
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.
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 [email protected] or follow @ByMadeleineA on Twitter