Veverimer: An Emerging Potential Treatment Option for Managing the Metabolic Acidosis of CKD

Abstract

Sodium bicarbonate is the mainstay treatment of the metabolic acidosis of chronic kidney disease but associated concerns center on administering sodium to patients with hypertension and sodium-retentive states. Veverimer (formerly referred to as TRC101), a drug candidate for which Tricida, Inc is seeking approval from the US Food and Drug Administration, is a novel nonabsorbable polymer that binds hydrogen cations and chloride anions in the gastrointestinal tract and then is excreted fecally, thereby increasing serum bicarbonate concentration without administering sodium. We examine the published evidence on the investigational use of veverimer in patients with chronic kidney disease and metabolic acidosis. We highlight the achieved increase in serum bicarbonate concentration without coadministering sodium, effects on physical functioning, and the safety record of the drug. We also scrutinize certain unanticipated findings: a lack of dose dependency in the increase in serum bicarbonate concentration observed and that despite the presumed large hydrogen chloride losses in feces, veverimer induces an isochloremic increase in serum bicarbonate concentration that is accompanied by a decrease in serum anion gap. We propose likely explanations for these puzzling findings and raise questions about veverimer's mode of action and its potential interaction with colonic bacterial flora. Additional work is required to fill these knowledge gaps that could have important clinical implications.

Keywords: CKD (chronic kidney disease); TRC101; Veverimer; acid retention; anion gap; colonic bacterial flora; gastric HCl binding; hypothesis; investigational drug candidate; isochloremic hyperbicarbonatemia; mechanism of action; metabolic acidosis of CKD; serum bicarbonate; short-chain fatty acids.