COMMENTARY: New Drugs on the Horizon for Functional and Motility Gastrointestinal Disorders

Introduction

This is a brief summary of the mechanism of action and current evidence of efficacy of new drugs, as yet unapproved by the Food and Drug Administration, that have the potential to impact the treatment of three commonly encountered functional or motility gastrointestinal disorders, specifically gastroparesis, abdominal pain, and bile acid-related bowel dysfunctions. The unapproved medications that are included were selected based on search in Clinicaltrials.gov that included interventional phase 2 or 3 clinical trials with results posted (17 for gastroparesis and 54 for irritable bowel syndrome), as well as a PubMed literature search. The selected medications and a summary of their site or mechanism of action are demonstrated in Figure 1 (1,2).

Figure 1. Mechanisms of action of new drugs in treatment of motility and functional gastrointestinal disorders. Reproduced in part from ref. 1, Vijayvargiya P, Camilleri M. Gastroenterology 2019;156:1233–1238 and from ref. 2, Camilleri M. Am J Physiol Gastrointest Liver Physiol 2019;317:G640-G650.

Ach= acetyl choline; CA = cholic acid; CDCA chenodeoxycholic acid; CTZ = chemoreceptor trigger zone; DCA= deoxycholic acid; DMV = dorsal motor nucleus of vagus nerve; FXR = farnesoid X receptor; 5-HT4: 5-hydroxytryptamine type 4; IBAT = ileal bile acid transporter (also known as apical sodium coupled bile acid transporter, ASBT); LCA= lithocholic acid; NFEPP = fentanyl derivative [(±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide]

I. Candidate Drugs for Gastroparesis

The promising drugs for gastroparesis target three different mechanisms:

a. The selective NK1 receptor antagonist, tradipitant (3)

Putative mechanism of action:

Tachykinin or neurokinin-1 receptor antagonists may have dual potential in gastroparesis: First, these agents reduce afferent mechanisms resulting in emesis through a direct effect on brain regions responsible for nausea and vomiting, inhibiting effects of substance P within the central emetic circuitry or through an effect on NK1 receptors on vagal afferents. A second mechanism with potential to alleviate symptoms is through the NK1 receptor antagonists’ alteration of the functional interplay between the acetylcholine and NK1R systems that stimulates smooth muscle contractions in the stomach. Two recent publications suggest that the predominant clinical effects of NK1 receptor antagonists may be mediated by effects on afferent or emetic centers. Thus, another NK1 receptor antagonist, aprepitant, was shown, in healthy humans, to increase fasting and postprandial gastric volumes (4) without retardation of gastric emptying; and tradipitant has demonstrated efficacy in the treatment of motion sickness (5). To date, there have been no published studies of the effects of tradipitant on gastric motor function. However, a mechanistic study of the pharmacodynamic effects of tradipitant in healthy human participants is under way (ClinicalTrials.gov NCT#04849559).

Evidence of efficacy:

Tradipitant, 85mg bid, has been tested in a multicenter, double-blind, placebo-controlled trial of 152 adults with gastroparesis treated for 4 weeks (3). Symptoms were assessed by the Gastroparesis Cardinal Symptom Index (GCSI) daily diary and other patient-reported questionnaires. There was a greater than 1-point improvement in GCSI score in 46.6% of patients on tradipitant compared with 23.5% of patients on placebo, as well as significant reduction in nausea scores and number of nausea-free days, particularly in patients with significant nausea and vomiting scores at baseline.

b. The ghrelin receptor agonist, relamorelin

Putative mechanism of action:

Ghrelin receptors are located in the nodose ganglion cell bodies of vagal afferents, neurons in the dorsal motor nucleus of vagus, and myenteric neurons throughout the gut. Several studies have documented relamorelin accelerated gastric emptying, in pharmacodynamic studies based on scintigraphic measurements in type 1 and type 2 diabetes, as well as stimulating postprandial antral motility in healthy participants.

