Merck & Co. has halted a pivotal trial of its β-secretase 1 (BACE1) inhibitor verubecestat in mild-to-moderate Alzheimer disease (AD) due to futility, providing a first critical failure for yet another class of amyloid-modulating drugs.

Trials have already sunk other classes aimed at controlling amyloid plaques, including γ-secretase inhibitors, which were designed to regulate a key step in amyloid processing, and anti-amyloid antibodies, which target amyloid directly. With these failures, several companies had turned their focus to BACE1 inhibitors, which act upstream of γ-secretase in amyloid processing.

One of the leading BACE1 inhibitors is Merck's verubecestat, with a phase II/III trial in more than 2,000 patients with mild-to-moderate AD that was expected to read out in mid-2017. The company instead halted the trial in February after an interim safety analysis found that there was “virtually no chance of finding a positive clinical effect”.

Although the failure is yet another blow to the embattled amyloid hypothesis of AD, it could be due to various other factors, including insufficient potency or poor pharmacokinetics. A leading theory is that amyloid-modulating drugs need to be on board earlier in the course of the disease to delay neurodegeneration. To this end, Merck is still running a phase III trial of its verubecestat in patients with prodromal AD. Top-line results from this trial are anticipated in 2019.

Four other companies have BACE1 inhibitors in mid- or late-stage trials, in various patient populations, including asymptomatic patients at risk for AD (Table 1).

Table 1 BACE1 inhibitors in mid- and late-stage trials
Full size table

In another recent AD setback, Eli Lilly terminated the phase III trial of its anti-amyloid antibody solanezumab in prodromal AD patients. Late last year, the monoclonal antibody failed in patients with mild-to-moderate AD and evidence of amyloid accumulation in the brain (Nat. Rev. Drug Discov. 16, 3–5; 2017).