Ardelyx runs into problems with tenapanor

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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.

T3MPO-1 results
6 of 12 treatment week results Tenapanor Placebo P value
Combined responder (primary endpoint) 27.0% 18.7% 0.02
CSBM responder (increase ≥1 CSBM from baseline) 33.9% 29.4% 0.27
Abdominal pain responder (≥30% abdominal pain reduction) 44.0% 33.1% 0.008

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.

The IBS-C landscape
Project Company Status Mechanism 2022e sales ($m)
Linzess Allergan/Ironwood Marketed Guanylate cyclase type-C receptor agonist 623
Trulance Synergy Pharmaceuticals Filed Guanylate cyclase type-C receptor agonist 244
Tenapanor Ardelyx Phase III Sodium & hydrogen exchanger 3 inhibitor 207
SYN-010 Synthetic Biologics Phase II Statin/HMG CoA reductase inhibitor 144
Source: EvaluatePharma.

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.

Phase III results with IBS-C candidates (versus placebo)
Linzess Trulance Tenapanor
Trial 1 Trial 2 Study 1 Study 2 T3MPO-1
Combined responder rate 34% 34% 30% 22-24% 27%
Treatment difference 13 points 20 points 12 points 7-10 points 8 points
CSBM responder rate 49% 48% 41-42%* 34%
Treatment difference 19 points 25 points 10-11 points 5 points
Abdominal pain responder rate 50% 49% 37-39%* 44%
Treatment difference 13 points 14 points 10-12 points 11 points
*Pooled analysts; Source: Linzess label, Synergy press release.

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.

Study Trial ID Data due
T3MPO-1 NCT02621892 Reported
T3MPO-2 NCT02686138 H2 2017

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

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