Merck and AstraZeneca are advancing their BACE inhibitor into pivotal trials, leaving Lilly behind.

The lowdown: Under the amyloid hypothesis of Alzheimer's disease, the amyloid precursor protein is cleaved by β-secretase (BACE) and then by γ-secretase to release amyloid-β, which forms the plaques that may be responsible for neurodegeneration. So far, however, amyloid-targeting antibodies and γ-secretase inhibitors have failed in Phase III trials to affect disease symptoms or progression. BACE inhibitors are now stepping up to the pivotal trial plate.

Merck and Co. are in the lead, since initiating in November a Phase III trial testing MK-8931 in 1,500 patients with amnestic mild cognitive impairment due to Alzheimer's disease (prodromal Alzheimer's disease). A Phase II/III trial is also underway, testing the drug in 1,960 patients with more advanced mild to moderate Alzheimer's disease. AstraZeneca is in close pursuit, announcing in February that it will advance its Phase I candidate AZD3293 into a pivotal Phase II/III trial this year. It has not yet disclosed trial design details.

But while Merck and AstraZeneca speed ahead, Lilly has put the brakes on its BACE inhibitor LY2886721. In January Lilly stopped a Phase II trial of the drug after observing abnormal liver biochemical tests. Lilly does not think that this toxicity was a class effect, and says it is still interested in developing BACE inhibitors.