Eli Lilly CEO David Ricks was confident last year that donanemab would best Biogen and Eisai’s approved Alzheimer's disease drug in a head-to-head battle. Now, the results are in—and Ricks was right.
In a trial comparing the two therapies, donanemab reduced brain amyloid plaque levels by 65.2% at six months compared to baseline, while Aduhelm reduced levels by 17% for the same time period. The donanemab data, which were shared Nov. 30 at the Clinical Trials on Alzheimer's Disease conference, comes from Lilly’s ongoing phase 3 study, dubbed TRAILBLAZER-ALZ 4.
“What's encouraging here is we’re comparing one drug that's already been approved and another drug that’s being considered for accelerated approval, and it looks like donanemab lowers amyloid plaque significantly more in six months than you can imagine under the current dosing regimen recommended by the FDA,” investigator Stephen Salloway, M.D., who presented the findings and serves as associate director of the Center for Alzheimer’s Disease Research at Brown University, told Fierce Biotech in an interview. “And it appears to do that safely.”
It’s the best possible scenario for Lilly after CEO Ricks touted the drug at 2022’s JP Morgan annual healthcare conference, telling Fierce Biotech: “If you're going to take on … the leader, you need to be the leader, and that's the purpose of this experiment.”
Since then, all eyes have turned to Eisai and Biogen's other Alzheimer's prospect lecanemab, which reported its own data at the conference, but Lilly is still keen to showcase donanemab's challenge to the only market entrant to date. The investigational antibody hit all primary and secondary goals of the six-month primary outcome analysis for TRAILBLAZER-ALZ 4. The study enrolled 148 patients with early, symptomatic Alzheimer’s, with investigators assessing superiority regarding the percentage of participants who reached complete amyloid plaque clearance at six months, as measured by PET scan.
At six months, 37.9% of donanemab-treated participants saw brain amyloid clearance compared to 1.6% of Aduhelm-treated patients, according to the new data.
Donanemab produced significant reduction of amyloid buildup in the brain and plasma phosphorylated tau (P-tau) in the blood after six months, which suggests that it changed the biology of Alzheimer’s early in treatment, Salloway said, though clinical significance still must be proved.
While the results appear strong for Lilly’s candidate, Aduhelm is fading from the market after a troubled launch. A narrow Medicare reimbursement policy was followed by Biogen pulling all commercial activities for Aduhelm and chopping its sales team as part of a cost-saving plan, leaving the company with minimal resources to manage existing patient access programs.
The landscape may have shifted since TRAILBLAZER-ALZ 4 started, but Salloway said the head-to-head trial is still extremely informative for the field, helping answer several questions about the speed and degree of amyloid lowering in Alzheimer’s. Most notably, the trial has provided the first active comparator data on amyloid plaque clearance in patients with early Alzheimer’s who are receiving amyloid-targeting therapies.
“There aren’t any trials like this,” Salloway said. “It gets us a step further and it's just encouragement that we are moving to target and we can do it relatively quickly and safely using careful monitoring.”
The data also give side-by-side insight about adverse events tied to treatment, specifically regarding amyloid-related imaging abnormalities (ARIA)—a known complication in the amyloid treatment class. The safety profile of both treatments was consistent with previously published studies, which showed ARIA to be the most common treatment-emergent adverse event in both groups. In the Aduhelm cohort, the incidence of ARIA was 26.1% with 4.3% being symptomatic, while the donanemab group was 25.4% with 2.8% symptomatic.
Donanemab’s higher amyloid clearance at six months compared to Aduhelm wasn’t associated with a higher rate of ARIA, Salloway pointed out.
“These data reinforce our confidence in donanemab’s unique mechanism of action based on reductions in key biomarkers of Alzheimer’s disease, amyloid plaque and P-tau,” Mark Mintun, M.D., Lilly's group VP of pain and neurodegeneration R&D, said in a Nov. 30 release.
ARIA rates can signal bleeding in the brain or swelling and are a growing concern in Alzheimer’s drug development, cropping up for Eisai’s and Biogen’s lecanemab in new data released this week. The therapy had been one of the few amyloid success stories, which Lilly leaders had previously touted as a win for the class as a whole. However, two treatment-related deaths and the new ARIA data have dimmed the initial glow surrounding the potential therapy, though Eisai continues to stand behind it, telling Fierce Biotech it doesn't think either death can be pinned on lecanemab.
Both donanemab and lecanemab are based off the foundational theory that reducing or preventing amyloid plaques in the brain may slow cognitive decline. The theory has disappointed in the clinic numerous times, most recently when Roche’s gantenerumab failed to improve the rate of cognitive and functional decline in two phase 3 clinical trials.
Still, Salloway thinks the lecanemab data are “the most encouraging data we've seen so far in terms of producing a consistent clinical benefit.” The therapy showed significant amyloid lowering and an ARIA rate below that of other programs, he added.
Lilly certainly still has a lot to prove, with Salloway noting that the current trial is small and doesn’t have a built-in clinical correlation measure. The study is set to have 12-month and 18-month secondary readouts, which he said will show how quickly clinical benefit kicks in and whether it grows over time, pointing out that Aduhelm typically takes longer to kick in.
TRAILBLAZER-ALZ 4 is one of five studies assessing donanemab for efficacy and safety, with Lilly anticipating a readout for its double-blind, placebo-controlled phase 3 study, dubbed TRAILBLAZER-ALZ 2, in the spring.
The FDA has also tagged donanemab with both priority-review and breakthrough-therapy designations to expedite development and review processes. In the meantime, scientists like Salloway will work to provide more answers about Alzheimer’s and the potential to modify its course.
“These effects are small,” Salloway said, “but they’re meaningful and we need to build on them.”