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Safety and efficacy of FDA-approved linaclotide reinforced with new phase 3 data

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Compared to placebo, linaclotide demonstrated a statistically significant and clinically meaningful improvement in spontaneous bowel movement(s) (SBM) frequency rate, and was subsequently approved by the FDA in June 2023.

Safety and efficacy of FDA-approved linaclotide reinforced with new phase 3 data | Image Credit: © ibreakstock - © ibreakstock - stock.adobe.com.

Safety and efficacy of FDA-approved linaclotide reinforced with new phase 3 data | Image Credit: © ibreakstock - © ibreakstock - stock.adobe.com.

Takeaways:

  • New phase 3 data on linaclotide (Linzess) for pediatric functional constipation published in The Lancet Gastroenterology & Hepatology.
  • The study included 328 participants aged 6 to 17, comparing linaclotide 72 mcg to placebo.
  • Linaclotide demonstrated significant improvement in spontaneous bowel movements (SBMs) compared to placebo.
  • Stool consistency, assessed by Bristol Stool Form Scale (BSFS), also improved with linaclotide.
  • Linaclotide was well-tolerated, with diarrhea as the most reported treatment-emergent adverse event.

New phase 3 data for linaclotide (Linzess; Ironwood Pharmaceuticals) for functional constipation in pediatric patients aged 6 to 17 years has been published in The Lancet Gastroenterology & Hepatology, reinforcing its safety and efficacy that led to an FDA approval in June 2023.1

Defined as a condition with hard and infrequent bowel movements that are difficult and often painful to pass, function constipation affects approximately 6 million children aged 6 to 17 years in the United States.2

The phase 3 double-blind, placebo-controlled, and multicenter trial (NCT04026113) featured 328 participants that received linaclotide 72 mcg or placebo (randomized 1:1). The primary endpoint was a 12-week spontaneous bowel movement(s) (SBM) frequency rate.1,2

Compared to placebo, linaclotide demonstrated a statistically significant and clinically meaningful improvement in SBM, according to a press release from Ironwood Pharmaceuticals. Linaclotide-treated patients achieved a greater than 2-fold least squares mean change from baseline in SBMs/week (2.220) vs placebo (1.050) (P < 0.0001).1

Stool consistency, assessed by Bristol Stool Form Scale (BSFS), revealed an improvement at week 12 with linaclotide compared to placebo. A greater increase in the linaclotide group was observed for change from baseline of 12-week complete SBM frequency rate compared to the placebo group (LSM CFB difference = 0.96 complete SBMs/week; 95% CI 0.51–1.40 [P < 0.0001]).1

The percentage of patients with at least 1 SBM within 24 or 48 hours of first dose was higher in the linaclotide group compared to placebo (24 hours: 30.5% vs 20.7% [P = 0.043]) (48 hours: 56.7% vs 38.4% [P = 0.0009]).1

“All the issues you have with a liquid medicine will go away for children who can take tablets, Kirk Thame, MD, associate professor, pediatric gastroenterology, hepatology, and nutrition, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee, told Contemporary Pediatrics in a video interview following the FDA approval of linaclotide.3

“Functional constipation is among the most common complaints pediatricians and pediatric GIs see in our patients,” said Miguel Saps, Chief of Division of Pediatric Gastroenterology, Hepatology, and Nutrition and the George E. Batchelor Endowed Chair in Pediatrics, University of Miami, University of Miami Health System in the press release.1

“The insights provided by the additional efficacy endpoints in this phase [3] clinical trial are an important supplement to clinicians’ knowledge about the available treatment options for this population,” added Saps.1

The most reported treatment-emergent adverse event from patients who received linaclotide was diarrhea (7 of 164 [4%]).1

Authors of the phase 3 study concluded that “linaclotide is an efficacious and well tolerated treatment for functional constipation in [pediatric] patients and has subsequently been approved by the [FDA] for this indication.”2

References:

  1. 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 release. Ironwood Pharmaceuticals. January 8, 2023. Accessed January 10, 2023.
  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. doi:10.1016/S2468-1253(23)00398-9
  3. Fitch, J. How linaclotide can change the functional constipation treatment landscape. Contemporary Pediatrics. June 13, 2023. Accessed January 10, 2023. https://www.contemporarypediatrics.com/view/how-linaclotide-can-change-the-functional-constipation-treatment-landscape
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