VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI and Mild AD: Dose Selection and Interim Safety Results

Abstract

BackgroundVaroglutamstat (PQ912), a small molecule glutaminyl cyclase (QPCT) inhibitor, reduces the brain levels of pyroglutamate‐3‐Aβ (N3pE‐Aβ), a toxic Aβ variant shown to play a pivotal role in the development and progression of Alzheimer’s disease (AD). Encouraging results reported in a prior Phase 2a study (NCT02389413) led to the initiation of a state‐of‐the‐art Phase 2b trial investigating multiple cognitive, safety and biomarker endpoints.MethodsVIVIAD (NCT04498650) is a multicentre randomized, placebo‐controlled, double‐blind, parallel group dose finding Phase 2b study in patients with cognitive impairment (MCI) and mild AD. Objectives are to evaluate the longterm efficacy (primary endpoint Cogstate NTB), safety and tolerability of oral varoglutamstat. The study will recruit 250 patients. The first 90 patients are randomised 1:1:1 (600 mg twice daily, (BID) or 300 mg BID varoglutamstat or placebo BID). An independent DSMB will unblind safety results after 90 patients have completed 24 weeks of treatment in June 2022 and decide on the varoglutamstat dose to be carried forward. The data remain blinded outside the DSMB. After the DSMB decision, all patients will be randomised 1:1 between the final dose of varoglutamstat and placebo and continue treatment up to 48‐96 weeks dependent on study entry date.ResultsThe study is currently enrolling patients in 22 AD study centers in 5 European countries (160 patients are randomised as of April 25, 2022). The safety data providing the base for the DSMB dose decision, the DSMB decision itself and the baseline characteristics of the patients enrolled into the trial so far will be reported at AAIC.ConclusionThe state‐of‐the art Phase 2b study VIVIAD is designed to yield important results in early AD for varoglutamstat, the first small molecule and only project in clinical development selectively targeting the de novo production of neurotoxic N3pE‐Aβ. The DSMB decision represents an important milestone within the Phase 2b study as it will recommend the dose of varoglutamstat considered to be safe for being carried forward to the study completion.