Submitted by Administrator on Sat, 16/03/2019 - 15:38
Dr Brian Ference, colleagues at the University of Cambridge, and a group of international collaborators have modelled the effects of life-long lowering of low density lipoprotein cholesterol (LDL-C) with a new type of drug called bempenoic acid. This study has been published in NEJM.
Using large-scale genetic epidemiological data and innovative quantitative techniques, the study represents a "naturally randomized trial" of the potential clinical safety and efficacy of lowering plasma LDL-C using ATP-citrate lyase inhibitors, a novel class of medicines currently in development.
This is the first Mendelian randomisation study that provides, in a single study, genetic validation for a therapeutic mechanism of action; genetic target validation for a novel therapy; genetic validation of the potential clinical benefit of therapies directed against that target; and genetic validation of the safety of the novel mechanism of action.
It is also the first Mendelian randomisation study published as a companion to the CLEAR Harmony trial, a randomised controlled trial (RCT). The study provides a biological context for interpreting the results of an early phase RCT evaluating ATP-citrate lyase inhibitors, directly informs the design of the pivotal Phase 3 clinical trial of cardiovascular outcomes for this class of medicines, and explicitly anticipates the expected clinical benefit of this class of agents whether used alone or in combination with other therapies.
As a result of the "naturally randomised trial" and randomised controlled trial being published together as companion manuscripts in the same issue of the NEJM, this study may represent a new paradigm where early phase RCTs are published together with a companion Mendelian randomisation study framed as a “naturally randomised trial” to guide the clinical development programme of
novel therapies.
This approach has the potential to fill the "translational gap" between discovering genetically validated therapeutic targets and anticipating their expected clinical relevance.
