Merck & Co.'s investigational Alzheimer's drug verubecestat reduces levels of amyloid-beta plaques in Phase I study

Merck & Co. on Wednesday announced that study data from an early-phase trial of the experimental therapy verubecestat, formerly known as MK-8931, were published in the journal Science Translational Medicine, with findings showing that the BACE1 inhibitor reduced levels of amyloid-beta plaques in the brains of patients with Alzheimer's disease. Merck also noted that it has initiated two Phase III trials of the oral therapy in the treatment of mild-to-moderate Alzheimer's disease and prodromal Alzheimer's disease, respectively. Merck Research Laboratories vice president Michael Egan remarked "we believe this research has the potential to contribute important evidence regarding the amyloid hypothesis…and we look forward to seeing the data from our ongoing Phase III clinical trials." 

In the Phase I study, 32 patients with mild-to-moderate Alzheimer's disease were randomised to treatment with verubecestat, at a dose of 12 mg, 40 mg or 60 mg, or placebo once daily for seven days. The investigators collected cerebrospinal fluid samples over 36 hours and assessed levels of amyloid-beta 40, amyloid-beta 42 and soluble amyloid precursor protein beta as biomarkers of BACE1 activity. 

According to Merck, verubecestat at doses of 12 mg, 40 mg and 60 mg caused a dose-dependent and sustained reduction in the levels of amyloid-beta 40 from baseline in the cerebral spinal fluid, of 57 percent, 79 percent and 84 percent, respectively.  Further, the researchers found no changes in vital signs and laboratory values linked to administration of the oral BACE1 inhibitor, while no treatment discontinuations associated with adverse events were recorded.

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Commenting on the findings, Rosa Sancho, head of research at Alzheimer's Research UK, remarked "there is a wave of potential new treatments currently being tested for dementia, with the results of these studies hotly anticipated over the course of the coming months and years." Sancho continued "as verubecestat works differently to other drugs currently being tested for Alzheimer's, if it proves successful, it could be an important weapon in the arsenal for doctors treating the disease in future." 

Regarding the late-stage studies, Merck explained that the EPOCH Phase II/III trial is evaluating efficacy and safety of oral doses of 12 mg or 40 mg of verubecestat compared to placebo in patients with mild-to-moderate Alzheimer's disease who are receiving standard of care treatment. The primary efficacy endpoints of the trial being the changes from baseline in the Alzheimer's Disease Assessment Scale Cognitive Subscale and Alzheimer's Disease Cooperative Study – Activities of Daily Living score, following 78 weeks of treatment. 

Meanwhile, the APECS Phase III study is evaluating the safety and efficacy of verubecestat in 1500 subjects with prodromal Alzheimer's disease compared to placebo. Specifically, patients will be randomised to receive either 12 mg, 40 mg of verubecestat, or placebo, once-daily. The primary endpoint of the trial is the change from baseline in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) score following 104 weeks of treatment. 

Matthew Kennedy, director of early discovery neuroscience at Merck, commented "we expect to complete the Phase 3 trial of verubecestat in patients with mild-to-moderate Alzheimer's disease in 2017," adding "we were pleased to have been granted Fast Track Status by the FDA and should the Epoch trial be successful, we plan to move forward with regulatory filing as quickly as possible." 

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