The new england journal of medicine Original Article Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease Michael F. Egan, M.D., James Kost, Ph.D., Pierre N. Tariot, M.D., Paul S. Aisen, M.D., Jeffrey L. Cummings, M.D., Sc.D., Bruno Vellas, M.D., Ph.D., Cyrille Sur, Ph.D., Yuki Mukai, M.D., Tiffini Voss, M.D., Christine Furtek, B.S., Erin Mahoney, B.A., Lyn Harper Mozley, Ph.D., Rik Vandenberghe, M.D., Ph.D., Yi Mo, Ph.D., and David Michelson, M.D.​​ ABSTRACT BACKGROUND Alzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques in From Merck Research Laboratories, Merck, the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein Kenilworth, NJ (M.F.E., J.K., C.S., Y. Mu- kai, T.V., C.F., E.M., L.H.M., Y. Mo, D.M.); by β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by Banner Alzheimer’s Institute, Phoenix, γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the AZ (P.N.T.); University of Southern Cali- cerebrospinal fluid of patients with Alzheimer’s disease. fornia, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, METHODS Las Vegas (J.L.C.); Gerontopole, INSERM We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evalu- Unité 1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University ate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in Hospital, Toulouse, France (B.V.); and patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The Leuven Institute of Neuroscience and Dis- coprimary outcomes were the change from baseline to week 78 in the score on the ease, Alzheimer Research Center, and the Laboratory for Cognitive Neurology, De- cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores partment of Neurosciences, Katholieke range from 0 to 70, with higher scores indicating worse dementia) and in the score on Universiteit Leuven, and Neurology, Uni- the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale versity Hospitals — both in Leuven, Bel- gium (R.V.). Address reprint requests to (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). Dr. Egan at Merck & Co., UG 4C-06, 351 N. Sumneytown Pike, North Wales, PA RESULTS 19454, or at michael . egan@ merck . com. A total of 1958 patients underwent randomization; 653 were randomly assigned to receive N Engl J Med 2018;378:1691-703. verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat DOI: 10.1056/NEJMoa1706441 at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The Copyright © 2018 Massachusetts Medical Society. trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P = 0.63 for the comparison between the 12-mg group and the placebo group and P = 0.46 for the comparison between the 40-mg group and the placebo group). The esti- mated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P = 0.49 for the comparison between the 12-mg group and the placebo group and P = 0.32 for the com- parison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS Verubecestat did not reduce cognitive or functional decline in patients with mild-to- moderate Alzheimer’s disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348.) n engl j med 378;18 nejm.org May 3, 2018 1691 The New England Journal of Medicine Downloaded from nejm.org by Diane Sanders on July 16, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. The new england journal of medicine lzheimer’s disease is character- ate dementia (scores range from 0 to 30, with ized by the deposition of amyloid-beta lower scores indicating poorer cognitive perfor- (Aβ) aggregates and neurofibrillary tan- mance).14 Patients could have been receiving an A 1 gles in the brain. The amyloid cascade hypoth- acetylcholinesterase inhibitor, memantine, or esis proposes that Aβ aggregates trigger the both, provided that they were receiving a stable spreading of tau-related neurofibrillary tangles dose for 3 months before screening. The diagno- and subsequent neuronal degeneration.2 Aβ is sis of Alzheimer’s disease was confirmed by an produced when amyloid precursor protein (APP) independent expert who reviewed the investiga- is cleaved sequentially by β-site APP–cleaving tor’s written narrative of the patient’s history, enzyme 1 (BACE-1; also referred to as β-secretase) including pertinent laboratory data and baseline and γ-secretase.3 Inhibition of BACE-1 is a poten- clinical measures. tial therapeutic strategy for slowing the progres- sion of Alzheimer’s disease by reducing the Trial Design production of Aβ. This approach differs from The trial was conducted at 238 centers in 21 previous approaches in which monoclonal anti- countries from November 2012 through April bodies were used to clear Aβ from the brain; 2017. A list of investigators is provided in the these earlier strategies showed a modest effect Supplementary Appendix, available with the full on measures of amyloid deposition, resulted in text of this article at NEJM.org. The trial con- little or no clinical efficacy in patients with sisted of a randomized, double-blind, placebo- symptomatic Alzheimer’s disease, and have been controlled, parallel-group, 78-week trial period associated with amyloid-related imaging abnor- (part 1), followed by an optional extension period malities.4-6 Other approaches to reducing amy- with a total planned duration of up to 5 years loid burden, such as γ-secretase inhibitors or (part 2). Part 1 was designed to include a phase 2 modulators,7,8 and active immunotherapy9 have lead-in safety cohort component that was intend- also been unsuccessful. ed to transition to a phase 3 trial if satisfactory Verubecestat is an oral BACE-1 inhibitor that safety results were observed. In the phase 2 lead-in has been shown to reduce the Aβ level in the safety period, patients were randomly assigned cerebrospinal fluid and brain of rodents and to receive, once daily, one of three oral dose nonhuman primates by more than 90%10,11 and levels of verubecestat (12 mg, 40 mg, or 60 mg) in the cerebrospinal fluid of healthy people or placebo. These dose levels were selected on and of patients with Alzheimer’s disease by more the basis of data from phase 1 studies in humans than 75%.11 We conducted a randomized, placebo- that suggested that doses of 12 mg and 40 mg controlled, phase 3 trial to determine whether reduced levels of Aβ-40 and Aβ-42, the major verubecestat at a dose of 12 mg per day or 40 mg metabolites of BACE-1 cleavage of APP, in cere- per day could slow disease progression in patients brospinal fluid by 60% (12 mg) or 75% (40 mg).11 with mild-to-moderate Alzheimer’s disease. The 60-mg dose level was included in the phase 2 lead-in safety cohort to explore the safety of this Methods high dose and was prespecified to be dropped for the phase 3 component of the trial. All the Patient Population assigned trial regimens were administered as Patients were eligible for enrollment in the trial identical-appearing tablets. if they were between 55 and 85 years of age and The first planned interim analysis, which was if they met standard research and clinical crite- conducted 3 months after the randomization of ria for dementia that was probably due to Alz- 200 patients, informed the decision to progress heimer’s disease.12,13 All the patients underwent to phase 3. The data from these first 200 pa- appropriate medical and neurologic evaluations, tients were excluded from the primary efficacy including magnetic resonance imaging (MRI) and safety analyses. Randomization continued (or computed tomography if MRI was contrain- during the 3 months after the 200th patient was dicated), to exclude patients who had alternative enrolled, during which time approximately 200 causes of dementia. Entry criteria included a score additional patients were randomly assigned to a of 15 to 26 on the Mini–Mental State Examina- trial group, including 53 patients who were as- tion (MMSE), which represented mild or moder- signed to receive a 60-mg dose of verubecestat 1692 n engl j med 378;18 nejm.org May 3, 2018 The New England Journal of Medicine Downloaded from nejm.org by Diane Sanders on July 16, 2018. For personal use only. No other uses without permission. Copyright © 2018 Massachusetts Medical Society. All rights reserved. Verubecestat for Mild-to-Moderate Alzheimer’s Disease and whose data were excluded from the primary personnel performed the outcome assessments in analyses. The patients who had been assigned patients were recorded, and a subset of these ses- to receive the 60-mg dose were switched to the sions underwent quality review by independent 40-mg dose for the remainder of the trial.