Evidence of efficacy:

Relamorelin, 30–100μg SC, has been in development for treatment of gastroparesis in the last decade. As summarized elsewhere (6), relamorelin shows promise in treating diabetic gastroparesis, with a reduction in core symptoms. It appears to be efficacious and well tolerated with low risk of neurological or cardiovascular adverse effects. An analysis of phase 2a and 2b trial data (7) has recently documented safety other than increased HbA1c and fasting blood glucose which likely resulted from acceleration of gastric emptying or an increase in postprandial glucose levels due to increased food intake caused by larger appetite induced by the ghrelin receptor agonist. In those trials, there was no proactive management of blood glucose levels, and this led to the recommendation to proactively monitor blood glucose levels to enhance glycemic control in diabetic patients receiving treatment with relamorelin, and this strategy has been implemented in the ongoing phase 3 trials of relamorelin (NCT03285308; NCT03426345).

c. The selective 5-HT4 receptor agonist, felcisetrag

Putative mechanism of action:

Felcisetrag is a highly selective and potent 5-HT4 receptor agonist with prokinetic activity throughout the gastrointestinal tract in experimental models (8). After intra-venous administration in healthy volunteers and in treatment of enteral feeding intolerance in critically ill patients, felcisetrag demonstrated prokinetic activity when administered over a short term (9).

Evidence of efficacy:

Felcisetrag (0.1mg; 0.3mg, 1.0mg i.v.) has been tested in a parallel group, placebo-controlled dose-response pharmacodynamic gastrointestinal and colonic transit study in patients with idiopathic (n=22) or diabetic (n=14) gastroparesis. Felcisetrag significantly accelerated transit of solids throughout the gut; pharmacokinetic results were dose- proportional, the medication was well-tolerated with no clinically significant adverse events on clinical laboratory, vital signs, or ECG. As an intravenously administered drug, felcisetrag may be effective for acute gastrointestinal motility disorders (which may result in hospitalization), and for enteral feeding intolerance in critically ill patients. Availability of an oral or subcutaneous formulation would be advantageous in clinical practice.

II. Novel Visceral Analgesics

a. Smart μ-opiate-receptor ligands

Putative mechanism of action:

μ-OR agonists induce analgesia through activation of G protein-mediated pathways and through recruitment of β-arrestin, which mediates receptor desensitization and internalization leading to activation of μ-ORs in endosomes. β-arrestin activation induces respiratory depression and inhibits gastrointestinal motility. One approach to circumvent these adverse effects has been the development of biased μ-OR ligands. One of these, oliceridine (TRV-130), was approved by the US Food and Drug Administration as an intravenous opioid for the management of moderate to severe acute pain in adults for whom alternative treatments other than opioids had failed. Similar biased ligands are also in development, PZM21 and SR-17018, and their pharmacological effects including analgesic properties and studies of respiratory depression in preclinical models have been described in detail (10). The analgesic actions of PZM21 have also been documented in non-human primates (11), and those of SR-17108 in mice (12).

An alternative smart approach to achieve analgesia with μ-OR activation and low risk of respiratory depression is provided by NFEPP, a fluorinated fentanyl molecule (13) that is activated selectively in acidic environment such as in sites of inflammation. In mice with 2.5% dextran sodium sulphate-induced colitis (14), NFEPP was associated with inhibition of visceromotor responses to colorectal distension, without decreased defecation or respiratory depression. In contrast to the μ-OR biased ligands which activate the GPCR pathway without activating β-arrestin, NFEPP (in addition to activation of the opioid GPCR signaling pathway) actually recruits β-arrestins and evokes μ-ORs endocytosis leading to activation of μ-ORs in endosomes. This occurs preferentially in acidified conditions, and this endosomal signaling is associated with superior pain relief in preclinical models (15).

