Linaclotide Effective for Functional Constipation in Children with Neurodevelopmental Disorders

Use of linaclotide (Linzess) offers significant benefits for relief of functional constipation among children with neurodevelopment disorders, according to new research.

An analysis of the pivotal phase 3 trial supporting approval from the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN 2024), results of the analysis demonstrate use of linaclotide provided similar benefits among children with neurodevelopmental disorders observed in the overall trial.¹

“So, the idea here is this is a unique population that we really want to better understand how to best manage their constipation in all forms, but with the introduction of linaclotide, the first FDA-approved treatment for pediatric constipation, I think we wanted to do a little bit of an in-depth analysis, given those specific concerns of those patients. That's what prompted this posthoc analysis,” explained lead investigator Hannibal Person, MD, assistant professor and medical director of the Center for Diversity and Health Equity at the University of Washington, in an interview with HCPLive at NASPGHAN 2024.

Earning a nod from the US Food and Drug Administration as the first therapy to receive approval for pediatric patients with functional constipation, linaclotide has quickly found its way into treatment algorithms for this patient population. The approval, which was awarded to Ironwood Pharmaceuticals, was based on data from a double-blind, placebo-controlled, randomized, multicenter phase 3 clinical trial.^1,2,3

The study enrolled 330 patients aged 6 to 17 years with functional constipation and randomized them in a 1:1 ratio to oral linaclotide 72 μg or placebo once daily for 12 weeks. Results of the overall trial suggested use of linaclotide was associated with significant improvement in the weekly spontaneous bowel movement frequency relative to placebo therapy during the 12-week treatment period (P <.0001).^2,3

At NASPGHAN 2024, Person presented data from an analysis examining outcomes among patients with functional constipation and comorbid neurodevelopment disorders, including aggressive behavior, ADHD, ASD, conduct disorder, disruptive mood dysregulation disorder, oppositional defiant disorder, sensory processing disorder, and tic disorders. Investigators pointed out were reported by the child's parent or legal guardian and corroborated by medical records when available.¹

“I think most general pediatricians and pediatric gastroenterologists have experienced sort of the difficulties these families face with managing functional constipation in kids with developmental disorders, and that can be really multifactorial,” Person explained.

Among the 328 patients in the study who received at least 1 dose of linaclotide or placebo therapy, 57 had a comorbid neurodevelopmental disorder. Of the 57 patients included in the current analysis, 25 had received linaclotide and 32 had received placebo therapy. Investigators noted baseline demographics were generally balanced between treatment groups.¹

Upon analysis, results indicated use of linaclotide was associated with a beneficial treatment effect for all efficacy endpoints, with the observed improvements in bowel function similar to those observed in the overall study population. Analysis of adverse events suggested the incidence of diarrhea treatment-emergent adverse events for children with functional constipation and comorbid neurodevelopmental disorders (linaclotide, 4.0% vs placebo, 0%) was similar to that observed in the overall study population (linaclotide, 4.3% vs placebo, 1.8%), which Person highlighted is a similar rate seen with laxatives and other modalities.¹

Further analysis drew attention to the rates of compliance among this patient population. In the analysis, results demonstrated approximately 96% of patients completing 8–12 weeks of treatment. Furthermore, patients in this subgroup achieved 96% or greater dosing compliance with once-daily oral administration of linaclotide or placebo therapy.¹

“The fact that the kids did well, just like their peers, was a really great sign,” Person added. “The other thing is the rate of adherence to the medication, which can be challenging with any child, but sometimes particularly challenging with this population—we had a very high rate, greater than 90% of adherence for 8 weeks of treatment, which was fantastic.”

References:

1. Person H, Hyams J, Sanghavi R, et al. A POST HOC ANALYSIS DESCRIBING THE EFFICACY AND SAFETY OF LINACLOTIDE IN PEDIATRIC PATIENTS WITH FUNCTIONAL CONSTIPATION AND COMORBID NEURODEVELOPMENTAL DISORDERS. Presented at NASPHGAN 2024 in Hollywood, Florida, from November 7 – November 9, 2024.
2. Center for Drug Evaluation and Research. FDA approves first treatment for pediatric functional constipation. U.S. Food and Drug Administration. June 12, 2023. Accessed November 9, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-first-treatment-pediatric-functional-constipation.
3. 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. Lancet Gastroenterol Hepatol. 2024;9(3):238-250. doi:10.1016/S2468-1253(23)00398-9