New Phase 3 Data Reinforces Safety, Efficacy of Linaclotide for Pediatric Functional Constipation

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The new data was published in The Lancet Gastroenterology & Hepatology and highlighted additional efficacy endpoints from the study used to support linaclotide’s FDA approval in 2023.

New data from a phase 3 study of linaclotide (Linzess) in pediatric patients 6-17 years of age with functional constipation is providing additional insight into its efficacy in this patient population and further supports its US Food and Drug Administration (FDA) approval for this indication.

Published in The Lancet Gastroenterology & Hepatology, the results highlight additional efficacy endpoints from the study used to form the basis of linaclotide’s FDA approval for pediatric functional constipation in 2023 and suggest a similar safety profile to that observed in prior linaclotide studies in adult patients.1

“Functional constipation is among the most common complaints pediatricians and pediatric GIs see in our patients,” said Miguel Saps, MD, chief of pediatric gastroenterology, hepatology, and nutrition and the George E. Batchelor Endowed Chair in Pediatrics at the University of Miami, in a press release.1 “The insights provided by the additional efficacy endpoints in this Phase III clinical trial are an important supplement to clinicians’ knowledge about the available treatment options for this population.”

A guanylate cyclase C agonist, linaclotide increases intestinal fluid secretion, accelerates transit, and decreases the activity of pain-sensing nerves in the intestine. Its initial FDA approval dates back to 2012 for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation in adults. The FDA approved a new indication of linaclotide to treat functional constipation in pediatric patients 6-17 years of age on June 12, 2023, making it the first and only FDA-approved prescription therapy for functional constipation in this patient population.2,3

The FDA decision for its use in pediatric patients was based on topline results from a multicenter, double-blind, phase 3 study in which linaclotide showed a statistically significant and clinically meaningful improvement in 12-week spontaneous bowel movement frequency rate compared to placebo. Eligible patients included those 6−17 years of age who met modified Rome III criteria for functional constipation. Upon enrollment, 328 study participants were randomly assigned in a 1:1 ratio to treatment with linaclotide 72 mcg (n = 166) or placebo (n = 164) for 12 weeks.1,3

The primary efficacy endpoint was change from baseline in the 12-week frequency rate of spontaneous bowel movements per week and the secondary efficacy endpoint was change from baseline in stool consistency over the 12-week treatment period.2

According to Ironwood’s January 8 press release, linaclotide improved patients’ 12-week spontaneous bowel movement frequency rate compared at a greater rate than placebo. Additionally, a statistically significant proportion of linaclotide-treated patients achieved > 2-fold least squares mean (LSM) change from baseline in spontaneous bowel movement frequency rate compared to placebo (2.220 vs 1.050; P <.0001).1

Investigators noted the percentage of patients with ≥1 spontaneous bowel movement within 24 or 48 hours of the first dose of study drug was greater in the linaclotide group (30.5% and 56.7%, respectively) compared to the placebo group (20.7% and 38.4%, respectively) (P = .043 for 24 hours and P = .0009 for 48 hours).2

Stool consistency as measured by Bristol Stool Form Scale scores showed greater improvement at week 12 in the linaclotide group compared to the placebo group (LSM change from baseline, 1.11 vs 0.69; LSM change from baseline difference, 0.42; 95% Confidence interval [CI], 0.21−0.64; P = .0001).1,2

Linaclotide was well-tolerated and had a similar proportion of patients with adverse events compared to placebo, demonstrating a safety profile consistent with prior linaclotide studies in adults. The most frequent treatment-related treatment-emergent adverse event was diarrhea (4% in the linaclotide group, 1% in the placebo group). Investigators noted there was a single serious adverse event of special interest, treatment-related severe diarrhea resulting in dehydration and hospitalization, in the linaclotide group that was resolved without sequelae after administration of intravenous fluids.2

“The publication of these results in The Lancet Gastroenterology & Hepatology adds to the body of knowledge about linaclotide and helps close the unmet needs gap in pediatric patients ages 6-17 with [functional constipation],” said Michael Shetzline, MD, PhD, chief medical officer, senior vice president, and head of research and drug development at Ironwood Pharmaceuticals.1


  1. Ironwood Pharmaceuticals. Ironwood Announces Publication in The Lancet Gastroenterology & Hepatology of New Linaclotide Phase III Data in Children and Adolescents Aged 6-17 Years with Functional Constipation. Press Releases. January 8, 2024. Accessed January 9, 2024.
  2. Di Lorenzo C, Khlevner J, Rodriguez-Araujo G, et al. Efficacy and safety of linaclotide in treating functional constipation in paediatric patients: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. The Lancet Gastroenterology & Hepatology.
  3. Ironwood Pharmaceuticals. Ironwood Pharmaceuticals Announces FDA Approval of New Indication for LINZESS® (linaclotide) for the Treatment of Functional Constipation in Pediatric Patients Ages 6-17 Years-Old. News. June 12, 2023. Accessed January 9, 2024.