Linaclotide (Linzess®
tablets 0.25 mg) is a
guanylate cyclase-C (GC-C) agonist with high selectivity and binding affinity to GC-C. In Japan,
linaclotide was approved for 〝irritable bowel syndrome with
constipation (IBS-C)〟 in December 2016 and 〝chronic
constipation (CC) (excluding
constipation due to organic disease)〟 in August 2018. Non-clinical studies demonstrated that
linaclotide binding to GC-C increases intracellular cyclic
guanosine monophosphate (cGMP), resulting in increased fluid secretion and gastrointestinal transit. In rats with colonic
hyperalgesia, but not in normal rats,
linaclotide suppressed the visceral nociceptive response, mediated by increased submucosal cGMP. In clinical studies in Japan, improvements were observed in the responder rates for global assessment of IBS symptom relief, complete spontaneous bowel movements in patients with IBS-C, and the frequency of spontaneous bowel movement in patients with CC, which were maintained during long-term treatment. Additionally, abdominal bloating, which has been associated with lower quality of life (QOL) and lower satisfaction with other approved
therapies, and IBS QOL were improved throughout treatment with
linaclotide.
Diarrhea, a consequence of
linaclotide's mechanism of action, was observed during the clinical studies, but was generally controllable by decreasing the
linaclotide dose. No drug resistance was observed during the clinical studies, unlike some other approved agents. These results of non-clinical and clinical studies demonstrate that
linaclotide can improve
constipation, various abdominal symptoms, and QOL with a favorable safety profile in patients with IBS-C and CC.