After the disappointing failures of highly anticipated anti-amyloid pipeline drugs, such as Pfizer/Johnson & Johnson’s bapineuzumab and Eli Lilly’s solanezumab, the focus of research in Alzheimer’s has increasingly turned to beta-secretase (BACE) inhibitors. Unlike the injectable monoclonal antibodies, the BACE inhibitors are oral small molecules.

This year has not started on the right foot for the BACE inhibitor class, however. In January 2018, Pfizer announced it would exit Alzheimer’s research. In February, Merck & Co. terminated verubecestat due to lack of efficacy. In May, Johnson & Johnson dropped atabecestat due to liver safety issues. The most recent BACE inhibitor to be abandoned is Eli Lilly/AstraZeneca’s lanabecestat in June. Lilly and AstraZeneca stopped two Phase III trials after an independent Data Monitoring Committee (DMC) stated that the trials were unlikely to meet their primary endpoints and should be stopped for futility. This further dented the BACE hypothesis, although the news was not unexpected.

Lilly can be credited with being among the first to test oral BACE inhibitors in humans, and despite several setbacks, the company has continued to invest a significant proportion of its R&D budget into Alzheimer’s disease. However, in November 2011, its BACE inhibitor LY-2811376 was discontinued due to toxicology findings. Subsequently, the company advanced its next-generation BACE inhibitor, LY-2886721, into Phase I and Phase II clinical trials—at the time, becoming the first BACE inhibitor to reach Phase II—but in June 2013, this asset was also terminated, due to abnormal liver biochemistry.

As shown in the table below, the yet-unproven BACE inhibitor class has suffered some major blows and Lilly certainly is not the only company to have pulled BACE inhibitor assets from clinical trials; however, it seems the company is not giving up on this mechanism of action despite lanabecestat’s termination. Lilly still has another two BACE inhibitor assets in the pipeline, leaving Eisai’s elenbecestat leading the race to secure a first-to-market position—if it ever does reach the market.

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