Advancements in drug development for diarrhea-predominant irritable bowel syndrome

ABSTRACT

Introduction: Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches.

Areas covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA.

Expert opinion: The new 5-HT₃ receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.

KEYWORDS:

• 5HT
• diarrhea-predominant irritable bowel syndrome
• drug pipeline
• eluxadoline
• IBS-D
• ramosetron

Article highlights

• IBS-D drug development must consider the latest criteria for IBS diagnosis as well as specific regulatory parameters for trial outcomes.

• Rifaximin efficacy further reinforces the role of microbiota in IBS-D pathophysiology.

• Ramosetron and eluxadoline represent promising therapeutic options; the former must cope with reluctant approval of 5HT3 blockers inWestern Countries, the latter with safety issues and treatment restrictions.

• Alternative PK approaches like negative allosteric modulation could be applied in the development of novel 5HT receptor modulators.

• The most promising experimental drug compounds for IBS-D show activity as mild immunomodulators and/or inhibitors of peripheral nerve firing.

• The majority of drug compounds in IBS-D pipeline still needs deeper understanding of mechanisms of action.

This box summarizes key points contained in the article.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.