Apraglutide Meets Primary Endpoint for Parenteral Support Reduction in Phase 3 STARS Trial

Kishore R Iyer, MBBS, FRCS, FACS

Credit: Mount Sinai

Ironwood Pharmaceuticals has announced positive topline results from the phase 3 STARS trial of once-weekly subcutaneous apraglutide for reducing parenteral support dependency in adult patients with short bowel syndrome with intestinal failure (SBS-IF).¹

According to the February 29 release, the trial met its primary endpoint for relative change from baseline in actual weekly parenteral support volume at week 24, with apraglutide (-25.5%) outperforming placebo (-12.5%; P = .001). Based on these results, Ironwood plans to submit a New Drug Application and other regulatory filings for the use of apraglutide in adult patients with SBS who are dependent on parenteral support.¹

“Reducing dependency on parenteral support and easing treatment burden are important goals for every patient with SBS-IF,” Kishore R Iyer, MBBS, FRCS, FACS, director of Adult and Pediatric Intestine Rehabilitation and Transplantation at Mount Sinai Hospital and coordinating principal investigator of the trial, said in the press release.¹ “The STARS topline results are significant as this is the first successful Phase III placebo-controlled study in SBS-IF patients with a GLP-2 analog with once-weekly dosing.”

An investigational, long-acting synthetic glucagon-like peptide-2 (GLP-2) analog, apraglutide is in development for a range of rare gastrointestinal diseases where GLP-2 can play a central role in addressing disease pathophysiology, including SBS and acute graft versus host disease. Positive final data from the phase 2 STARS Nutrition program were presented during a late-breaker oral presentation at United European Gastroenterology (UEG) Week 2023, highlighting its acceptable safety profile and ability to improve intestinal absorption as indicated by 50% parenteral support volume and energy content decrease, resulting in 1 or more days off parenteral support.^1,2

A global, multicenter, double-blind, randomized, placebo-controlled trial, STARS evaluated the efficacy and safety of weekly subcutaneous injections of apraglutide in adult patients with SBS-IF. With 164 patients enrolled and 163 dosed, STARS represents the largest phase 3 trial in SBS-IF to date.¹

According to the release, participants were stratified approximately 50/50 (stoma vs colon-in continuity) and evaluated over 24 weeks. The colon-in-continuity population was evaluated over 48 weeks. Patients were randomized in a 2:1 ratio to either once weekly apraglutide or placebo. The primary endpoint was relative change from baseline in actual weekly parenteral support volume at week 24. Key secondary endpoints included:

• Patients who achieved a reduction from baseline of ≥ 1 day per week of parenteral support at week 24 (all patients)
• Relative change from baseline in actual weekly parenteral support volume at week 24 (stoma population)
• Patients who achieved a reduction from baseline of at least 1 day/week of parenteral support at week 48 (colon-in-continuity population)
• Patients reaching enteral autonomy at week 48 (colon-in-continuity population).

Apraglutide demonstrated statistical significance for the first 2 key secondary endpoints, with more patients in the combined population achieving ≥ 1 day per week off parenteral support relative to baseline at week 24 versus placebo (43.0% vs 27.5%; P = .040) and more patients treated with apraglutide versus placebo demonstrating improvement in relative change from baseline in actual weekly parenteral support volume at week 24 in the stoma population (-25.6% vs -7.8%; P <.001).¹

Although apraglutide was numerically favorable for the third and fourth key secondary endpoints specific to colon-in-continuity patients in assessing ≥ 1 day per week off parenteral support versus baseline (51.8% vs 44.4%) and reaching enteral autonomy at week 48 (12.5% vs 7.4%), these results were not statistically significant relative to placebo.¹

According to the release, apraglutide was generally well-tolerated with safety results generally consistent with the safety profile demonstrated in apraglutide studies to date.¹

“Patients with SBS-IF bear the dual burden of a devastating condition and a complex treatment regimen that includes hours of parenteral support, which significantly impacts their quality of life and carries a risk of severe complications such as infection,” said Michael Shetzline, MD, PhD, chief medical officer, senior vice president, and head of research and drug development at Ironwood Pharmaceuticals.¹ “We believe these results demonstrate the potential for apraglutide to improve the standard of care for all adult patients with SBS dependent on parenteral support as the only GLP-2 with once-weekly administration, if approved.”

References:

1. ^{Ironwood Pharmaceuticals. Ironwood Pharmaceuticals Announces Positive Topline Results from Global Phase III Trial of Once-Weekly Apraglutide in Adults with Short Bowel Syndrome with Intestinal Failure (SBS-IF). Press Releases. February 29, 2024. Accessed February 29, 2024. https://investor.ironwoodpharma.com/press-releases/press-release-details/2024/Ironwood-Pharmaceuticals-Announces-Positive-Topline-Results-from-Global-Phase-III-Trial-of-Once-Weekly-Apraglutide-in-Adults-with-Short-Bowel-Syndrome-with-Intestinal-Failure-SBS-IF/default.aspx}
2. ^{Brooks, A. Apraglutide Reduces Parenteral Support Dependency in Patients with SBS-IF, CIC. HCPLive. October 19, 2023. Accessed February 29, 2024. https://www.hcplive.com/view/apraglutide-reduces-parenteral-support-dependency-in-patients-with-sbs-if-cic}