Ardelyx runs towards next phase with tenapanor

Positive phase III results for Ardelyx’s novel hyperphosphataemia candidate tenapanor sent the company’s share price up 14% yesterday – but a high rate of diarrhoea remains the project’s Achilles heel. Ardelyx played down the side effect, with its chief executive, Mike Raab, highlighting the rate of study dropouts due to diarrhoea of “only” 7.8%.

He even tried to put a positive spin on the issue, saying during a conference call that many dialysis patients were constipated and that tenapanor might provide a benefit here. Still, with a second phase III study in hyperphosphataemia in end-stage renal disease due to start in mid-2017, the company will need to keep a close eye on this problem.

Diarrhoea affected 39% of patients receiving tenapanor in the phase III study, above the 19-24% rate seen with marketed phosphate binders, the current standard of care. However, the dropout rate was lower than the 14-20% seen with Sanofi’s Renvela and Keryx’s Auryxia in clinical studies, Leerink analysts noted.

Ardelyx’s chief development officer, David Rosenbaum, stressed that bowel movement frequency was within the normal range in all groups, and that there was only a “minimal” increase in the tenapanor patients. The project might be “bringing people to a new normal”, he believes.

Primary endpoint win

Notwithstanding the diarrhoea, the study met its primary endpoint, showing a significant reduction in serum phosphorus levels from the end of the eight-week treatment period to the end of the four-week randomised withdrawal stage.

There was a mean decrease of 1.01mg/dl over the placebo group, which Leerink analysts say is viewed by nephrology specialists as clinically meaningful. However, Ardelyx had hoped for a reduction of at least 1.5mg/dl, in line with phosphate binders.

Nevertheless, Mr Raab was bullish about the data, saying that in the patients who responded “we have seen levels of phosphate lowering unlike those seen in other studies”. The 49% of patients classed as responders had a mean reduction of 2.56mg/dl.

Tenapanor, which is given twice a day, could also have a convenience benefit over the current standard of care. Mr Raab pointed out that hyperphosphataemia patients take up to 19 pills per day, half of which are phosphate binders, and nearly 50% of patients are non-compliant.

Ardelyx plans to press on into a second, longer phase III study. It did not give many details, saying it will meet the FDA to nail down the final protocol. This will likely include a 26-week open-label treatment period, with randomised withdrawal followed by an additional 26-week long-term safety extension.

While phosphate binders soak up phosphorus in food, as an NHE3 sodium transporter tenapanor is designed to decrease absorption across the GI tract. If it is approved, Ardelyx says it will become the first non-phosphate binder treatment for hyperphosphataemia.

Leerink analysts, who now give tenapanor a 70% chance of success, forecast peak sales of $377m.

Tenapanor has two even more important readouts this year from two phase III trials in the bigger indication of constipation-predominant irritable bowel syndrome – a condition where tenapanor's unintended consequences could become its main asset.

To contact the writer of this story email Madeleine Armstrong in London at [email protected] or follow @ByMadeleineA on Twitter