Eli Lilly and AstraZeneca have pulled the plug on two phase 3 trials of BACE inhibitor lanabecestat in Alzheimer’s disease. The partners stopped the studies after an independent interim analysis deemed they were destined to fail.

Lilly, which picked up lanabecestat from AstraZeneca in 2014, has yet to share any data from the trials. But what is known reflects badly on lanabecestat, the BACE class and the amyloid hypothesis. Across two trials designed to assess lanabecestat in around 4,000 patients with early or mild Alzheimer's, lanabecestat has failed to improve scores on the ADAS-Cog13 Alzheimer’s assessment scale.

The interim review prompted Lilly and AstraZeneca to start working with sites to wind up the two trials, plus a 1,400-person extension to the study of patients with early forms of the disease. That looks to mark the end for lanabecestat, at least as a monotherapy in symptomatic patients.

Whitepaper Download Reducing the Complexity and Costs of Channel Planning and Logistics How can you make the process of bringing your product to market less complex while also reducing costs? This Whitepaper identifies opportunities to simplify channel strategies for biopharma companies, their customers and patients. Discover how you can deliver savings and innovation to your business. Download for Free

If lanabecestat ends up on the scrapheap, it will have plenty of company. Lilly has already walked away from one BACE inhibitor, as has Roche. More recently, Merck’s BACE drug, verubecestat, failed to move the needle at interim reviews in patients with prodromal and mild-to-moderate Alzheimer’s, prompting the early cessation of two phase 3 trials. Janssen also recently dropped work on its BACE program.

With Merck’s verubecestat failing to improve outcomes despite reducing amyloid-beta, there is now significant doubt about the hypothesis. At best, the string of failures suggests that inhibiting amyloid formation using BACE drugs may only be effective before Alzheimer’s has taken hold.

RELATED: Eisai and Biogen’s BACE drug lowers amyloid levels, but not Alzheimer’s symptoms

That suggestion casts a long shadow over the remaining BACE programs. Biogen and Eisai, like Merck, moved a BACE inhibitor into pivotal trials on the back of midphase data showing an effect on amyloid levels. History suggests that biomarker change will fail to translate into improved cognition in phase 3. Amgen and Novartis’ strategy of giving a BACE inhibitor to presymptomatic people at risk of Alzheimer’s is less encumbered by past failures but has similarly uncertain prospects.

The long, growing track record of Alzheimer’s drugs showing promise in phase 2 but failing in phase 3 has deterred drug developers like Pfizer from assigning internal teams to the indication. But the size of the financial and therapeutic opportunities, plus evolving understanding of CNS disease and how to study it, means others continue with the perhaps quixotic quest.

Lilly, which has suffered more than its fair share of Alzheimer’s setbacks, is among the companies still plugging away at the disease.

“Lilly remains dedicated to Alzheimer's disease research as we have been for the last three decades,” Daniel Skovronsky, M.D., Ph.D., president of Lilly Research Labs, said in a statement. “We won't give up on finding a solution for Alzheimer's patients.”