Ardelyx runs into problems with tenapanor

Hitting the primary endpoint in a pivotal trial is not always the end of a company’s problems – just ask Ardelyx. What looked on the surface like a win in the T3MPO-1 trial of tenapanor was overshadowed by seemingly lower efficacy versus rival constipation-predominant irritable bowel syndrome therapies (see tables below).

This, along with a high rate of diarrhoea with tenapanor, spooked investors who sent Ardelyx’s stock down 39% on Friday. The company will have to hope that data from its second phase III study in constipation-predominant IBS (IBS-C), T3MPO-2, due in the second half of this year, will allay these concerns.

Down T3MPO

T3MPO-1’s primary endpoint was response rate, with response defined as at least a 30% reduction in abdominal pain and an increase of one or more complete spontaneous bowel movements (CSBMs) in the same week for at least six weeks of the 12-week treatment period.

The trial met this but fell short on a key secondary endpoint, the CSBM responder rate.

In addition, 15% of patients receiving tenapanor suffered diarrhoea, versus 2% of the placebo group, and the discontinuation rate due to diarrhoea was 6% in the treatment arm.

Tenapanor is not the only IBS-C candidate to be linked with diarrhoea – this is also a common side effect with Allergan and Ironwood’s approved therapy, Linzess, which is nevertheless expected to become the best-selling IBS-C treatment by 2022, according to EvaluatePharma sellside consensus.

Linzess seems to have the edge over tenapanor on efficacy, although the usual caveats about cross-trial comparisons apply. On the same six out of 12 weeks responder endpoint, Ironwood’s product showed a 13 and 20-point benefit over placebo in two trials, against the 8-point difference seen in T3MPO-1. And, unlike tenapanor, the Linzess group had a significant improvement in CSBM response versus placebo.

Synergy’s Trulance, which in January received FDA approval in chronic idiopathic constipation and is awaiting the go-ahead in IBS-C, also looks slightly better than tenapanor, particularly at the higher dose studied. The project also met the CSBM responder endpoint in a pooled analysis of its two phase III trials.

Importantly, Trulance has a lower incidence of diarrhoea than both of the other candidates, at 4%. Linzess had a diarrhoea rate of 20% in its pivotal trials.

The IBS-C field is looking increasingly competitive and, if Trulance is approved, its side-effect profile could help it take market share from Linzess. Tenapanor, lagging behind on timing, efficacy and adverse events, might have a hard time getting a toehold in the market. If its prospects are to improve, Ardelyx will need better results from T3MPO-2.

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow @ByMadeleineA on Twitter