Eli Lilly has submitted its Alzheimer’s disease drug candidate for FDA review, and the pharmaceutical giant is now revealing a more complete look at the clinical data supporting an application that could make the therapy the second anti-amyloid antibody to win full regulatory approval.
Lilly had previously said its drug, donanemab, led to a 35% slowing in the decline associated with Alzheimer’s. Those results were for patients with intermediate levels of tau, another protein that’s also characteristic of Alzheimer’s progression. In patients with low-to medium-levels of tau, representing an earlier stage of the disease, treatment with the Lilly drug led to a nearly 39% reduction in disease progression. That reduction translates to between a 4.4 months and 7.5 month delay in reaching the same level of cognitive and functional decline compared to those who received a placebo.
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Lilly presented the results on Monday during the Alzheimer’s Association International Conference in Amsterdam. The results were also published in the Journal of the American Medical Association (JAMA).
Mark Mintun, group vice president neuroscience research & development at Lilly, said the data demonstrate to both the company and the broader Alzheimer’s field the importance of early treatment of the disease.
“Going early should be able to slow this disease even more than we’ve shown here,” Mintun said, speaking during the presentation.
Donanemab is an antibody designed to target and break up plaques of amyloid beta, a protein that builds up in the brain as Alzheimer’s progresses. Anti-amyloid drugs target either soluble or insoluble forms of the protein. Lilly’s drug goes after insoluble forms of amyloid, in contrast to Eisai’s recently approved Alzheimer’s drug Leqembi, which addresses soluble forms.
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The Phase 3 test for Lilly’s donanemab enrolled 1,736 patients with early symptoms of Alzheimer’s disease and signs of both amyloid and tau. Study participants were stratified according to tau levels. Participants who were assigned to receive donanemab were allowed to stop taking it once they achieved pre-defined criteria of amyloid clearance. Lilly said about half of patients who received the study drug met that benchmark at 12 months and seven of every 10 participants reached it at 18 months.
The study met the main goal of showing a slowing in decline in the intermediate group, which had 1,182 patients. In a pre-specified analysis of a subgroup of participants with low-to-medium tau, Lilly reported a greater benefit in these patients with an earlier stage of Alzheimer’s. In 214 patients who had mild cognitive impairment, the study drug slowed decline by 60% according to Clinical Dementia Rating-Sum of Boxes (CDR-SB), a scale used to assess Alzheimer’s patients. That’s the same scale used to evaluate the Leqembi and Biogen’s Aduhelm. While cross-trial comparisons are tricky, results from the pivotal study of Eisai’s Leqembi showed a 27% slowing in cognitive decline in patients with early Alzheimer’s measured after 18 months of treatment.
Using another scale called Integrated Alzheimer’s Disease Rating Scale, or iADRS, results showed donanemab slowed decline by 46% in patients in the low-to-medium tau group. In the subgroup of 534 patients classified as having mild dementia due to Alzheimer’s, the Lilly drug slowed decline by 38% on CDR-SB and by 30% according to iADRS.
However, study participants with high tau levels, representing a more advanced stage of Alzheimer’s, did not experience the same benefit. According to the JAMA paper, a post-hoc analysis of this subgroup showed no differences in the treatment arm compared with the placebo cohort during the 18-month trial.
“Compared with significant differences in the low/medium tau population, this supports the hypothesis that a greater benefit from amyloid-lowering therapies may occur when initiated at an earlier disease stage,” the study authors wrote.
Mintun said the FDA submission has been completed and Lilly is preparing to seek regulatory approvals in other markets as well. An FDA decision for donanemab is expected by the end of this year.
Public domain image by Flicker user NIH Image Gallery
