Ironwood felled by mixed data in short bowel syndrome trial

Ironwood Pharma has issued an upbeat assessment of phase 3 trial data with apraglutide for short bowel syndrome (SBS), but missed secondary outcome measures led to a sharp decline in its share price.

Ironwood acquired the once-weekly GLP-2 analogue as part of a $1 billion deal to buy VectivBio last year, which was effectively a bet on the outcome of the phase 3 STARS trial of apraglutide in patients with SBS and intestinal failure (SBS-IF), as the drug was VectivBio’s only clinical-stage drug candidate.

SBS-IF is a rare and severe form of organ failure condition in which patients become dependent on parenteral support (PS), in some cases needing infusions of parenteral nutrition for up to 15 hours per day. It affects an estimated 18,000 adult patients in the US, Europe, and Japan.

As it turned out, apraglutide hit its primary endpoint in the study, reducing the volume of PS needed by patients by 25.5% at 24 weeks, compared to a 12.5% decline for the placebo group, according to Ironwood.

The drug also met two of four secondary endpoints, increasing the chances that patients with SBS-IF could have at least one day free of PS in a week and reducing the need for PS in patients with a stoma fitted.

Investors were nervous, however, about the two missed secondary endpoints – both in ‘colon-in-continuity’ patients who have a largely intact colon and typically require less support – and shares in the company fell almost 40% after the announcement of the results.

In that group, apraglutide was unable to achieve a significant improvement in the proportion of patients able to achieve at least one day per week off PS, as well as being free of the need for infusions (enteral autonomy) at 48 weeks.

Ironwood’s preliminary explanation for the result is a high placebo response rate, resulting from the trial’s design, which encouraged patients to reduce their parenteral nutrition use over time.

Ironwood has said the data should be strong enough to file for FDA approval of apraglutide as a treatment for adult SBS patients dependent on PS, and the company’s chief medical officer, Michael Shetzline, said the drug has the potential to “improve the standard of care” for patients.

The scale of the sell-off likely stems from concerns that apraglutide may not have the compelling efficacy needed to supplant Takeda’s SBS therapy Gattex (teduglutide), another GLP-2 analogue that has been FDA-approved since 2012, but which needs to be administered daily.

Gattex had US sales of around $540 million in 2022, but is now at the end of its patent life and facing the threat of low-cost generic competition that could introduce downward pricing pressure into the SBS treatment market.

Ironwood’s drug will also be compared with another long-acting GLP-2 analogue, Zealand Pharma’s glepaglutide, which was filed with the FDA last December as a twice-weekly therapy for SBS delivered using an autoinjector. It was also tested as a once-weekly regimen, but that was unable to show a significant improvement in weekly PS requirement in clinical trials.

Another long-acting GLP-2 drug, 9 Meters Biopharma’s vurolenatide, reached phase 3 testing for SBS, but was discontinued after the company ran out of money and filed for bankruptcy last year.