Ironwood Late-Breaker Oral Presentation at Digestive Disease Week® Reinforces Potential of Once-Weekly Apraglutide for Adults with Short Bowel Syndrome with Intestinal Failure (SBS-IF)
– New data highlight both stoma and colon-in-continuity (CIC) patients drove the positive primary endpoint with significant relative change from baseline in weekly parenteral support (PS) volume reduction at week 24 –
– Additional secondary endpoints show significant increases in days off PS and clinical responder rates with apraglutide, including achieving enteral autonomy in both stoma and CIC patients –
– Data from largest GLP-2 Phase III study to date adds to body of evidence on safety and efficacy of once-weekly apraglutide in adults with SBS-IF –
– New details on safety and tolerability to be presented; showing apraglutide to be well tolerated with a safety profile consistent with previously reported apraglutide studies in this patient population –
SBS-IF, a rare chronic debilitating malabsorptive condition in which patients are dependent on PS, affects an estimated 18,000 adult patients in the
The late-breaking data at DDW are from the largest global SBS-IF clinical trial conducted to date and are being shared during an oral presentation titled “Efficacy and Safety of
Findings from the late-breaking presentation include:
- Significantly more apraglutide-patients gained additional days off from PS per week at week 24 versus placebo (≥2 days: 24.5% vs 11.3%, p=0.021; ≥3 days: 11.8% vs 1.9%, p=0.006)
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Significantly more apraglutide-treated patients in the overall and the stoma populations were clinical responders and clinical high responders (defined as ≥20% and ≥40% PS volume reduction, respectively), at both weeks 20 and 24 versus placebo
- Overall population: Clinical responders 42.7% vs 20.8%, p=0.003; Clinical high responders 22.7% vs 9.4%, p=0.018
- Stoma subpopulation: clinical responders 40.7% vs 15.4%, p=0.02; clinical high responders 20.4% vs 0%, p=0.009
- Seven apraglutide-treated patients achieved enteral autonomy (three in the stoma subpopulation, four in the colon-in-continuity subpopulation) by week 24 (6.4% apraglutide vs 0% placebo, p=0.006). Three additional colon-in-continuity patients achieved enteral autonomy by week 48: 7/56 [12.5%] apraglutide vs 2/27 placebo [7.4%], p=0.387.
“Given the burden that parenteral support places on people living with SBS-IF, the goal of treatment is to importantly gain additional days off PS, and ultimately achieve enteral autonomy in those who can achieve it,” said Kishore R Iyer, MBBS, FRCS (Eng), FACS, Director of Adult and Pediatric Intestine Rehabilitation & Transplantation at
Apraglutide also demonstrated statistical significance on two key secondary endpoints, with more patients in the combined population achieving at least one day/week off PS relative to baseline at week 24 versus placebo (43.0% vs. 27.5%; p=0.040) and more patients treated with apraglutide versus placebo demonstrating improvement in relative change from baseline in actual weekly PS volume at week 24 in the stoma subpopulation (-25.6% vs. -7.8%; p<0.001). Apraglutide was well-tolerated, with no new safety signals identified and the safety profile was consistent with previous apraglutide studies.
“Our data at DDW reflect Ironwood’s key priorities, which focus on advancing the treatment of GI diseases,” said
In addition to the STARS Phase III oral presentation, Ironwood, and its collaborators presented data highlighting findings across the apraglutide development program.
Impact of once weekly apraglutide on intestinal absorption
Three posters were presented by
- “Changes in Bowel Morphology and Motility Assessed by MRI in Patients with Short Bowel Syndrome Intestinal Failure (SBS-IF) and Colon-In-Continuity Treated with Apraglutide” (poster number Su1946) demonstrated that apraglutide treatment was associated with small bowel lengthening and increased duodenal wall thickness suggesting an intestinotrophic (stimulates/regulates growth of intestinal tissue) effect that may contribute to an increased surface area for absorption. The authors note that whether bowel lengthening results from a direct effect of apraglutide vs. changes in motility with passive elongation is subject of further investigation.
- “Parenteral Support Weaning, Clinical Benefit and Improved Patient Reported Outcomes in Short Bowel Syndrome Intestinal Failure (SBS-IF) Patients with Colon-In-Continuity Treated with The Long-Acting Glucagon-Like Peptide-2 (GLP-2) Analog Apraglutide” (poster number Su1947) showed that apraglutide has an acceptable safety profile and is associated with significant reductions in PS needs in SBS-IF patients with colon-in continuity, resulting in days off PS and subjective improvement based on patient reported outcomes.
