Ironwood Faces Setback as FDA Requires New Phase 3 Trial for GI Drug Apraglutide

Ironwood Pharmaceuticals is re-evaluating its strategic direction after the U.S. Food and Drug Administration (FDA) requested an additional Phase 3 clinical trial before considering approval of its gastrointestinal drug candidate, apraglutide. The long-acting GLP-2 analog is being developed for patients with short bowel syndrome (SBS) who rely on parenteral support (PS), a form of intravenous nutrition essential for those with severe digestive system impairment.

The company had submitted a rolling application for approval earlier this year, banking on a prior Phase 3 trial that showed promising—though imperfect—results, as well as long-term extension data. These data included 27 patients who were able to discontinue PS while on apraglutide. At the time of submission, Ironwood also undertook a major restructuring, cutting its workforce in half to concentrate efforts on bringing apraglutide to market.

However, a pharmacokinetic review of the original trial revealed that the actual exposure and dosage levels of apraglutide were lower than intended, attributed to issues with dose preparation and administration. Despite this, Ironwood had hoped the existing data would suffice for regulatory consideration.

Those hopes were dashed after recent discussions with the FDA, which made it clear that a new confirmatory Phase 3 trial would be required to proceed. In response, Ironwood has committed to working with the agency on designing this new trial. Simultaneously, the company has retained Goldman Sachs to explore strategic alternatives aimed at maximizing shareholder value.

The setback comes after a similar development last December, when Zealand Pharma's own GLP-2 analog treatment for SBS was rejected by the FDA due to insufficient evidence, reinforcing the stringent standards the agency is applying in this therapeutic area.

“We are disappointed in this outcome, as we firmly believe apraglutide has the potential to provide tremendous value to patients with SBS-IF, who suffer from increased mortality and diminished quality of life,” said Ironwood CEO Tom McCourt in a statement. “We remain committed to identifying the best path forward to bring apraglutide to patients and continue to believe it can be a blockbuster therapy. In parallel, we will explore all strategic options to deliver value to our shareholders.”

Ironwood acquired apraglutide in 2023 through a $1 billion acquisition of VectivBio, positioning the drug as a potentially best-in-class treatment, citing its potency, selectivity, and convenient once-weekly dosing.

The earlier Phase 3 study showed that apraglutide led to a 25.5% reduction in weekly PS volume after 24 weeks, compared to a 12.5% reduction in the placebo group, successfully meeting the trial’s primary endpoint. Two secondary goals were also achieved, including an increase in the number of patients who experienced at least one PS-free day per week and improved PS reduction among patients with stomas.

However, the trial fell short of two secondary endpoints among patients with colon-in-continuity (CIC), who represent about half of the estimated 18,000 SBS patient population worldwide. The other half comprises individuals with stomas. This disparity sparked skepticism among investors, who questioned whether apraglutide could outperform Takeda’s existing SBS therapy, Gattex.

Later in the year, Ironwood released subgroup analysis suggesting that apraglutide provided consistent benefits across both stoma and CIC patient groups, in an effort to address those concerns.

As Ironwood navigates this regulatory roadblock, the company remains hopeful that apraglutide can fulfill its promise—and is now tasked with proving it once again in a fresh clinical trial.

Source: https://www.fiercebiotech.com/biotech/ironwood-rethinks-options-after-fda-demands-another-phase-3-trial-gi-drug

This is non-financial/medical advice and made using AI so could be wrong