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.
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.
|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|
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)|
|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|