Ardelyx, a clinical-stage company focused on enhancing the treatment of patients with cardiorenal and gastrointestinal (GI) diseases, has reported that the phase III clinical trial evaluating the efficacy and safety of tenapanor as a treatment for hyperphosphatemia in patients with end-stage renal disease (ESRD) who are on dialysis met its primary endpoint and was generally well-tolerated.

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 5.7mg/dL. Notably, in this group, 33% of patients had a reduction in serum phosphorus of greater than 3mg/dL. 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 -1.01mg/dL, median of -1.3mg/dL) and met its primary endpoint (95% CI -1.44, -0.21; LSmean -0.82mg/dL; p=0.01). Only 7.8% of patients discontinued treatment due to GI side effects.

Hyperphosphatemia is a condition of higher than normal levels of serum phosphorus in the blood that is estimated to affect more than 745,000 people with ESRD who are on dialysis in major developed countries.

"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," said Geoff Block M.D., director, clinical research at Colorado Kidney Care, and a phase III investigator. "My patients are often required to take more than 19 pills per day, of which, nearly half are phosphate binders. 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 III study and evaluating the full potential of this novel agent."

"We are very pleased with the overall efficacy and improved tolerability profile of tenapanor in this study. The magnitude of the reduction of serum phosphorus in a large%age of patients treated with tenapanor in this trial surpassed our expectations," said Mike Raab, president and chief executive officer of Ardelyx. "We are highly confident in tenapanor and look forward to further establishing its clinical and commercial value in the next Phase 3 trial."

Tenapanor was well-tolerated in the trial. In the eight-week treatment period, the only adverse event that affected more than five% 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).

The results from this trial support Ardelyx's plans to initiate the second phase III study of tenapanor for the treatment of hyperphosphatemia in ESRD patients on dialysis in mid-2017. This phase III 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.

"What is particularly exciting about these data is the innovation that we are bringing to patients on dialysis who have relied on the available binder treatments for decades," said Dr. Reg Seeto, chief operating officer of Ardelyx. "These positive data from our first phase III study are an important milestone for Ardelyx. They are essential to our ability to achieve our goal of establishing leading, revenue-generating cardiorenal and GI business units over the next five years, and bringing important new medicines to underserved patients."

The phase III 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 3mg or 10mg twice-daily and in a dose-titration arm starting at 30mg twice-daily with the option to down-titrate once a week during the first four weeks to 20, 15, 10 and 3mg 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. The responder population, which was reviewed by the FDA, is defined as patients who demonstrate a greater than or equal to 1.2mg/dL decrease in serum phosphorus from baseline during the initial eight-week treatment period.