Tenapanor Supplants Support for 2018 NDA Submission

Ardelyx released positive results from its second phase 3 study of tenapanor for irritable bowel syndrome with constipation (IBS-C) in support of its New Drug Application (NDA) submission in 2018.

The T3MPO-2 trial hit statistical significance for the primary and secondary endpoints evaluated for topline results, demonstrating the ability to normalize bowel movements.

"The results from this clinical trial clearly demonstrate the potential of tenapanor to offer a new option, which works through a completely unique mechanism of action, for people with IBS-C and their treating physicians,” David Rosenbaum, PhD, chief development officer, Ardelyx, told MD Magazine. “If approved, we believe that tenapanor is will become an important new treatment for patients."

The trial was conducted in 593 patients meeting the ROME III criteria for the diagnosis of IBS-C. Patients were randomized 1:1 to receive either 50 mg of tenapanor (n=293) or placebo (n=300) twice daily.

A 2-week screening period occurred during which patients with active IBS-C, based on bowel movement frequency and abdominal pain score recorded in a daily phone diary, were randomized into the trial.

Throughout the screening period, baseline scores were well-balanced between the tenapanor and placebo groups. The mean weekly CSBMs were .11 and the mean abdominal pain score was 6.26 on a 0—10 scale, where 0 was no 10 and 10 was severe.

The primary endpoint of the combined responder rate of 6/12 weeks showed a greater proportion of tenapanor-treated patients

versus placebo-treated patients (36.5% versus 23.7%) who experienced at least a 30% reduction in abdominal pain and an increase of 1 or more complete spontaneous bowel movements (CSBM) in the same week for at least 6 of the 12 weeks of treatment, showing a clear benefit in treated patients.

Secondary endpoints included a CSBM responder rate of 6/12 weeks, abdominal pain responder week of 6/12 weeks, combined responder rate of 9/12 weeks, abdominal pain responder rate of 9/12 weeks, and durable responder rates of 9/12 weeks — all 3 durable responder endpoints are identical to the 9/12 week responder endpoints, except the response must also occur in 3 of the last 4 treatment period weeks.

“Tenapanor works through NHE3 inhibition vs. the current therapies which are pro-secretory drugs that work through chloride channels,” Rosenbaum said. “The primary endpoint data in T3MPO-2, which support its approvability, are the highest 6 of 12-week combined responder rate data across all phase 3 clinical trials reported in the industry, and the 9 of 12-week data are best-in-class demonstrating tenapanor’s ability to normalize bowel function. In addition, tenapanor showed a fast onset-of-action (1 week) with consistent response across 26 weeks of the trial, and was well-tolerated with very low rate of discontinuations.”

The drug was well tolerated and consistent across previous clinical trials. The adverse effects observed in more than 2% of patients in the tenapanor-treated group that were also greater than the placebo-treated group were diarrhea (16% vs. 3.7%), flatulence (3.1% vs. 1%), nasopharyngitis (4.4% vs. 3.7%), and abdominal distention (3.4% vs. 0.3%). The placebo adjusted discontinuation rate due to diarrhea was 5.8%.

Based on topline results from 2 positive phase 3 trials, Ardelyx will likely submit a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for tenapanor in treatment of IBS-C in the latter half of 2018.

Patients that completed T3MPO-1 and T3MPO-2 are eligible for T3MPO-3, the open-label, long-term safety trial allowing patients to receive tenapanor for up to 1 year. The fully enrolled trial is expected to conclude in late 2017, and results will be included in the NDA submission.

Tenapanor is also being tested as a treatment for elevated levels of phosphorous in the blood in patients suffering from end stage renal disease.

A press release was made available.