A phase 2b trial of Ironwood Pharmaceuticals’ IW-3718 has met its primary endpoint, teeing the heartburn candidate up to move into a pivotal trial and on to blockbuster sales. But the positive narrative spun by Ironwood’s management failed to convince investors, who seized on perceived underwhelming efficacy data and drove down the company’s stock.
The divergence in interpretations of the data centers on whether the statistically-significant result against the primary endpoint is big enough to justify predictions of $2 billion-a-year sales.
Adults with uncontrolled gastroesophageal reflux disease (GERD) who took 1500 mg of Ironwood’s IW-3718 on top of a proton pump inhibitor (PPI) experienced a median decrease in heartburn severity of 58% after eight weeks of treatment. The median decrease in participants who received the PPI plus a placebo was 46%.
That 12 percentage point difference was big enough to achieve statistical significance with a p value of 0.04. But Ironwood CSO Mark Currie, Ph.D. had previously primed investors to expect a bigger numerical difference between IW-3718 and placebo. When asked in May what Ironwood needed to see in the data to definitively move into phase 3, Currie said “we powered this specific study for 15% improvements on heartburn severity over placebo.”
Ironwood’s inability to clear that self-imposed bar led to its stock trading down 8%. But to the company the relevant point isn’t whether the improvement was 12 or 15 percentage points. It is that a double-digit, statistically-significant improvement was seen at all.
“There’s been literally a graveyard of drugs that have attempted to ... show a meaningful improvement on top of PPIs. This is the first time we’ve seen this kind of incremental improvement on top of PPIs,” Ironwood chief commercial officer Tom McCourt said on a conference call with investors.
McCourt referred back to the degree of improvement PPIs showed over H2-receptor antagonists in clinical trials to make his case for the blockbuster potential of IW-3718.
“They saw a very comparable improvement in relief of heartburn severity. Think about how successful PPIs were on top of H2s. We’re seeing a similar separation between the two treatment options. So, to me, this is very encouraging,” he said.
When Cochrane reviewed seven clinical trials that compared PPIs to H2-receptor antagonist, it found about 50% of participants who received the newer class of medicine experienced heartburn remission. The figure among subjects who received H2 drugs was about 30%.
IW-3718 caused a 45% or greater reduction in heartburn severity in 53% of patients in the phase 2b. The figure for the PPI cohort was 37%.
McCourt also pointed to a mean decrease in regurgitation frequency—55% for IW-3718 compared to 37.9% for PPIs—to argue the phase 2b data indicate a bright future for the controlled-release, gastric-retentive formulation of a bile-binding resin.
Ironwood is now preparing for end of phase 2 meetings with FDA and beyond that for a pivotal trial it expects to start in the second half of next year.