Ardelyx's Tenapanor Meets all Goals in Phase III IBS-C Study

Ardelyx reported positive results from T3MPO-2, its second Phase 3 study of tenapanor for irritable bowel syndrome with constipation (IBS-C). The study hit statistical significance for the primary endpoint and all secondary endpoints evaluated for the topline results and demonstrated the ability to normalize bowel movements. The primary endpoint, the combined responder rate for six of 12 weeks, showed that a greater proportion of tenapanor-treated patients compared to placebo-treated patients (36.5% vs. 23.7%, p<0.001) had at least a 30 percent reduction in abdominal pain and an increase of one or more complete spontaneous bowel movements (CSBM) in the same week for at least six of the 12 weeks of the treatment period. In addition, tenapanor achieved statistical significance for the CSBM and abdominal pain responder rates in the six of 12 and nine of 12-treatment weeks, with a consistent response across the 26 weeks of the study. Tenapanor was well-tolerated in treated patients.

“These results are a game-changer for patients with IBS-C, their treating physicians and for Ardelyx as a company,” said Mike Raab, president and chief executive officer of Ardelyx. “They demonstrate the significant benefit tenapanor can have for patients with IBS-C, importantly, leading to a normalization of bowel movements for many patients. These results show that tenapanor has significant potential in the market and bolsters our commitment to identify the ideal collaboration partner to help ensure that we reach the most patients possible who would benefit from therapy.”

“IBS-C is a highly burdensome and difficult-to-treat condition affecting more than 11 million people in the United States, and often preventing them from engaging in day-to-day activities, such as going to work, exercising and even meeting socially with family and friends,” said William Chey, M.D., University of Michigan. “Based on tenapanor’s unique mechanism of action, which relies upon the inhibition of sodium absorption, and the exciting data reported today, tenapanor has the potential to be an important advancement and a new treatment option for patients suffering from IBS-C.”

T3MPO-2 Trial Design
T3MPO-2 is a 26-week, double-blind, placebo-controlled, multi-center, randomized trial. The trial was conducted in a total of 593 patients meeting the ROME III criteria for the diagnosis of IBS-C. Patients were randomized one-to-one to receive either 50 mg of tenapanor (n=293) or placebo (n=300) twice-daily. The trial included a two-week screening period, during which patients with active disease, based on bowel movement frequency and abdominal pain score recorded in a daily phone diary, were randomized into the trial.

T3MPO-2 Top-line Efficacy Results
During the two-week screening period, the baseline scores were well-balanced between the tenapanor and placebo groups. The mean weekly CSBMs were 0.11 and the mean abdominal pain score was 6.26 (on a 0 – 10 scale where 0 was no pain and 10 was very severe). Key data are as follows:

Table 1
6 of 12 Treatment Week Results	Tenapanor	Placebo	P value
Combined responder (primary endpoint) (abdominal pain and CSBM responder)	36.5%	23.7%	p<0.001
CSBM responder (increase ≥ 1 CSBM from baseline)	47.4%	33.3%	p<0.001
Abdominal pain responder (≥ 30% abdominal pain reduction)	49.8%	38.3%	p=0.004

Table 2
9 of 12 Treatment Week Results	Tenapanor	Placebo	P value
Combined responder (abdominal pain and CSBM responder)	18.4%	5.3%	p<0.001
CSBM responder (increase ≥ 1 CSBM from baseline and ≥3 CSBM/week)	22.2%	6.0%	p<0.001
Abdominal pain responder (≥ 30% abdominal pain reduction)	35.8%	26.7%	p=0.015

Table 3
Durable Responder Results (9 of 12 and >3 of last 4 treatment weeks)	Tenapanor	Placebo	P value
Combined responder (abdominal pain and CSBM responder)	18.1%	5.0%	p<0.001
CSBM responder (increase ≥ 1 CSBM from baseline and ≥3 CSBM/week)	21.2%	5.7%	p<0.001
Abdominal pain responder (≥ 30% abdominal pain reduction)	34.8%	26.7%	p=0.028

T3MPO-2 Safety Results
Tenapanor was well-tolerated, consistent with the experience across previous clinical trials. The only adverse events observed in more than two percent of patients in the tenapanor-treated group that were also greater than placebo were diarrhea (16.0% vs. 3.7%), flatulence (3.1% vs. 1.0%), nasopharyngitis (4.4% vs. 3.7%) and abdominal distension (3.4% vs. 0.3%). The placebo adjusted discontinuation rate due to diarrhea was 5.8 percent.

Based on positive results from two positive Phase 3 trials, Ardelyx is on track to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration for tenapanor for the treatment of IBS-C in the second half of 2018. Final, detailed results from the study are expected to be presented at a medical meeting in 2018.

T3MPO-3
Patients who have completed T3MPO-1 and T3MPO-2 are eligible to enter T3MPO-3, Ardelyx’s open-label, long-term safety trial where patients can continue to receive tenapanor for up to one year. T3MPO-3 is fully enrolled and expected to conclude in late 2017. The results of the trial will be included in the NDA submission for tenapanor for the treatment of patients with IBS-C.

T3MPO-2 Primary and Secondary Endpoint Definitions

Primary Endpoint:

Combined responder rate (6/12 week): A six of 12-week combined responder is a CSBM responder and an abdominal pain responder during the same week for six of 12 weeks.

Secondary Endpoints:

CSBM responder rate (6/12 week): A six of 12-week CSBM responder is a patient that has an increase of at least one CSBM from baseline during a week for six of 12 weeks.
Abdominal pain responder rate (6/12 week): A six of 12-week abdominal pain responder is a patient that has at least a 30 percent decrease in abdominal pain from baseline during a week for six of 12 weeks.
Combined responder rate (9/12 week): A nine of 12-week combined responder is a nine of 12 week CSBM responder and an abdominal pain responder during the same week for nine of 12 weeks.
CSBM responder rate (9/12 week): A nine of 12-week CSBM responder is a patient that has an increase of at least one CSBM from baseline and at least three CSBMs during a week for nine of 12 weeks. Normal bowel function is characterized by at least three bowel movements a week up to three bowel movements a day.
Abdominal pain responder rate (9/12 week): A nine of 12-week abdominal pain responder is a patient that has at least a 30 percent decrease in abdominal pain from baseline during a week for nine of 12 weeks.
Durable responder rates (9/12 week): All three durable responder endpoints – combined responder rate, CSBM responder rate and abdominal pain responder rate – are identical to the nine of 12-week responder endpoints, except the response must also occur in three of the last four treatment period weeks.