Veverimer does not delay CKD progression

Treatment with once-daily veverimer did not delay chronic kidney disease (CKD) progression, according to the results of the phase III VALOR-CKD trial.

“We found that in this study, treatment with veverimer did not result in a slowing of CKD progression or improvement in physical function,” said lead author Associate Professor Navdeep Tangri from the Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada, at Kidney Week 2022.

This international (346 sites in 35 countries), double-blind trial included 1,480 patients (mean age 65.1 years, 42 percent female) with CKD (estimated glomerular filtration rate [eGFR] 20–40 mL/min/1.73 m² [mean 29.1 mL/min/1.73 m²]) and serum bicarbonate levels 12–20 mEq/L (mean 17.5 mEq/L). They were randomized 1:1 to receive veverimer or placebo QD.

Median urine albumin-to-creatinine ratio (UACR) at baseline was 201 mg/g and patients had a median 5-year predicted risk of kidney failure of 32 percent. Most patients (>98 percent) were on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and about 12 percent were on background alkali supplements. Fifty-six percent of patients had a history of diabetes, while 98 and 32 percent had a history of hypertension and heart failure, respectively.

Patients treated with veverimer did not experience a reduction in kidney disease progression (a composite of developing end-stage kidney disease [ESKD]*, sustained ≥40-percent reduction from baseline in eGFR levels, or death due to kidney failure) compared with those treated with placebo (20.2 percent vs 20.1 percent; hazard ratio [HR], 0.99, 95 percent confidence interval, 0.78–1.24; p=0.898). [Kidney Week 2022, abstract FR-OR65]

Change in Kidney Disease Quality of Life total score between baseline and 12 months did not differ between the veverimer and placebo groups (between-group difference 0; p=0.871), nor did time to ESKD or renal death (HR, 0.96; p=0.831) or time to the primary endpoint event or cardiovascular (CV) mortality (HR, 1.03; p=0.751).

Doubling of serum creatinine levels from baseline also did not differ between groups (HR, 1.13; p=0.546), nor did ≥50-percent reduction from baseline in eGFR levels (HR, 1.09; p=0.557), time to recurrent hospitalization (HR, 0.94; p=0.535), time to CV mortality (HR, 0.99; p=0.956), or time to all-cause mortality (HR, 1.02; p=0.869).

“We did not find any meaningful interactions or differences that highlighted a benefit in one subgroup over another,” said Tangri.

Treatment-emergent adverse event (TEAE) rates were similar between the veverimer and placebo groups, both non-serious (54.1 percent vs 53.5 percent) and serious (26.7 percent vs 27.8 percent) TEAEs. The rates of hypertension and hyperkalaemia were comparable between groups.

“Veverimer was safe and well tolerated in older adults with advanced CKD and metabolic acidosis, with no differences in frequent or serious AEs,” said Tangri.

“Epidemiologic studies show that metabolic acidosis is associated with progression of CKD and impaired physical function,” said Tangri. Small studies have shown that reducing this acid load delays CKD progression and improves physical function, he added.

“In this trial, treatment with veverimer did not result in a clinically significant improvement of serum bicarbonate levels,” he continued. “The bicarbonate levels in patients randomized to placebo (~21 mEq/L) may have limited our ability to achieve a clinical or biochemical benefit from correction of metabolic acidosis,” he concluded.