- "Apraglutide Treatment in Short Bowel Syndrome with Intestinal Failure (SBS-IF) and Colon-In-Continuity is Associated with Increased Oral Intake and Improved Energy and Carbohydrate Absorption at 48 Weeks" (poster number Su1948) showed that in patients with SBS-IF and colon-in-continuity, apraglutide treatment resulted in an early reduced fecal output and improved wet weight absorption. After 48 weeks, oral intake was increased despite stable fecal output, leading to increased energy and carbohydrate absorption.
Impact of apraglutide on gastric emptying
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"The Effect of Apraglutide on Gastric Emptying in Healthy Individuals: A Phase 1 Randomized, Placebo-Controlled, Double-Blind, Single-Center Trial" (poster number Su1949) was presented by
Gerard Greig ,Ironwood Pharmaceuticals . The data suggest that apraglutide does not affect gastric emptying of liquids in healthy individuals, as measured by acetaminophen pharmacokinetics (PK), and can therefore be used in a broad patient population.
Irritable Bowel Syndrome with Constipation (IBS-C) and Functional Constipation
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“Real World Prescribing Patterns for Pediatric Patients with Functional Constipation and Irritable Bowel Syndrome with Constipation” (presentation number Su2047) was presented by
Julie Khlevner , M.D., New York Presbyterian Morgan Stanley Children’s Hospital,New York, NY , showing that, based on a retrospective, observational study, approximately one-third of children and adolescents diagnosed with FC or IBS-C were prescribed medication for constipation during a five year period (January 2018 –June 2023 ). Polyethylene glycol 3350 was the most frequently prescribed medication for pediatric FC and IBS-C, followed by lactulose. -
“Efficacy, Safety, and Time to Response of Linaclotide in Patients ≥ 65 with Irritable Bowel Syndrome with Constipation” (presentation number Tu1653) will be presented by
Lin Chang , M.D.,David Geffen School of Medicine atUCLA ,Los Angeles, CA. The data were based on a post hoc analysis of >2,000 adults with IBS-C. Treatment-emergent adverse events were similar in both age groups and were consistent with the known safety profile of linaclotide in patients with IBS-C. -
“Assessing US Healthcare Disparities in IBS Diagnosis: A National Survey Analysis” (presentation number Tu1027) will be presented by Christopher V Almario, M.D., MSHPM,
Cedars Sinai Medical Center ,Los Angeles, CA , summarizing survey data from nearly 90,000 adults in the US. The study analyzed healthcare-seeking behavior, including the likelihood of seeing a healthcare provider (HCP) and the type of HCP seen. Respondents who identified as Black orAfrican American were less likely to be diagnosed with IBS than those who identified as White, even after controlling for potential confounding variables, such as socioeconomic status and symptom severity.
About STARS
The STARS (STudy of ApRaglutide in SBS) pivotal Phase III trial represents the largest Phase III trial in SBS-IF to date.
This global, multicenter, double-blind, randomized, placebo-controlled trial evaluated the efficacy and safety of weekly subcutaneous injections of apraglutide in adult patients with SBS-IF. STARS randomized 164 patients 2:1 and 163 were dosed to receive either once-weekly apraglutide or placebo. Patients were stratified approximately 50/50 by remnant bowel anatomy (stoma vs. colon-in continuity) and evaluated over 24 weeks (stoma and colon-in-continuity subpopulations) and 48 weeks (colon-in-continuity subpopulation only). The primary endpoint was relative change from baseline in actual weekly PS volume at week 24. Key secondary endpoints included patients who achieved a reduction from baseline of at least 1 day/week off PS at week 24 (overall population); relative change from baseline in actual weekly PS volume at week 24 (stoma subpopulation); patients who achieved a reduction from baseline of at least 1 day/week off PS at week 48 (colon-in-continuity subpopulation); and patients reaching enteral autonomy at week 48 (colon-in-continuity subpopulation).
The study was conducted in 18 countries with enrollment from 68 study sites.
About STARS Nutrition
STARS Nutrition is the first-ever study to prospectively evaluate the clinical benefit of a GLP-2 analog specifically in patients with colon-in-continuity. This multicenter, open-label Phase II metabolic balance study was designed to evaluate the effect of once-weekly apraglutide 5-mg subcutaneous injection on intestinal absorption in SBS-IF patients with colon-in-continuity at 52 weeks. Safety and parameters indicative of clinical efficacy, including PS volume and energy content reduction, were assessed. The study enrolled nine adult patients with a mean age of 46.8 years.
