Efficacy, Safety, and Tolerability of Linaclotide and Plecanatide for Treatment of IBS-C and Chronic Constipation: A Systematic Review and Pooled Analysis of RCT Data

Abstract

Introduction: Linaclotide and plecanatide are guanylate cyclase-C receptor agonists which have demonstrated efficacy for IBS-C and Chronic Constipation (CC). The aim of this study is to assess the magnitude of benefit, safety and tolerability. Methods: MEDLINE, clinicaltrials.gov, and abstracts from DDW/ACG Annual Meetings were searched for double-blind, placebo-controlled RCTs. Study selection criteria were use of FDA-responder endpoints and medication doses approved for use and/or being studied in Phase III RCTs. Additional plecanatide data was extracted from publicly available SEC filings. Dichotomous results were pooled from RCT data to yield an unadjusted odds ratio with 95% CIs. Results: Two linaclotide Phase III RCTs in IBS-C, two linaclotide Phase III RCTs in CC, one plecanatide Phase IIb RCT in IBS-C, and one plecanatide Phase IIb RCT in CC were included. Analysis of Phase IIb plecanatide RCTs is limited to the 3.0mg dose which is being studied in Phase III RCTs. For CC, linaclotide 145ug (OR = 4.6; 95% CI = 2.7, 8.1) and plecanatide 3.0mg (OR = 2.2; 95% CI = 1.3, 3.8) were superior to placebo based on the FDA-responder endpoint. Both linaclotide (OR = 5.2; 95% CI = 3.0, 9.2) and plecanatide (OR= 8.3; 95% CI = 2.4, 43.5) were more likely than placebo to produce diarrhea. Linaclotide (OR = 10.3; 95% CI = 2.5, 91.2) was more likely than placebo to lead to discontinuing drug due to diarrhea and plecanatide trended toward this outcome (OR: = 7.1; 95% CI = 0.9, 319.5; Fisher's exact p = 0.07). For IBS-C, linaclotide 290ug (OR = 2.4; 95% CI = 1.9, 3.1) and plecanatide 3.0mg (OR = 2.6; 95% CI = 1.3, 5.5) were superior to placebo based on the 12-week FDA-responder endpoint. In a 12-week linaclotide trial (OR = 6.6, 95% CI = 3.6, 12.8), a 26-week linaclotide trial (OR = 9.6; 95% CI = 4.9, 21.1), and a 12-week plecanatide trial (OR=infinity; 95% CI: 2.25, infinity), treatment was more likely than placebo to produce diarrhea. Linaclotide led to more discontinuation of drug due to diarrhea in the 12-week trial (OR = 23.7; 95% CI = 3.8, 979.4) and 26-week trials (OR = 18.8; 95% CI = 2.9, 786.9). Plecanatide trended toward this outcome (OR=infinity, 95% CI=1.35, infinity; Fisher's Exact p = 0.06). Since zero placebo-treated patients had diarrhea in the plecanatide IBS-C RCT, ORs for diarrhea=infinity. Conclusion: Linaclotide and plecanatide both demonstrate efficacy for CC and IBS-C and report similarly increased rates of diarrhea and discontinuation due to diarrhea with IBS-C and CC.