"What we've accomplished from then to now is what we dreamt of," Ardelyx Inc. CEO Mike Raab told BioWorld, referring to stellar phase III data with Na-hydrogen exchanger 3 (NHE3) transporter blocker tenapanor in irritable bowel syndrome (IBS-C), unveiled less than a week before the 10-year anniversary of the firm's founding. "Companies like ours don't get the attention at times from the world out there," he said, because they lack headline-grabbing approaches such as immuno-oncology and often face "a tougher, more extensive path to success."
Having traveled such a path, Fremont, Calif.-based Ardelyx may get that attention now. Officials made known the new data from T3MPO-2 – the second phase III trial with tenapanor – shortly before the market closed Wednesday, and Ardelyx shares (NASDAQ:ARDX) were up more than 60 percent in after-hours trading.
The firm aims to submit an NDA during the second half of next year, and will offer full results from the latest experiment at a scientific meeting.
Inhibiting the NHE3 transporter reduces the absorption of dietary sodium into the bloodstream, which means more sodium in the gut, which in turn boosts fluid and loosens stool. Tenapanor helps with pain, too. T3MPO-2 hit statistical significance for the primary endpoint and all secondary endpoints evaluated in the top-line results. The primary endpoint, combined responder rate (CRR) for six of 12 weeks, showed that a greater proportion of tenapanor-treated patients compared to those given placebo (36.5 percent vs. 23.7 percent, p<0.001) had at least a 30 percent reduction in abdominal pain and an increase of one or more complete spontaneous bowel movements (CSBMs) in the same week for at least six of the 12 weeks of the treatment period. Well-tolerated, tenapanor also made the statistical grade for CSBM and abdominal pain responder rates in the six of 12 and nine of 12 treatment weeks, with a consistent response across all 26 weeks of the study.
Twice-daily tenapanor works locally in the gastrointestinal (GI) tract with minimal systemic exposure, Raab said, a factor especially important in IBS-C, where "safety is paramount. You saw big pharma and other companies leave GI because when drugs like Zelnorm were pulled from the market given safety issues," researchers "want to run away from [treating] people who are otherwise healthy." In the spring of 2007, Novartis AG, of Basel, Switzerland, agreed to discontinue marketing and sales of Zelnorm (tegaserod maleate) for IBS-C and chronic idiopathic constipation (CIC) because of what the FDA said was an increased risk of serious cardiovascular adverse events associated with the drug, including heart attacks, unstable angina and stroke.
Ardelyx estimates 11 million people in the U.S. have IBS-C, mostly women of childbearing age. Other estimates go as high as 13 million, but there's general agreement that 35 million are afflicted with IBS. Of that number, about a third each has IBS-C, IBS with diarrhea and IBS with mixed symptoms.
David Rosenbaum, chief development officer, called attention to the nine of 12-week CRR rate of 18.4 percent. "What's so significant there is that we're actually bringing people into the normal range," he said, which is considered to be a bowel movement frequency from three times per week to three times per day. "The idea, and this has been borne out in market research, is that people really want to get into the normal range. They don't want just an increase in one CSBM," the primary endpoint of the trial. Tenapanor's 18.4 percent number is "50 percent better than what's observed with other drugs," he said, and noted that adverse events in the trial proved benign as well.
"The third thing, which we need to always remind people of, is that this is a novel mechanism. This works on sodium, and it works by inhibiting the absorption; it's not a pro-secretory agent. The other therapies out there work as pro-secretory agents on chloride."
Competitor DTC work 'only benefits us'
Although "increasing [patients'] bowel movements to have a CSBM one, two or three times a week is a huge deal, to get people to go once or twice a day like they used to do five years ago, that's a whole other story," Rosenbaum conceded. A CSBM is distinguished by the patient's "sensation of complete evacuation," he said, adding that pain relief is no small matter. "They stay home because they're in so much pain," he said.
Linzess (linaclotide), from Cambridge, Mass.-based Ironwood Pharmaceuticals Inc. and partner Allergan plc, of Dublin, is approved for IBS-C and CIC. In June, New York-based Synergy Pharmaceuticals Inc. said the FDA accepted its supplemental NDA for Trulance (plecanatide) in IBS-C. Trulance is already marketed for CIC. The PDUFA date for the new indication is Jan. 18, 2018. Amitiza (lubiprostone) from Rockville, Md.-based Sucampo Pharmaceuticals Inc. with Takeda Pharmaceutical Co. Ltd., of Osaka, Japan, won the FDA's go-ahead for CIC in adults, for opioid-induced constipation in adults with chronic noncancer pain, and IBS-C in women older than 18. (See BioWorld Today, Aug. 31, 2012.)
Ardelyx also has tenapanor at the phase III stage for hyperphosphatemia.
BTIG analyst Timothy Chiang predicted investors would "key in" particularly on the IBS-C results. In an August report, he appreciated the drug's unique mechanism of action and said that, "in our view, tenapanor could be a meaningful new potential treatment for patients suffering from hyperphosphatemia and IBS-C. We believe both of these segments are sizeable market opportunities, with most of the treatments for hyperphosphatemia requiring patients to take a significant number of pills on a daily basis."
In February, Ardelyx disclosed phase III data with tenapanor for hyperphosphatemia in patients with end-stage renal disease who are on dialysis. The experiment met its primary endpoint and was generally well-tolerated, with the responder population (n=80 out of 164) turning up 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 the group, 33 percent of patients had a reduction in serum phosphorus of greater than 3 mg/dL. The study demonstrated a statistically significant difference in serum phosphorus levels from the end of the 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 percent CI -1.44, -0.21; LS mean -0.82 mg/dL; p=0.01). Only 7.8 percent of patients discontinued treatment due to GI side effects. (See BioWorld Today, Feb. 16, 2017.)
In IBS-C, May brought data from the first phase III study. Ardelyx said the trial achieved statistical significance for the primary endpoint and seven of eight secondary endpoints. The primary endpoint, the CRR for six of 12 weeks, showed that a greater proportion of tenapanor-treated patients compared to placebo-treated patients (27 percent vs. 18.7 percent, p=0.02) had at least a 30 percent reduction in abdominal pain and an increase of one or more CSBMs in the same week for at least six of the 12 weeks of the treatment period. Wall Street was less than satisfied, and shares lost 39 percent of their value that day.
Asked about the prospect of an advisory committee meeting to evaluate tenapanor, Rosenbaum said, "I do not expect it to happen." The FDA has provided clear guidance regarding what's needed in IBS-C, and in more 1,800 people treated "no safety issues at all" have cropped up. Adcoms are usually sparked by "equivocal results or some safety issues, but this is very straightforward," in his view.
But CEO Raab said Wednesday that, based on data that Ardelyx had before the latest results from T3MPO-2, he was confident that the company will have no trouble finding a partner for tenapanor. He is also convinced "that we do not need the kind of sales force you see Allergan and Ironwood deploying. That's roughly 1,500 people. If you look at the Ironwood-alone sales force, it's about 200 to 300 people," which "is the appropriate sizing that you need to have significant penetration. There are plenty of potential partners with whom we've begun addressing the opportunity."
Ardelyx also has done extensive market research, he said, and the direct-to-consumer advertising that Ironwood and Allergan have undertaken "only benefits us."