Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial

Abstract

Background: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis.

Methods: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial.

Results: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002).

Conclusions: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned.

Trial registration: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.

Keywords: Chronic kidney disease; Disparity; Metabolic acidosis; Physical function; Serum bicarbonate; Sex; Veverimer; Women.

Conflict of interest statement

VSM, DEW, NT, EL and DAB were paid consultants to Tricida, Inc. in connection with the development of this manuscript. VSM, DEW, NT and DAB are members of advisory boards at Tricida, Inc. and report consultancy and personal fees from Tricida, Inc. VSM is listed on patents related to work for Tricida, and reports stock or stock options in Tricida. VSM reports additional consulting fees from Tricida, Equillium, Myovant, Rigel, Corvidia, Acuta, Frazier, Intarcia, PTC Bio and Sanifit outside the submitted work. DAB reports stock and stock options from Tricida during and outside this work. DAB was the lead investigator for the phase 1/2 study of veverimer (TRCA-101) sponsored by Tricida and is on the advisory board for the ongoing VALOR-CKD post-marketing study sponsored by Tricida. DAB also reports consulting fees from Amgen, Sanofi/Genzyme, Fresenius/Relypsa/Vifor, personal fees as a medical advisory board member from Sanifit, speaker fees from Sanofi/Genzyme and stock ownership in Amgen and past stock ownership in Relypsa, all outside this work. DAB reports grant support from the National Institutes of Health and Renal Research Institute, both outside this work.

© 2022. The Author(s).

Figures

Fig. 1

Participant Flow for Women Subgroup. In the parent study, 5 patients discontinued treatment in the veverimer group (1 dialysis, 1 adverse event, 3 withdrawal or discontinuation for other reasons) and 4 patients discontinued treatment in the placebo group (2 died, 1 adverse event, and 1 withdrawal) before week 12. Five patients in the veverimer group and 6 patients in the placebo group declined to participate in the extension study, and one patient in the placebo group was ineligible for participation in the extension study. In the overall extension study, 3 patients discontinued treatment in the veverimer group (1 withdrawal and 2 lost to follow-up) and 8 patients discontinued treatment in the placebo group (2 died, 1 dialysis, 3 withdrawals, 1 lost to follow-up, and 1 other)

Fig. 2

Veverimer Effects on Serum Bicarbonate. A The top line shows the composite endpoint at treatment week 52. The two lower lines depict each component of the primary endpoint (percentage of patients who had a ≥ 4 mmol/L increase or normalization of serum bicarbonate at week 52). P-values are for the difference in proportions between the veverimer and placebo groups. B Change in serum bicarbonate from baseline to week 52. C Serum bicarbonate levels over time. The baseline serum bicarbonate was 17.2 (0.2) mmol/L and 17.3 (0.2) mmol/L in the veverimer and placebo groups, respectively. LS, least squares; SE, standard error

Fig. 3

Veverimer Effects on Physical Function. A Change from baseline in KDQOL-PFD. B Change from baseline in time to complete the repeated chair stand test. KDQOL-PFD, Kidney Disease Quality of Life physical function domain; SE, standard error