypothesis?
The results of the trial do seem to suggest that treatments aimed at amyloid can slow cognitive decline and modify the progression of Alzheimer’s. However, that in itself does not suggest that targeting amyloid alone is an optimal strategy. While the treatment did indeed seem to slow down the rate of cognitive decline in trial participants, it did not improve their condition, nor did it reverse the disease, which should be the true end goal of Alzheimer’s research.
While the results of the trial are most welcome, it may be that this 32 percent slowing of disease progression is about as good as it gets by just targeting the amyloid alone. The next logical step to see if this can be improved on would be to combine anti-amyloid treatments such as donanemab with an anti-tau drug. It could well be the case that only by addressing both tau and beta-amyloid at once can the disease be reversed.
Based on this data, the researchers have modified their Trailblazer 2 Phase 2 trial for 500 participants and upgraded it to a Phase 3 trial with 1,500 people.
We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer’s disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer’s Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini–Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.
A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P=0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.
Conclusion
Donanemab is the first anti-amyloid drug to successfully demonstrate disease modification and reach its endpoint in Phase 2 trials, which alone is a cause for some celebration. Hopefully the expanded Phase 3 trial will help confirm that removing amyloid is a viable strategy and pave the way for exploring combined anti-amyloid and anti-tau approaches.
Literature
[1] Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., … & Skovronsky, D. M. (2021). Donanemab in Early Alzheimer’s Disease. New England Journal of Medicine.
