Lilly kick-starts speedy FDA review for Alzheimer's hopeful donanemab, cans 2nd candidate

 The great Alzheimer's R&D resurgence continues as Eli Lilly nabs an accelerated FDA review for its mixed bag drug donanemab, while also plotting direct head-to-head tests against Biogen’s new and controversial therapy Aduhelm.

But wait, there's more. Lilly is also terminating a phase 2 Alzheimer's asset called zagotenemab after the drug failed a phase 2 clinical trial. Executives touted the therapy to Fierce Biotech as recently as September, when Mark Mintun, M.D., Sr. VP of Neuroscience R&D for Lilly, said that results for a phase 2 study of the large molecule anti-tau antibody were eagerly awaited. Lilly now says the drug "failed to meet the primary endpoint in a Phase 2 study."

Let's start with the FDA news where, in third-quarter earnings posted early Tuesday morning, Lilly said a rolling submission had been started with the agency, where data can be added as it comes in for the memory-wasting disease therapy donanemab.

This is also being done under an accelerated approval and specifically in early Alzheimer's disease, as the U.S. Big Pharma hopes to ride the Alzheimer's train which pulled out of the station with Biogen's recent approval for Aduhelm.

That approval has, however, proven highly controversial, given that the data for the green light were mixed and partly mined from a sub group of patients. The decision relied largerly on the biomarker of clearing amyloid, something that has in the past not seen significant improvements in helping Alzheimer's patients.

This, alongside a price tag of around $50,000 per patient, has seen doctors in the U.S. balk, with Biogen at last count only making $300,000 from the med, despite being on the market for a good few months now.

Lilly acknowledged the tough road ahead for donanemab, with SVP and Chief Scientific and Medical Officer Daniel Skovronsky, M.D., Ph.D., taking a shot at Biogen's early sales numbers during the Tuesday morning earnings call. 

"Given the current environment, we think it's reasonable to have modest expectations for the scale of patient impact for anti-amyloid therapies available under accelerated approval prior to the readout of their definitive phase 3 data," Skovronsky said. 

Should Lilly's therapy be approved under the accelerated pathway in the second half of the year, Skovronsky expects to have clinical trial results to confirm the effect by mid-2023. This throws down the gauntlet to Biogen, which was granted nine years to complete a confirmatory study for Aduhelm. 

"The window of accelerated approval without definitive phase 3 data is likely to be brief," Skovronsky said. 

Not discouraged by the issues of Biogen, Lilly is in fact hoping to capitalize on the drama. Alongside the rolling submission news, the Indianapolis Big Pharma also laid down plans for a key phase 3 trial, to be known as TRAILBLAZER-ALZ 4, as a head-to-head comparing donanemab to Aduhelm (aducanumab) “to assess superiority of brain amyloid plaque clearance in early symptomatic Alzheimer's disease.”

Initial primary endpoint results from the study should be available in the second half of 2022, according to Skovronsky. Enrollment is expected to begin this year, and will be keenly watched by the market and the FDA. If donanemab can out-do Aduhelm—and Lilly can be savvy on pricing—the company could have a more marketable drug on its hands; though it will likely need to show some impact on the disease too, or fall into the same issues Aduhelm has faced.

The head to head trial may not get at the key question facing all of the companies working on Alzheimer's therapies: Do they work? Skovronsky said the trial will be small and short, with an endpoint focused on removing plaque rather than clinical efficacy. 

"If we believe that plaque lowering is the appropriate surrogate, that question will certainly be answered in the next year to 18 months," he said.

There’s no slam dunk here though: while Aduhelm appeared to open the gates for new Alzheimer's approvals after such a long dearth of hope, the agency was burned by the green light as AdComm members left in droves arguing that the therapy should have been rejected. Now the agency is under investigation, with calls for scrutiny over how and why Aduhelm passed the finish line.

This backdrop means Lilly cannot expect an easy ride for donanemab, which like Aduhelm also has seen some murky past results. Earlier in the year the pharma talked up data from a phase 2 clinical trial that was hailed as showing a “significant slowing of decline” in Alzheimer’s disease patients.

But in March when the full results were shared, the donanemab data turned out to be a mixed bag, with a slight win on one disease scale undermined by a failure on a more widely used measure of Alzheimer’s.

It appeared as if the drug may have been better off on the back burner—but Aduhelm spurred Lilly back into action and the rolling submission we see today.

Moving on to zagotenemab, this therapy was listed as the next-in-line behind donanemab with the phase 2 results coming soon. Now, that trial has failed and Lilly is cutting its loses. Skovronsky said the therapy "was unable to modulate tau spread in the brain."

Lilly sent some mixed signals on whether tau therapies will continue to be a part of Lilly's pipeline. On one hand, Skovronsky said the pharma plans to continue to study it as a potential target for slowing cognitive decline in Alzheimer's. 

But then, he added during the Q&A: "At present, I don't see a path forward for this antibody and I would be reluctant to invest in really any anti-tau antibody."

https://www.fiercebiotech.com/biotech/eli-lilly-kickstarts-speedy-fda-review-for-alzheimer-s-hopeful-donanemab-plots-aduhelm-head