Phase III Success for CKD Complication Tx

The investigational drug veverimer was safe and effective for treating patients with metabolic acidosis from chronic kidney disease, according to phase III data.

In a 40-week extension study, only 2% of those on veverimer had serious adverse events compared with 5% of those on placebo — two of which were deaths — Donald Wesson, MD, of Baylor Scott & White Health and Wellness Center in Dallas, and colleagues reported in The Lancet.

Veverimer, a non-absorbed polymer, works by selectively binding to and removing hydrochloric acid from the gastrointestinal tract, which thus increases concentrations of serum bicarbonate. These findings build upon the 12-week multicenter parent study; safety and efficacy of the study drug were maintained for 52 consecutive weeks.

Further demonstrating safety — the study’s primary endpoint — the results showed that only 3% of patients receiving veverimer prematurely discontinued the treatment compared with 10% of those on placebo. Also, none of the patients who discontinued veverimer did so due to an adverse event.

Only 8% of those on veverimer had any adverse event relating to the renal system versus 15% of the placebo patients.

As for efficacy, which was measured in four secondary endpoints, significantly more individuals on veverimer maintained higher serum bicarbonate levels compared with placebo through 52 weeks even at week one, the researchers reported.

More people on veverimer had a 4 mEq/L (4 mmol/L) or greater increase of serum bicarbonate (63% vs 38%). Also, 57% of those on veverimer had normalization of serum bicarbonate during the study — ranging from 23 to 29 mEq/L — compared with 27% on placebo.

Significant improvements in physical functioning, as reported by the participants and measured with the Kidney Disease and Quality of Life Short Form-36, question 3, were also seen in patients on veverimer. Compared with those in the placebo group, those treated with veverimer saw an average difference in physical functioning of 12 points. Also demonstrating an improvement in physical functioning, those on the treatment had an improvement in mean time needed to perform the chair stand test — 4.3 second decrease for the veverimer group vs 1.4 second decrease for the placebo group.

The parent study included 124 individuals with non-dialysis-dependent chronic kidney disease and metabolic acidosis who were given a starting dose of 6 g oral veverimer once daily as suspension in water with food compared with 93 on placebo. After the 12-week study, 114 individuals on veverimer and 82 on placebo chose to continue in the extension, maintaining their blinded treatment. During this time, no addition of concomitant therapy or uptitration was allowed.

At baseline, all individuals had to have a bicarbonate level of 12-20 mEq/L and an estimated glomerular filtration rate of 20-40 mL/min per 1.72 m², Wesson, et al. noted.

“Metabolic acidosis in non-dialysis-dependent patients with chronic kidney disease has traditionally been treated with sodium-based alkali supplements, which might cause gastrointestinal and volume related-adverse effects,” the researchers explained, highlighting the dearth of available treatments for this chronic condition. Other care recommendations also typically include increasing fruit and vegetable intake to reduce net acid intake, the team added.

Writing in an accompanying commentary, Jeffrey Kraut, MD, of UCLA David Geffen School of Medicine Sciences in Los Angeles, and Kalani Raphael, MD, of the University of Utah Health in Salt Lake City, called the findings “compelling,” and said “more work needs to be done to establish the precise role of veverimer in the treatment of chronic metabolic acidosis.”

Kraut and Raphael added that because current treatment includes administration of sodium bicarbonate, sodium or potassium citrate, or increased fruits and vegetables — i.e., therapies that are safe and relatively inexpensive — veverimer should not be compared only with placebo.

Another caveat, the commentators said, was that over 95% of the study participants were white adults, and there were no pediatric patients.

“The effect of the ingestion of other drugs commonly taken by the general population that could affect gastric acid secretion, such as proton-pump inhibitors, on the bicarbonate-raising effect of veverimer needs to be evaluated,” Kraut and Raphael suggested.

Veverimer’s manufacturer, Tricida, announced plans to seek accelerated approval for the drug and expects to submit a New Drug Application to the FDA later this year.