Merck Stops Phase 3 Trial of Verubecestat in Early Alzheimer’s Patients Amid Concerns Over Benefit
In another blow to hopes for an effective Alzheimer’s treatment, Merck announced that it is stopping its Phase 3 clinical study testing verubecestat (MK-8931) in patients with early stage disease.
No specific reason was given, but lack of effectiveness in data compiled to date is a likely cause.
The decision follows a cease-trial recommendation by an external Data Monitoring Committee, after a recent interim safety analysis concluded the APECS study (NCT01953601) was unlikely to show positive treatment benefit compared to the risk could be established by continuing.
“We are disappointed with this outcome, especially given the lack of treatment options for patients suffering from Alzheimer’s,” Roger M. Perlmutter, MD, president at Merck Research Laboratories, said in a press release. “We are grateful to the patients and caregivers who participated in this study, and despite this outcome, Merck remains committed to developing novel therapies for the treatment of Alzheimer’s and other neurodegenerative diseases.”
At roughly the same time, Biogen disclosed that it will recruit 510 more patients to its two Phase 3 studies — EMERGE (NCT02484547) and ENGAGE (NCT02477800) — on aducanumab (BIIB037), a potential treatment targeting amyloid plaques in early Alzheimer’s patients, according to a company webcast and news reports. Roughly 255 new patients will be brought into each ongoing trial, both set to end in 2022. Together, the trials will now enroll a total of 3,210 patients.
The company made this decision after a sample re-estimation revealed “more variability on the primary endpoint than assumed … to maintain 90% power,” Biogen’s chief medical officer, Al Sandrock, said in the Feb. 14 webcast that was part of the Leerink Partners 7th Annual Global Healthcare Conference. Like in the aducanumab studies, the verubecestat trial also had changes in cognitive impairment as a primary measure.
Sandrock said he did not consider the change in enrollment to affect “our assumptions about [treatment] efficacy” and described the re-estimation as routine.
Merck’s double-blind APECS trial was assessing the safety and efficacy of verubecestat in prodromal (early) Alzheimer’s patients. The investigational drug inhibits BACE1, one of the two key enzymes in the generation of beta-amyloid, the main component of plaque buildup in Alzheimer’s.
Participants had been randomly assigned to treatment with once-daily verubecestat (12 mg or 40 mg) or placebo.
The study’s primary efficacy outcome was changes in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score, an assessment of dementia severity, after 104 weeks of treatment. Trial data will be presented at an upcoming medical conference, Merck said in its release.
Biogen’s ENGAGE and EMERGE rials also evaluate changes in CDR-SB, comparing monthly, intravenous doses of aducanumab with placebo. Both studies started in 2015. Fewer patients than expected are dropping out of the study, the company noted in the webcast, adding that total recruitment is still expect to finish over the summer. Biogen expects to end primary evaluations of ENGAGE in 2019 and of EMERGE in 2020. Enrollment information is available on each trials identification number.
Aducanumab, a human antibody that targets aggregated forms of beta-amyloid, demonstrated positive results in an earlier extension study of a Phase 1 trial (NCT01677572), where, after 36 months of treatment, amyloid plaque deposits were lower in many patients’ brains than the level a scan would identify as constituting Alzheimer’s.
Symptom assessments also suggested that patients continued to benefit in their second and third years of treatment.