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Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation.
Am J Gastroenterol. 2021 02 01; 116(2):354-361.AJ

Abstract

INTRODUCTION

Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects.

METHODS

This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate.

RESULTS

Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo.

DISCUSSION

Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

Authors+Show Affiliations

Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA.Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.Ironwood Pharmaceuticals, Inc., Boston, Massachusetts, USA.Imbria Pharmaceuticals, Boston, Massachusetts, USA.AbbVie, Inc., Madison, New Jersey, USA.AbbVie, Inc., Madison, New Jersey, USA.AbbVie, Inc., Madison, New Jersey, USA.Ironwood Pharmaceuticals, Inc., Boston, Massachusetts, USA.Cyclerion Therapeutics, Cambridge, Massachusetts, USA.Ironwood Pharmaceuticals, Inc., Boston, Massachusetts, USA.

Pub Type(s)

Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33065589

Citation

Chey, William D., et al. "Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation." The American Journal of Gastroenterology, vol. 116, no. 2, 2021, pp. 354-361.
Chey WD, Sayuk GS, Bartolini W, et al. Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation. Am J Gastroenterol. 2021;116(2):354-361.
Chey, W. D., Sayuk, G. S., Bartolini, W., Reasner, D. S., Fox, S. M., Bochenek, W., Boinpally, R., Shea, E., Tripp, K., & Borgstein, N. (2021). Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation. The American Journal of Gastroenterology, 116(2), 354-361. https://doi.org/10.14309/ajg.0000000000000967
Chey WD, et al. Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation. Am J Gastroenterol. 2021 02 1;116(2):354-361. PubMed PMID: 33065589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation. AU - Chey,William D, AU - Sayuk,Gregory S, AU - Bartolini,Wilmin, AU - Reasner,David S, AU - Fox,Susan M, AU - Bochenek,Wieslaw, AU - Boinpally,Ramesh, AU - Shea,Elizabeth, AU - Tripp,Kenneth, AU - Borgstein,Niels, PY - 2020/05/21/received PY - 2020/08/27/accepted PY - 2020/10/17/pubmed PY - 2021/3/2/medline PY - 2020/10/16/entrez SP - 354 EP - 361 JF - The American journal of gastroenterology JO - Am J Gastroenterol VL - 116 IS - 2 N2 - INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype. SN - 1572-0241 UR - https://www.unboundmedicine.com/medline/citation/33065589/Randomized_Trial_of_2_Delayed_Release_Formulations_of_Linaclotide_in_Patients_With_Irritable_Bowel_Syndrome_With_Constipation_ L2 - https://Insights.ovid.com/pubmed?pmid=33065589 DB - PRIME DP - Unbound Medicine ER -