Editorial: repurposed linaclotide and the quest for abdominal pain management in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with significant unmet clinical need, especially for management of abdominal pain. The precise drivers of abdominal pain are unclear and probably variable in different subsets of patients with IBS. Linaclotide, a guanylate cyclase (GCC) agonist, is approved to treat constipationpredominant IBS (IBSC). Immediate release (IR) linaclotide provided nociception in a TNBSinduced rodent model of colonic allodynia, and in stress models.1 In mice, colonic GCC and extracellular cGMP release in response to linaclotide provided visceral nociception.2 Recently, two delayedrelease formulations of linaclotide (ileal DR1 and ileocaecal/caecal DR2/MD7246) were developed to explore potential nociceptive properties. In a phase 2b study in patients with IBSC pati, the IR and DR1 formulations led to higher responder rates for abdominal pain and constipation. However, the response with MD-­7246­(30–­300 μg) was similar to placebo.3 Lembo et al have presented a 12week doubleblind, placebocontrolled­ dose-­ranging­ trial­ of­ 300,­ 600­ or­ 1200 μg MD7246 in patients with diarrhoeapredominant IBS (IBSD).4 All doses were well tolerated and safe. No differences were observed between treatment groups and placebo for the primary endpoint (30% pain responder for >6/12 weeks).­Although­there­were­some­numerical­ differences­for­40%­and­50%­responders­with­the­300 μg dose, none reached statistical significance. This is the first trial of a linaclotide formulation in patients with IBSD. Although colonic hypersensitivity has been shown in both IBSC and IBSD,5 it is plausible that the contribution of this mechanism towards overall abdominal pain and the mechanisms for hypersensitivity differ. One study showed that the small intestine may play an important role in chemosensitivity in both IBSC and IBSD.6 As postulated by the authors, the colonic microenvironment or faster transit in patients with IBSD may result in greater degradation and limited bioavailability of linaclotide. Factors associated with the study population and design might also have influenced the results. Patients with Rome IVdefined IBS have greater pain and symptom severity than those meeting Rome III criteria.7 Furthermore, this trial enrolled­patients­with­pain­≥4­and ≤9­on­an­11-­point­scale.­Although­ the enrolment criteria were exhaustive, details on psychiatric comorbidities were missing. Treatment compliance could not be fully determined based on the presented results. Although placebo response rates were high, they were comparable with other IBS trials.8 The authors speculated that use of composite endpoints (pain and diarrhoea) along with higher thresholds for pain reduction may have resulted in lower placebo response. Pain reduction with IR formulation in IBSC is at least partly driven by secretory effects. Although supported by some preclinical data, it is plausible that linaclotide does not have a substantial primary nociceptive property. Regardless, this well conducted trial outlines the challenges in conceptualising IBSC and IBSD within the current framework, and highlights our lack of understanding of drivers of pain in IBS subtypes. The investigators are to be lauded for their efforts in modifying a well tolerated agent and for conducting this trial to target pain, a critically underaddressed symptom in IBS.