A hiccup for Ironwood Pharmaceuticals’ phase II project IW-3718 will do nothing for the company’s hopes to expand beyond the constipation therapy Linzess. A look at the group's pipeline reveals a dearth of novel late-stage projects, with only reformulations of its existing drugs anywhere near the market (see table below).
The mixed data with IW-3718 – the study met its primary endpoint but fell short of the goal that Ironwood had set itself – put a phase III trial, planned for next year, on shaky ground. Ironwood will hope that focusing on the higher dose will give it a good enough result for approval. However, investors did not seem so sure, sending the group’s stock down 8% yesterday.
|Project||Indication||Pharmacology class||2022e sales ($m)||Trial(s)|
|Duzallo||Hyperuricaemia/gout||URAT 1, SURI & xanthine oxidase inhibitor||78||-|
|Linaclotide Delayed Release-1 (DR1)||IBS-C||GUCY type-C receptor agonist||-||Phase III to begin H2 2017|
|IW-3718||Gastro-oesophageal reflux disease||Bile acid sequestrant||27||NCT02637557; reported|
|IW-1973||Pulmonary hypertension, type 2 diabetes||sGC activator||-||NCT02906579, NCT03091920; data H2 2017|
|IW-1701||Achalasia||sGC activator||-||NCT02931565; data H2 2017|
|Linaclotide Delayed Release-2 (DR2)||Non-constipation subtypes of IBS||GUCY type C receptor agonist||-||-|
|Source: EvaluatePharma, company website.|
Not good enough?
The phase II trial enrolled gastro-oesophageal reflux disease patients whose symptoms were not controlled by proton pump inhibitors (PPIs). They received IW-3718 dosed at 500mg, 1,000mg or 1,500mg plus a PPI, versus a PPI plus placebo.
Ironwood only released data for the highest dose, suggesting that the lower doses did not show a significant improvement on the primary endpoint, change from baseline in heartburn severity.
In addition, the benefit with the 1,500mg dose, although significant, did not meet the threshold that Ironwood had previously said was clinically meaningful – it had been hoping for a 15 percentage point separation from the control group, but this only reached 12 points.
Secondary endpoint data were also mixed: the trial found a 45% reduction in weekly heartburn severity, but Ironwood did not give details on the proportion of heartburn-free days, suggesting that this endpoint was not met.
Mizuho analysts believe that IW-3718 is still approvable in spite of the setback, noting that the 15-point difference was not an FDA-mandated target but rather had been set by Ironwood. They added that the trial was exploratory, small, and carried out in a tough patient population.
But Wells Fargo analysts were more pessimistic, calling the data “OK, but unimpressive”. In May they described IW-3718 as Ironwood’s next potential blockbuster, something that now looks less likely.
The misstep puts more pressure on Ironwood’s pipeline, and the group's most advanced project does not look up to the job. Duzallo, a fixed-dose combination of the gout mainstay therapy allopurinol and Ironwood’s Zurampic, is due an approval decision from the FDA by the end of August, but sales of Zurampic monotherapy do not bode well.
Zurampic brought in just $300,000 in the first quarter, making the EvaluatePharma sellside consensus forecast of $34m for this year look out of reach.
Next up is a delayed-released version of linaclotide, the active ingredient of Linzess, which is due to go into phase III in constipation-predominant irritable bowel syndrome this year. Ironwood hopes that the next-generation project could improve abdominal pain relief over the older drug, but it is debatable whether this will give its franchise much of a boost.
Further behind are IW-1973 and IW-1701, which are expecting phase II data this year in diabetes with hypertension and achalasia, a condition that affects the oesophagus, respectively.
Ironwood still has a chance to succeed with IW-3718 and put its attempt to diversify back on track – but the latest data have made the company’s task that little bit harder.