Merck is calling off its Phase 2 and 3 EPOCH trial of verubecestat as a treatment for mild-to-moderate Alzheimer’s disease because preliminary results indicate it is not effective.
The decision was made after an external review board known as the Data Monitoring Committee (eDMC) reported there was “virtually no chance of finding a positive clinical effect” from the trial. The product’s safety was not at issue, the committee said.
The committee also recommended that Merck continue its APECS study, which is examining verubecestat’s effect on patients with an earlier stage of Alzheimer’s — known as prodromal Alzheimer’s — or people with memory problems who are still functionally independent.
Verubecestat is a small inhibitor of the beta-site amyloid precursor protein that is involved in the development of Alzheimer’s. It acts by cleaving to, and therefore deactivating, the BACE1 enzyme. That short-circuiting contributes to the accumulation of faulty beta-amyloid in neurons, disrupting their activity.
The EPOCH study (NCT01739348) was a placebo-controlled, randomized trial evaluating the safety and effectiveness of two oral doses of verubecestat — 12 mg and 40 mg. Some patients got a 12-mg dose once a day, others a 40-mg dose, and others a placebo. The 78-week study involved patients with mild-to-moderate Alzheimer’s.
The primary endpoint, or measuring stick, was changes in patients’ Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) score and in their Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) score. Results will be presented at a scientific meeting, Merck said.
The Phase 3 APECS (NCT01953601) study is testing the safety and effectiveness of the same verubecestat regimens and a placebo in patients with prodromal Alzheimer’s, a stage when the very earliest symptoms appear. The study’s endpoint is changes in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score from the study’s start to up to 104 weeks of treatment. Results are expected in early 2019.
“Alzheimer’s disease is one of the most pressing and daunting medical issues of our time, with inherent, substantial challenges to developing an effective disease-modifying therapy for people with mild-to-moderate disease,” Roger Perlmutter, Merck Research Laboratories’ president, said in a news release. “Studies such as EPOCH are critical, and we are indebted to the patients in this study and their caregivers.
“While we are disappointed that a benefit was not observed in this study, our work continues with APECS, which is studying verubecestat in people with less advanced disease,” he said.
UsAgainstAlzheimer’s, a non-profit association that supports Alzheimer’s patients, praised Merck’s investment, researchers’ work and trial participants’ commitment.
“The spirited work of Merck and other drug companies that are concentrating vast resources into a cure for Alzheimer’s is not underappreciated,” George Vradenburg, co-founder and chairman of UsAgainstAlzheimer’s, said in a news release. Each outcome, some of which are “assuredly disheartening, builds our knowledge and leads us closer to a solution for the millions of people with Alzheimer’s or related dementias,” he said.
“Just as we have before, we will keep working incessantly, passionately and strategically so that the next round in this fight goes to us,” he added.
The disappointing news came three months after Eli Lilly’s solanezumab failure. The solznezumab announcement prompted Vradenburg to issue an open letter on the importance of continued research and development of Alzheimer’s therapies.