About Short Bowel Syndrome
SBS is a serious and chronic condition where there is diminished absorptive capacity for fluids and/or nutrients, sometimes requiring dependence on parenteral support to maintain health. Short bowel syndrome typically occurs because of extensive intestinal resection, and patients with SBS who are chronically dependent on parenteral support, also referred to as SBS with intestinal failure (SBS-IF), often experience significant quality of life impact and are at risk of severe complications such as infection. An estimated 18,000 adult patients suffer from SBS-IF in the
About Apraglutide
Apraglutide is an investigational, next-generation, long-acting synthetic GLP-2 analog being developed for a range of rare gastrointestinal diseases where GLP-2 can play a central role in addressing disease pathophysiology, including short bowel syndrome with intestinal failure (SBS-IF) and Acute Graft-Versus-Host Disease (aGVHD).
About LINZESS
LINZESS® is the #1 prescribed brand in the
LINZESS is not a laxative; it is the first medicine approved by the FDA in a class called GC-C agonists. LINZESS contains a peptide called linaclotide that activates the GC-C receptor in the intestine. Activation of GC-C is thought to result in increased intestinal fluid secretion and accelerated transit and a decrease in the activity of pain-sensing nerves in the intestine. The clinical relevance of the effect on pain fibers, which is based on nonclinical studies, has not been established.
In
LINZESS Important Safety Information
INDICATIONS AND USAGE
LINZESS® (linaclotide) is indicated for the treatment of both irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults and functional constipation (FC) in children and adolescents 6 to 17 years of age. It is not known if LINZESS is safe and effective in children with FC less than 6 years of age or in children with IBS-C less than 18 years of age.
IMPORTANT SAFETY INFORMATION
WARNING: RISK OF SERIOUS DEHYDRATION IN PEDIATRIC PATIENTS LESS THAN 2 YEARS OF AGE
LINZESS is contraindicated in patients less than 2 years of age. In nonclinical studies in neonatal mice, administration of a single, clinically relevant adult oral dose of linaclotide caused deaths due to dehydration.
Contraindications
- LINZESS is contraindicated in patients less than 2 years of age due to the risk of serious dehydration.
- LINZESS is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.
Warnings and Precautions
- LINZESS is contraindicated in patients less than 2 years of age. In neonatal mice, linaclotide increased fluid secretion as a consequence of age-dependent elevated guanylate cyclase (GC-C) agonism, which was associated with increased mortality within the first 24 hours due to dehydration. There was no age dependent trend in GC-C intestinal expression in a clinical study of children 2 to less than 18 years of age; however, there are insufficient data available on GC-C intestinal expression in children less than 2 years of age to assess the risk of developing diarrhea and its potentially serious consequences in these patients.
Diarrhea
- In adults, diarrhea was the most common adverse reaction in LINZESS-treated patients in the pooled IBS-C and CIC double-blind placebo-controlled trials. The incidence of diarrhea was similar in the IBS-C and CIC populations. Severe diarrhea was reported in 2% of 145 mcg and 290 mcg LINZESS-treated patients and in <1% of 72 mcg LINZESS-treated CIC patients.
- In children and adolescents 6 to 17 years of age, diarrhea was the most common adverse reaction in 72 mcg LINZESS-treated patients in the FC double-blind placebo-controlled trial. Severe diarrhea was reported in <1% of 72 mcg LINZESS treated patients. If severe diarrhea occurs, dosing should be suspended and the patient rehydrated.
Common Adverse Reactions (incidence ≥2% and greater than placebo)
- In IBS-C or CIC adult patients: diarrhea, abdominal pain, flatulence, and abdominal distension.
- In FC pediatric patients: diarrhea.
Please see full Prescribing Information including Boxed Warning: https://www.rxabbvie.com/pdf/linzess_pi.pdf
LINZESS® and
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Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Investors are cautioned not to place undue reliance on these forward-looking statements, including statements about the assessment of the data from the Phase III STARS clinical trial of apraglutide; the efficacy, safety and tolerability of apraglutide; Ironwood’s plan to submit an NDA and marketing applications to other regulatory filings for apraglutide; the estimated adult population who suffer from SBS-IF in the
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