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Off BACE: AZ/Lilly drop Alzheimer’s drug lanabecestat

Another BACE candidate is abandoned, leaving just one remaining in the pipeline

AstraZeneca and Eli Lilly have abandoned their Alzheimer’s drug candidate lanabecestat after an interim look at phase III data suggested there was little chance of showing efficacy.

The demise of the BACE1 inhibitor – also known as AZD3293/LY3314814 – adds to the litany of failures among drugs intended to treat Alzheimer’s, and specifically those trying to slow down the neurodegenerative disease by impeding the cascade of molecular events that lead to the formation of the amyloid plaques that characterise the disease.

It’s also another blow to the fast-contracting group of companies developing BACE inhibitors for dementia. A few weeks ago, Merck & Co abandoned its BACE1 inhibitor verubecestat, and with lanabecestat following the same path that just leaves Eisai and Biogen’s increasingly precarious-looking elenbecestat (E2609) in late-stage clinical testing.

AZ said today that its decision was based on interim data from two studies – the AMARANTH trial in early Alzheimer’s disease and DAYBREAK-ALZ study in mild Alzheimer’s dementia. In both cases, the data monitoring committees concluded they “were not likely to meet their primary endpoints upon completion and therefore should be stopped for futility.”

Dan Skovronsky

“The complexity of Alzheimer’s disease poses one of the most difficult medical challenges of our time, and we are deeply disappointed for the millions suffering from this devastating disease,” said Daniel Skovronsky, president of Lilly Research Labs (pictured).

“We are grateful for the contributions of the study participants and their families and encourage them to consider other Alzheimer’s disease clinical trials.”

The ever-lengthening list of failed trials for amyloid-targeting drugs prompted an editorial in the New England Journal of Medicine (NEJM) earlier this year to declare the approach all-but dead. Author Paul Murphy of the University of Kentucky wrote that “we may very well be nearing the end of the amyloid-hypothesis rope, at which point one or two more failures will cause us to loosen our grip and let go.”

There is still plenty of clinical trial activity on the go in the amyloid area, however, with late-stage studies ongoing for candidates including Biogen/Neurimmune’s aducanumab, Roche/AC Immune’s crenezumab and Roche/Chugai’s gantenerumab.

Those trials adhere to the idea that the way to unlock the efficacy of amyloid-targeting drugs is to give them as early as possible in the course of the disease, although so far data read-outs for amyloid drugs in early-stage patients have been equally unsuccessful.

Some research groups are now looking at running trials in patients with amyloid in their brains but no symptoms – that includes a trial of Lilly’s amyloid-targeting antibody solanezumab that failed a phase III programme some years ago – and others in the planning stages could even include younger people in their 50s in the earliest stages of amyloid accumulation.

One of the main challenges has been identifying patients in the pre-symptomatic or ‘prodromal’ Alzheimer’s stage, and earlier this year the FDA released draft guidance to try to help sponsors design trials in this setting and measure outcomes.

Article by
Phil Taylor

12th June 2018

From: Research

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