Lilly files Alzheimer's drug donanemab as Cortexyme rival fails trial

Eli Lilly has followed through on its plan to file for approval of its Alzheimer's disease candidate donanemab, and is planning to take on Biogen and Eisai with a head-to-head trial against their recently-approved Aduhelm drug.

Lilly has also picked up an accelerated review for donanemab from the FDA, which is assessing the drug under a rolling license application that will see data submitted to the agency as it becomes available.

It could result in a conditional approval – based on the phase 2 TRAILBLAZER-ALZ study – in the second half of next year if all goes to plan for Lilly.

The drugmaker isn't however expecting sales to gather much momentum even if donanemab is approved, at least until the data from the confirmatory phase 3 study TRAILBLAZER-ALZ 2 comes in, currently due in 2023.

That has certainly been the case for Aduhelm (aducanumab), which brought in just $300,000 in sales in the third quarter and according to Biogen will remain "minimal" until a Medicare reimbursement review concludes, with a verdict expected early in 2022.

Lilly is seeking approval for donanemab in early-stage Alzheimer's, and is hoping to get a speedy FDA green light on the back of amyloid clearance data as a surrogate marker for clinical efficacy, which is controversial as it does not reliably track with cognitive improvements in Alzheimer's trials.

The impact of donanemab on cognitive decline was hard to interpret from the phase 2 trial, as benefits did not seem to correlate with amyloid plaque reduction using an initial statistical analysis, although Lilly crunched the numbers with a second model and said it had found an association.

The drugmaker has been emboldened to file early as a result of the controversial Aduhelm approval, which is seen as opening the door to swift FDA reviews for new Alzheimer's therapies and conditional approvals ahead of pivotal trial readouts.

Biogen and Eisai's confirmatory trial isn't expected to generate results for several years, so Lilly has an opportunity to leapfrog Aduhelm if its phase 3 study is positive.

Added to that, the drugmaker is also planning a comparative study – TRAILBLAZER-ALZ 4 – that will pit donanemab directly against Aduhelm on their ability to clear amyloid plaques from the brains of patients with early symptomatic Alzheimer's.

Results from that study could be available in the second half of next year, although it still doesn't address the debate about the validity of amyloid clearance as a surrogate marker for clinical efficacy.

There was bad news for Lilly elsewhere is its Alzheimer's pipeline as it announced the demise of anti-tau protein antibody zagotenemab, which had reached phase 2 but failed to have an impact on its primary endpoint.

Cortexyme trial disappoints

Elsewhere, a non-amyloid approach to treating Alzheimer's pioneered by US biotech Cortexyme has suffered a setback after missing its objectives in a late-stage trial.

The company's drug atuzaginstat targets a bacteria called Porphyromonas gingivalis, usually found in the mouths of people with periodontal disease, that has been associated with an increased risk of Alzheimer’s in some studies.

The phase 2/3 GAIN study in 643 patients showed no impact of the drug on scales used to monitor cognition in Alzheimer's patents overall, although Cortexyme maintains there was a "clinically significant" benefit in a subgroup of 242 patients with P. gingivalis detectable in their saliva at the start of the trial.

The biotech said the data could allow it to design further studies that will enrol patients most likely to benefit from atuzaginstat, and is working on "next steps to advance this breakthrough treatment for the benefit of patients and their families."