Lilly shares full pivotal data on Alzheimer's drug, revealing how it shapes up against Leqembi

Eli Lilly has held the grand reveal of the Alzheimer’s disease trial data it hopes will secure FDA approval for donanemab by the end of the year. The update shows improvements over placebo continued to grow over the course of the study, even after patients stopped taking the drug, but confirmed concerns about safety and the value of treating patients early.

Lilly demonstrated that its anti-amyloid-beta antibody donanemab is a genuine challenger to Eisai and Biogen’s Leqembi in May, when it released phase 3 data linking the drug candidate to a 35% slowing of cognitive decline and a 39% lower risk of advancing to the next stage of the disease versus placebo. The readout suggested, with caveats about cross-trial comparisons, that donanemab may have an edge over Leqembi in terms of efficacy, but that safety and effects in certain subgroups could be weaknesses. 

The Big Pharma used the 2023 Alzheimer's Association International Conference (AAIC) to share a fuller look at data and, by extension, the potential strengths and weaknesses of donanemab. At an embargoed AAIC media event held ahead of the full presentation, Mark Mintun, M.D., group vice president, neuroscience research and development at Lilly, showed how the effect of donanemab increased over time.

As Mintun showed, the gap between the treatment and placebo groups on a cognition scale went from 1.42 at week 24 to 2.62 at week 52 and 3.25 by week 76. Patients stopped taking donanemab when their amyloid plaques disappeared. On average, patients only spent 47 weeks on the drug, yet people continued to deteriorate more slowly than their peers on placebo after they stopped taking the antibody.

“There was no downside of taking them off drug,” Mintun said. “In fact, compared to the overall group ... this group is actually doing a little better, even though they're spending the last six months on average off drug. Since all those people are off drug as they went down to 18 months, they probably will continue to separate and get benefit afterwards.”

“That's a hope,” Mintun added. “We don't have data for that.”

Stopping treatment reflects a belief that there is no need to keep giving the antibody once it has cleared amyloid plaques. Amyloid accumulates for years before causing symptoms and, as such, Lilly is still some way off figuring out whether re-treatment will be needed. “We're thinking four to five years out before the average patient would get to that point,” Mintun said.

The effect of donanemab in different subgroups is a more immediate concern. Lilly achieved its headline 35% slowing of cognitive decline in a low-medium tau population. Adding in the high tau patients caused the improvement over placebo to fall to 22% on the primary cognition endpoint and had similar effects on other measures. 

In the high tau group, the effect of donanemab on the primary and a key secondary endpoint fell short of statistical significance. The finding raises doubts about the benefits of giving the antibody to people who have high levels of tau. As it stands, physicians lack an FDA-approved blood test for tau. John Sims, M.D., head of medical, donanemab at Lilly, doesn’t see that as a barrier to the use of the drug.

“It's not required, because it's not enough to tell you not to treat the patient. It can't tell you whether this person is going to have a good response or not respond. It gives you a sense of probability, a bit like cancer,” Sims said. “Early stage is probably a better response than later stages, but you're still going to treat the patient and give them a chance.”

Decisions about whether to treat patients who have a lower likelihood of responding are complicated by medicines that have harmful side effects. For donanemab and similar Alzheimer’s drugs, amyloid-related imaging abnormalities causing edema (ARIA-E) are the primary concern. And on that front, donanemab may be at a disadvantage versus Leqembi.

Lilly previously reported a 24% rate of ARIA-E in recipients of donanemab—compared to 2.1% in the placebo arm and 13% in the pivotal Leqembi study—and three deaths linked to the brain swelling disorder. Sims discussed the deaths and whether the drug is suitable for use in people on certain blood medicines. 

“We do not see an increased risk of bleeding with anticoagulants or with antiplatelet therapies,” Sims said. “There's been caution and the FDA has put this as a caution on the labels. I think the wording is appropriate because, at a theoretical level, we know antiplatelets and anticoagulation increase bleeding generally in the body and we know that there's bleeding associated with the treatment.”

The rate of ARIA-E varied by APOE ε4 carrier status. The rate increased from 15.7% in non-carriers to 22.8% in heterozygous carriers and 40.6% in homozygous carriers. Leqembi’s label calls out the effect of APOE status on ARIA-E risk but the rates in its pivotal study were lower.

Such comparisons will factor into prescribing decisions if physicians soon have two Alzheimer’s drugs to choose from. Lilly completed a filing with the FDA in the second quarter and expects to receive an approval decision by the end of the year. Submissions in other parts of the world are planned for the next six months.