Ardelyx Inc. announced that tenapanor, its investigational treatment for hyperphosphatemia in end-stage renal disease patients, met its primary endpoint in a phase 3 study.

Key trial results

The responder population (n=80 out of 164) had a mean reduction in serum phosphorus from baseline to the end of the eight-week treatment period of 2.56 mg/dL, with a reduction of up to 5.7 mg/dL. In this group, 33% of patients had a reduction in serum phosphorus of greater than 3 mg/dL. The responder population, which was reviewed by the U.S. Food and Drug Administration, is defined as patients who demonstrate a greater than or equal to 1.2 mg/dL decrease in serum phosphorus from baseline during the initial eight-week treatment period.

The study demonstrated a statistically significant difference in serum phosphorus levels from the end of the eight-week treatment period to the end of the four-week randomized withdrawal period between the tenapanor-treated group and the placebo-treated group in the responder patient population (mean -1.01 mg/dL, median of -1.3 mg/dL) and met its primary endpoint (95% CI -1.44, -0.21; LSmean -0.82 mg/dL; p=0.01). Only 7.8% of patients discontinued treatment due to GI side effects.

“The reduction in serum phosphorus in many patients treated with tenapanor is remarkable. These data validate tenapanor’s unique mechanism of action and its potential to be the first non-phosphate binder treatment for this difficult-to-manage disorder,”

“My patients are often required to take more than 19 pills per day, of which, nearly half are phosphate binders,” said Geoff Block M.D., director, clinical research at Colorado Kidney Care, and a Phase 3 investigator. “The efficacy of tenapanor with only a few small pills, combined with its GI tolerability, has the potential to change the way in which we treat our patients in the future. I look forward to participating in the next Phase 3 study and evaluating the full potential of this novel agent.”

About the trial

The Phase 3 trial was an eight-week, double-blind, randomized trial, with a four-week placebo-controlled randomized withdrawal period. Ardelyx enrolled a total of 219 ESRD patients with hyperphosphatemia who are on dialysis. Enrolled patients were randomized evenly into three arms, in which all groups received tenapanor for eight weeks.

Tenapanor was administered at doses of 3 mg or 10 mg twice-daily and in a dose-titration arm starting at 30 mg twice-daily with the option to down-titrate once a week during the first four weeks to 20, 15, 10 and 3 mg twice-daily, based on GI tolerability. After the end of the eight-week treatment period, patients were re-randomized 1:1 to either remain on their current tenapanor dose or switch to placebo for a four-week, placebo-controlled, randomized withdrawal period.

The primary endpoint of the trial is the difference in change in serum phosphorus between the pooled tenapanor-treated patients and placebo-treated patients from the end of the eight-week treatment period to the end of the four-week randomized withdrawal period, in the responder population.

Tolerability endpoints included stool consistency as measured by the Bristol Stool Form Scale and frequency.

Tenapanor was well-tolerated in the trial. In the eight-week treatment period, the only adverse event that affected more than five percent of patients treated with tenapanor was diarrhea (39%), a patient-reported side effect of loosened stool or increased frequency in bowel movements regardless of magnitude.

In the four-week randomized withdrawal period, there was a diarrhea rate of 1.2% for patients treated with tenapanor compared with 2.4% on placebo. Treatment discontinuations due to diarrhea for patients treated with tenapanor was 7.8% (n=17). There were no discontinuations due to diarrhea in the randomized withdrawal period.

In order to fully assess GI tolerability, patients used an eDiary to record the frequency of daily bowel habits, as well as stool form using the Bristol Stool Form Scale (BSFS). During the eight-week treatment period, there was a 0.4 per day increase in bowel movement frequency from baseline, and during the four-week randomized withdrawal period, there was a 0.29 per day increase as compared to placebo. Bowel movement frequency was within the normal range in all groups.

During the eight-week treatment period, there was a 0.87 point increase in BSFS from a baseline score of 4.2, out of a maximum of seven, where seven is liquid stool. During the four-week randomized withdrawal period, there was a 0.7 point difference in BSFS between placebo (4.4) and tenapanor treatment (5.1).

Second Phase 3 trial

Ardelyx said it plans to initiate the second Phase 3 study of tenapanor for the treatment of hyperphosphatemia in ESRD patients on dialysis in mid-2017.

This Phase 3 study will include a 26-week open-label treatment period, with a randomized withdrawal period followed by an additional 26-week long-term safety extension. Full details of the final trial design are under consultation with advisors and will be disclosed upon study initiation.

Ardelyx plans to submit detailed results from its first Phase 3 trial for presentation during the American Society of Nephrology Kidney Week taking place in New Orleans from October 31 to November 5, 2017.