T3MPO change for Ardelyx

After Ardelyx’s phase III win yesterday investors were quick to forgive its previous pivotal stumble, pushing the group’s shares up 57% this morning. While some might hope that the results could help the company hook a partner, there are reasons to be cautious even if tenapanor does get approved for constipation-predominant irritable bowel syndrome (IBS-C).

Firstly, the latest trial, T3MPO-2, met all of its endpoints but does not show tenapanor to be any better than Allergan and Ironwood’s marketed IBS-C drug Linzess – though the usual caveats about across-trial comparisons apply (see tables below). And secondly, T3MPO-2 did nothing to allay the concerns about diarrhoea raised by T3MPO-1.

Tenapanor phase III results
Tenapanor   Placebo  P value  Tenapanor Placebo P value
Combined responder (primary endpoint)* 27% 19% 0.02 37% 24% <0.001
CSBM responder (increase ≥1 CSBM from baseline)* 34% 29% 0.27 47% 33% <0.001
Abdominal pain responder (≥30% abdominal pain reduction)* 44% 33% 0.008 50% 38% 0.004
*Percentage of subjects with response for 6 out of 12 weeks; CSBM: Complete spontaneous bowel movements; Source: Company press release.

True, Linzess has also been linked with this side effect: around 20% of Linzess-treated patients experienced diarrhoea in its phase III trials, compared with 15-16% in the tenapanor studies. As it stands, tenapanor is looking similar to Linzess on both efficacy and diarrhoea, and even if Ardelyx gets its drug approved it will have a hard task wresting market share away from its larger rival (Ardelyx runs into problems with tenapanor, May 15, 2017).

Cross trial comparison of placebo-adjusted benefit with tenapanor vs Linzess vs Trulance in IBS-C
Tenapanor Linzess Trulance
T3MPO-1 T3MPO-2 Trial 1 Trial 2 Study 1 Study 2
Combined responder (primary endpoint)* 8 13 13 20 12 8
CSBM responder (increase ≥1 CSBM from baseline)* 5 14 19 25 10**
Abdominal pain responder (≥30% abdominal pain reduction)* 11 12 12 14 10**
Diarrhoea rate 15-16% 20% 4%
Dosing Twice-daily Once-daily Once-daily
*Percentage point difference between placebo and active group; **Pooled analysis; Data for 3mg dose only. CSBM: Complete spontaneous bowel movements; Source: Company press releases; Linzess label.

Ardelyx plans to file tenapanor in the second half of 2018. It will need a partner to fight the commercial might of Allergan; indeed, meeting analyst forecasts depend on it finding one. EvaluatePharma sellside consensus estimates that tenapanor will have sales of $831m by 2022, which would make it the biggest IBS-C drug that year – but $507m of this is expected to accrue to a partner.

If approved, tenapanor could also go up against Synergy’s Trulance, which was launched in March for chronic idiopathic constipation, and has been filed with the FDA for IBS-C, with an approval decision due by January 24, 2018.

Trulance has the same mechanism of action as Linzess. Although cross-trial comparisons suggest it is less effective than Linzess, and perhaps tenapanor – based on T3MPO-2 rather than T3MPO-1 data – Synergy's candidate has shown a lower rate of diarrhoea, at around 4%, which could help it capture sales – and make life harder for Ardelyx, since it seems like a more enticing asset for a potential partner. That said, the fact that no bigger players have bitten yet might also bode ill for Ardelyx.

Indeed, while confidence among Ardelyx shareholders was high today, it is worth remembering that at $8.50 its stock is well off its high of $33 in December 2014, and its market cap sits at a mere $256m.

Top IBS-C therapies
Annual sales by indication ($m)
Product Company Generic name Pharmacological class Status 2016 2022e
Tenapanor Ardelyx tenapanor hydrochloride NHE 3 inhibitor Phase III - 831*
Linzess Allergan linaclotide GUCY type-C receptor agonist Marketed 327 560
Trulance Synergy Pharmaceuticals plecanatide GUCY type-C receptor agonist Filed - 223
SYN-010 Synthetic Biologics lovastatin Statin/HMG CoA reductase inhibitor Phase II - 154
*Includes undisclosed partner sales. Source: EvaluatePharma.

Some analysts still believe that there will be a place on the market for tenapanor, even with an undifferentiated efficacy profile. Wedbush wrote that its unique mechanism of action could help adoption, particularly in patients who fail on or cannot tolerate Linzess; they added that around two-thirds of Linzess-treated patients failed a responder analysis in phase III.

Ardelyx is also studying tenapanor for hyperphosphataemia in end-stage renal disease patients on dialysis, and plans to start a second phase III trial by the end of this month. This is in the same realm as the chronic kidney disease indication that Astrazeneca backed out of in 2015.

Ardelyx has already lost one partner. The latest data might not help it find another.

To contact the writers of this story email Madeleine Armstrong in London or Jonathan Gardner in Virginia at [email protected] or follow @ByMadeleineA or @ByJonGardner on Twitter

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