Julie Khlevner, MD: Linaclotide for Pediatric Functional Constipation

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We sat down with Julie Khlevner, MD, to discuss new efficacy endpoint data from the phase 3 study used to support the FDA approval of linaclotide for pediatric functional constipation.

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

Linaclotide is a guanylate cyclase C agonist whose 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.

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 compared to placebo. Further data was published in The Lancet Gastroenterology and Hepatology detailing additional efficacy endpoints.

“Sustained efficacy and safety has been shown in adults with chronic idiopathic constipation and IBS with predominant constipation symptoms treated with linaclotide. In addition, what we know is that expression of the GCC mRNA has been found in children older than 6 months in the duodenum, and in children older than 12 months in the colon. As a result, linaclotide had the potential to be a therapeutic option to treat symptoms of functional constipation in the pediatric population,” explained Julie Khlevner, MD, associate professor of pediatrics and director of the Pediatric Gastrointestinal Motility Center at Columbia University Medical Center, in an interview with HCPLive.

For inclusion in the study, patients were required to be 6−17 years of age and meet modified Rome III criteria for functional constipation. Upon enrollment, 328 participants were randomly assigned in a 1:1 ratio to treatment with linaclotide 72 mcg (n = 166) or placebo (n = 164) for 12 weeks. The primary efficacy endpoint was change from baseline in the 12-week frequency rate of spontaneous bowel movements per week, while the secondary efficacy endpoint was change from baseline in stool consistency over the 12-week treatment period.

Results showed linaclotide improved patients’ 12-week spontaneous bowel movement frequency at a greater rate than placebo and 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 the 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). Additionally, 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).

Khlevner sat down with the editorial team of HCPLive Gastroenterology for further insight into the burden of functional constipation in pediatric patients, linaclotide’s mechanism of action, and what the current study added to clinicians’ arsenal of knowledge about the use of this treatment in this patient population.

Brooks, A. New Phase 3 Data Reinforces Safety, Efficacy of Linaclotide for Pediatric Functional Constipation. HCPLive. January 9, 2024. Accessed January 17, 2024.