Stealing Third BACE

Developing drugs for Alzheimer’s disease is a fraught undertaking. With a whopping drug failure rate of 96.6 percent – including some high-profile phase III failures – big pharma has seen little reward for their efforts in this arena. So the news that BACE1 inhibitor verubecestat is moving into phase III trials is being greeted with (cautious) optimism.

A popular, though disputed, explanation for what causes Alzheimer’s disease is the amyloid cascade hypothesis, which suggests that amyloid β (Aβ) peptides clump together to form insoluble amyloid plaques in the brain – leading to disruption of normal brain function and neuronal death.

There are two types of amyloid-targeting therapies currently being investigated by pharma. Monoclonal antibodies (mAbs) work to clear the amyloid plaques by targeting and binding to Aβ – Biogen’s aducanumab has been shown to remove the build-up of amyloid in the brain and slow the decline in memory and thinking skills in people with Alzheimer’s disease in a phase I study (1). BACE1 inhibitors, on the other hand, are small molecules that target BACE1 – the enzyme responsible for the initiation of the production of the Aβ peptide in the brain. But both mAbs and BACE1 inhibitors have previously run into safety concerns.

In a recent study, the Merck BACE inhibitor discovery team, at Merck Sharp & Dohme (MSD), successfully took their BACE1 inhibitor – verubecestat – through a phase I clinical trial (1). The drug was well tolerated and there were no study discontinuations due to adverse events.

“While we want to be careful to manage expectations and not draw conclusions beyond what the science currently supports, we are very encouraged by the findings from our Phase I studies,” says Matthew Kennedy, Director Merck Neuroscience and the program’s lead biologist. “In initial Phase I studies of healthy volunteers and people with Alzheimer’s disease, patients taking verubecestat over a one week period showed significant decreases in the levels of Aβ in the cerebral spinal fluid of up to 80 percent.”

Following an initial phase II safety analysis, the researchers are now pursuing two phase III studies – one in patients with mild-to-moderate Alzheimer’s disease, and another in patients with prodromal stage Alzheimer’s (mild cognitive impairment and a positive amyloid PET scan) – they will be completed in 2017 and 2019 respectively.

“We believe that these clinical trials represent an important test of the amyloid cascade hypothesis and that the data produced will potentially have broader implications for the entire field and significantly contribute to our overall understanding of the disease process and etiology,” says Kennedy.