Evidence of efficacy:

Studies in humans with these novel μ-opiate-receptor ligands are eagerly awaited. In addition, it is not yet proven that the degree of inflammation in functional or motility disorders results in sufficient tissue acidification to activate the fluorinated fentanyl; preclinical models (14) show that an average tissue pH acidification by 0.33 units is sufficient to activate NFEPP.

b. Cannabinoid type 2 receptor (CB2R) agonist

Putative mechanism of action:

Olorinab, a CBR2 receptor agonist, reduced pain reduced visceromotor response to colorectal distension in rat TNBS colitis and a mouse model of chronic visceral hypersensitivity (16).

Evidence of efficacy:

The CB2R agonist, olorinab, is being tested for its potential analgesic effects in irritable bowel syndrome (IBS). In a randomized, open-label, parallel-group, multicenter, phase 2a study of 14 patients with quiescent Crohn’s disease randomized to 25 or 100 mg oral olorinab tid for up to 8 weeks, the average abdominal pain score improved from baseline at weeks 4 and 8 and was associated with a higher number of pain-free days per week and proportion of abdominal pain responders (17). In a recent announcement (18), the company reported that in a phase 2b clinical trial, olorinab administered orally three times daily at three separate doses to 273 patients with IBS (NCT04043455) missed its primary endpoint (reduction in daily abdominal pain score). However, in patients with moderate to severe pain at baseline, the 50-mg dose was linked to a 1.64 point reduction in pain scores (scale 0-10) compared to placebo. The future development of this medication for visceral pain is unclear.

III. Modulating Bile Salt Effects for Bowel Dysfunction

a. Ileal bile acid transport inhibitor, elobixibat

Putative mechanism of action:

Approximately 15% of patients with IBS-C have reduced total bile acids and levels of the secretory bile acid, deoxycholic acid, in fecal samples collected over 48 hours on a 100 g fat diet (19). In these patients, lower levels of excretion of bile acids into feces correlated with slower colonic transit. As reviewed elsewhere (20), elobixibat accelerated colonic transit in several species including humans, induced giant migrating contractions during defecation in dogs. Phase 4 studies conducted in patients treated with elobixibat have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content (21) without significant alterations in the microbiome.

Evidence of efficacy:

Elobixibat (up to 10mg/day) is approved in Japan for the treatment of chronic constipation. Multiple placebo-controlled, randomized trials of elobixibat, including mechanistic phase 2a trials, multicenter phase 2b trials in the United States and Japan, and phase 3 trials including long-term safety and efficacy in Japan have been published and are reviewed elsewhere (20). The drug is efficacious in the treatment of constipation, including severe constipation, and is safe and well tolerated.

b. Farnesoid X receptor agonists, obeticholic acid and tropifexor

Putative mechanism of action:

Farnesoid X receptor (FXR) agonists stimulate the synthesis and subsequent release of FGF-19 from ileal epithelial cells and inhibit bile acid synthesis by hepatocytes. This results in reduced intraluminal concentration of BAs in the colon, relieving the diarrhea. It is estimated that up to a third of adults with symptoms consistent with functional diarrhea or IBS-D have increased fecal bile acid excretion or serological markers of increased bile acid synthesis (1).

Evidence of efficacy:

Although this class of medications is being developed predominantly for the treatment of NAFLD (22,23) or cholestatic liver diseases, the same mechanism of action that results in reduced bile acid synthesis by hepatocytes may also prove beneficial for patients with functional diarrhea associated with increased colonic or bile acid levels, also called bile acid diarrhea (BAD). Two small placebo-controlled trials have proven pharmacodynamic efficacy of two FXR agonists, obeticholic acid (24) (6-ethyl chenodeoxycholic acid, approved for the treatment of primary biliary cholangitis) and tropifexor (25) (a non-bile acid), which respectively improved stool index and slowed ascending colon emptying in patients with BAD.

Conclusion

Several novel medications are promising for functional and motility gastrointestinal disorders and, with formal proof of efficacy and safety in patients, they should enhance care of patients.