Linaclotide

Mechanism (as reported)

Linaclotide is described in the provided sources as a guanylate cyclase C receptor agonist. (PMIDs: 31643353, 38533633, 23464519, 36770675)

Key findings (each cites a source)

• Linaclotide has been described as a guanylate cyclase C receptor agonist used as an oral treatment for chronic constipation and irritable bowel syndrome. (PMIDs: 31643353, 23464519) [PMID 31643353, 23464519]
• A phase 3 randomized, double-blind, placebo-controlled multicenter trial in children aged 6–17 years with functional constipation reported statistically significant improvement in spontaneous bowel movement (SBM) frequency over 12 weeks versus placebo, and also reported improvement in stool consistency. (PMID: 31643353) [PMID 31643353]
• In that phase 3 pediatric functional constipation trial, diarrhoea was reported as the most frequent treatment-emergent adverse event with higher incidence in the linaclotide group than placebo, and one serious adverse event of special interest involving severe diarrhoea with dehydration and hospitalisation was reported as treatment-related and resolved without sequelae. (PMID: 31643353) [PMID 31643353]
• A phase 2 randomized, double-blind, placebo-controlled multicenter trial in children aged 6–17 years with functional constipation reported a numerical improvement in SBM frequency with increasing linaclotide doses and reported diarrhoea as the most reported treatment-emergent adverse event, described as mild with none severe. (PMID: 38533633) [PMID 38533633]
• A phase 2 randomized, double-blind, placebo-controlled study in children aged 7–17 years with IBS-C reported numerical improvement in overall SBM frequency with increasing linaclotide doses compared with placebo and reported diarrhoea and pain as the most reported treatment-emergent adverse events, described as mostly mild with none severe. (PMID: 38504394) [PMID 38504394]
• A systematic literature review and meta-analysis comparing lubiprostone, linaclotide, and elobixibat for chronic constipation reported that the drugs showed similar efficacy in the meta-analysis/NNT analysis, while number-needed-to-harm results indicated distinct safety profiles, with linaclotide linked to the highest risk of nausea and diarrhoea. (PMID: 38166671) [PMID 38166671]
• A synthetic chemistry study reported a new regioselective synthesis of the cysteine-rich peptide linaclotide via selective formation of three disulfide bonds using mild oxidation reactions in solid phase and liquid phase approaches. (PMID: 36770675) [PMID 36770675]
• A review/overview article described linaclotide as a first-in-class GC-C receptor peptide agonist and stated that it received approval in the USA and Europe for IBS-C and chronic idiopathic constipation. (PMID: 23464519) [PMID 23464519]