02 May 2018

Today Merck formally published the findings from the discontinued Phase 3 EPOCH trial of the BACE inhibitor verubecestat in mild to moderate Alzheimer’s disease. Michael Egan from Merck previously reported the bulk of the data at last year’s Clinical Trials on Alzheimer’s Disease conference (Dec 2017 conference news). The paper confirms that participants taking the drug declined at the same rate as the placebo group on the primary outcome measures, the ADCS-ADL and the ADAS-Cog11, as well as on a secondary measure, the CDR sum of boxes. The new analysis includes additional secondary measures, the MMSE and NPI, which also showed no difference between treatment and placebo groups. ApoE4 carriers did not differ from noncarriers on any clinical measure.

The biomarker data did show some differences on drug. As reported previously, the treatment group had a slight decline in plaque load as measured by amyloid PET, with the SUVR falling by 0.02 to 0.04. They also lost slightly more hippocampal volume and total brain volume than controls. The paper adds data on cerebrospinal tau levels, reporting no difference between drug and placebo in either total tau or phosphorylated tau. As expected from the drug’s mechanism of action, levels of Aβ40, Aβ42, and sAPPβ in CSF fell sharply, by up to 80 percent in the high-dose group.

Adverse events were more frequent in the treatment groups, with 9 percent of the high-dose group and 8 percent of the low-dose group stopping treatment because of them, compared with 6 percent of the placebo group. The most common side effects ascribed to the drug were rashes, falls, and insomnia. Rashes were almost twice as common in the treatment groups than in controls, with 10–12 percent of the former reporting them. Hair color changed in about 2 percent of people taking the BACE inhibitor, matching findings from animal studies. People in the treatment groups lost an average of 3.5 pounds during the trial.

Some psychiatric side effects cropped up, as well. The treatment groups had anxiety, while about 6 percent of participants on drug reported feeling suicidal, compared with 3 percent of controls. The investigators judged the severity of suicidal thoughts to be mild, and the majority of participants reporting them had a past history of psychiatric disorders. The researchers did not see any increase in delirium, nor any brain edema, with verubecestat treatment.—Madolyn Bowman Rogers