On November 2, 2016, Merck & Co. reported positive results from its Phase I trial evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of verubecestat (also known as MK-8931), an oral drug for the potential treatment of Alzheimer’s disease (AD). Verubecestat is a small-molecule, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor that aims to reduce the amyloid protein buildup in the AD brain. The drug is the first BACE1 inhibitor to progress to Phase III trials and is currently being tested in two Phase III trials, positioning it to be a first-in-class drug. Since there are no approved treatments that can halt or slow down the progression of neurodegeneration in AD, pharmaceutical companies are racing to launch the first disease-modifying therapy in this market. If verubecestat is found to be effective, it could be this much-need therapy.

AD is a neurodegenerative disease that leads to dementia in older adults, particularly over the age of 65. Although there are treatments that can relieve some of the symptoms, they only provide short-term improvement to the cognitive and functional symptoms. Therefore, there is an urgent need for disease-modifying treatments. As such, pharmaceutical companies are focusing on developing drugs that target amyloid-beta (Aβ) peptides, one potential cause of AD.

Verubecestat acts by blocking BACE1 enzyme from cleaving amyloid precursor protein (APP) during Aβ formation. Aβ formation involves sequential cleavage of APP by BACE1 and γ-secretase, and as a result, many of the recent drug development efforts have focused on inhibitors or modulators of these enzymes. However, a few prominent trials of γ-secretase inhibitors, namely Eli Lilly’s semagacestat and Bristol-Myers Squibb’s avagacestat, have recently failed due to serious side effects. In terms of BACE1 inhibitors, AstraZeneca/Eli Lilly’s AZD3293 is currently the only other drug in this class in late-phase trials, while a previous clinical trial involving Eli Lilly’s BACE1 inhibitor, LY2886721, has been terminated due to liver toxicity and Roche’s RG7129 was terminated for an unknown reason. In stark contrast, verubecestat has proved safe and tolerable, in addition to also providing a hint of the drug’s efficacy in the small Phase I trial in humans.

In the current Phase I, randomized, double-blind, placebo-controlled, multiple- dose study, verubecestat was tested in 32 mild to moderate AD patients. Verubecestat reduced cerebrospinal fluid (CSF) Aβ40 (a surrogate marker for BACE1 activity in the brain) by 57, 79, and 84% at 12, 40, and 60-mg doses of verubecestat, respectively. Similar reduction was seen in healthy non-elderly individuals, and verubecestat showed favorable pharmacokinetic properties. Single and multiple doses of verubecestat were generally well-tolerated and adverse events in AD patients were comparable to those seen in the placebo group. Given the positive results, Merck has already initiated two Phase III trials, the EPOCH study and the APECS study, which are expected to be completed in 2019 and 2021, respectively.

Verubecestat’s recent news has no doubt amplified the excitement around BACE1 inhibitors as a new way of treating AD. Merck has overcome the common difficulties, to design a treatment that penetrates through the blood-brain barrier to the site of action in the brain and is orally bioavailable. However, the impact of BACE1 inhibition in preventing and treating AD is still unclear. Therefore, a major challenge for verubecestat to succeed in Phase III trials is to understand the level of BACE1 inhibition, and therefore Aβ lowering, required for sufficient functional efficacy. Furthermore, understanding of the stage at which AD should be treated will minimize the risk of late-phase attrition. Finally, testing the drug in prodromal AD is a strategy recently employed by Eli Lilly with its anti-amyloid antibody, solanezumab, and Merck is certainly well placed to lead this race by following suit in its Phase III APECS study.