Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD\u2014VIVIAD

E G B Vijverberg,P Alexandersen,F Weber,A R Bihlet,T M Axelsen,N D Prins,K Fuchs,K Henriksen,J E Harrison,Philip Scheltens,K Kühn-Wache

doi:10.1186/s13195-021-00882-9

Abstract

BackgroundVaroglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD.MethodsThis paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics.ResultsTo be expected early 2023ConclusionThis state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta.Trial registrationClinicalTrials.gov Identifier: NCT04498650

Highlights

Alzheimer’s disease (AD) affects approximately 47 million people worldwide and the prevalence will triple by 2050 [1]
It has become clear that the concentration of soluble β-amyloid (AB)-oligomers is more closely associated with clinical symptoms than amyloid plaque burden itself [3,4,5], by causing more synaptotoxicity, neuroinflammation, and neurodegeneration
In human autopsy studies on AD patients, pGluAB42 was found to constitute 10–50% of the total amyloid burden, but not found in plaques of subjects without signs or symptoms of AD, suggesting a significant role in the development of AD [15, 16], making the processes involved with pGluAB42 an interesting therapeutic target, highlighted by the recent encouraging news regarding donanemab, a monoclonal antibody targeting pGluAB42 [17]

Summary

Introduction

Alzheimer’s disease (AD) affects approximately 47 million people worldwide and the prevalence will triple by 2050 [1]. After the accelerated approval of aducanumab by the FDA on June 7, 2021, the AD field is even more motivated to develop new therapeutic targets associated with amyloid beta aggregation in the brain as well as other possible disease modifying targets [2]. In human autopsy studies on AD patients, pGluAB42 was found to constitute 10–50% of the total amyloid burden, but not found in plaques of subjects without signs or symptoms of AD, suggesting a significant role in the development of AD [15, 16], making the processes involved with pGluAB42 an interesting therapeutic target, highlighted by the recent encouraging news regarding donanemab, a monoclonal antibody targeting pGluAB42 [17]. Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD

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Conclusion