An Overview of the Effects of Tenapanor on Visceral Hypersensitivity in the Treatment of Irritable Bowel Syndrome with Constipation

Abstract

Background

Patients with irritable bowel syndrome with constipation (IBS-C) experience persistent abdominal pain, a common symptom leading to greater healthcare utilization and reports of treatment non-response. Clinically significant improvements in abdominal pain were observed in clinical trials of tenapanor, a first-in-class inhibitor of sodium/hydrogen exchanger isoform 3 (NHE3), for the treatment of IBS-C in adults.

Aim

This narrative review reports the current knowledge about visceral hypersensitivity as a mechanism for abdominal pain in patients with IBS-C and explores the published evidence for hypothesized mechanisms by which tenapanor may reduce visceral hypersensitivity leading to the observed clinical response of decreased abdominal pain.

Findings

Abdominal pain is experienced through activation and signaling of nociceptive dorsal root ganglia that innervate the gut. These sensory afferent neurons may become hypersensitized through signaling of transient receptor potential cation channel subfamily V member 1 (TRPV1), resulting in reduced action potential thresholds. TRPV1 signaling is also a key component of the proinflammatory cascade involving mast cell responses to macromolecule exposure following permeation through the intestinal epithelium. Indirect evidence of this pathway is supported by observations of higher pain in association with increased intestinal permeability in patients with IBS. Tenapanor reduces intestinal sodium absorption, leading to increased water retention in the intestinal lumen, thereby improving gastrointestinal motility. In animal models of visceral hypersensitivity, tenapanor normalized visceromotor responses and normalized TRPV1-mediated nociceptive signaling.

Conclusion

By improving gastrointestinal motility, decreasing intestinal permeability and inflammation, and normalizing nociception through decreased TRPV1 signaling, tenapanor may reduce visceral hypersensitivity, leading to less abdominal pain in patients with IBS-C. Therapies that have demonstrated effects on visceral hypersensitivity may be the future direction for meaningful abdominal pain relief for patients with IBS-C.

Keywords:

• IBS-C
• NHE3
• abdominal pain
• TRPV1
• sodium absorption
• intestinal permeability

Abbreviations

BID, twice daily; DRG, dorsal root ganglia; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; IL-6, interleukin 6; NHE, sodium/hydrogen exchanger; NHE3, sodium/hydrogen exchanger isoform 3; RR, relative risk; TRPV1, transient receptor potential cation channel subfamily V member 1.

Acknowledgments

Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Ashfield MedComms (US), an Inizio company, and was funded by Ardelyx, Inc.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Prashant Singh reports no conflicts of interest in this work. Gregory S. Sayuk consulted for AbbVie/Ironwood, Ardelyx, Inc., Regeneron/Sanofi, and Salix and served on speakers bureaus for and received honoraria from AbbVie/Ironwood, Ardelyx, Inc., GI Health Foundation, Regeneron/Sanofi, Rome Foundation, and Salix. David P. Rosenbaum, Kenji Kozuka and Susan Edelstein are employees of Ardelyx, Inc. Lin Chang has served on a scientific advisory board for Ardelyx, Inc. Lin Chang also reports personal fees/grants from Atmo, Arena, Bausch Health, Ironwood, and AbbVie; stock options from Trellus Health, Food Marble, and ModifyHealth, outside the submitted work. In addition, Lin Chang has a patent Ref.: 2018-578-2 (Serial number 63/499,017) issued. These authors report no other conflicts of interest in this work.

Additional information

Funding

Medical writing and editing support for this review article was funded by Ardelyx, Inc.