This is a brief summary of the mechanism of action and current evidence of efficacy of new drugs, as yet unapproved by the US Food and Drug Administration (FDA), that have the potential to affect the treatment of 3 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 sites or mechanisms of action are shown in Figure 1.1Vijayvargiya P. Camilleri M. Current practice in the diagnosis of bile acid diarrhea.Gastroenterology. 2019; 1: 1233-1238Abstract Full Text Full Text PDF Scopus (22) Google Scholar,2Camilleri M. What’s in the pipeline for lower functional gastrointestinal disorders in the next 5 years?.Am J Physiol Gastrointest Liver Physiol. 2019; 3: G640-G650Crossref Scopus (2) Google Scholar The promising drugs for gastroparesis target 3 different mechanisms. 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 volumes4Jacob D. Busciglio I. Burton D. et al.Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant.Am J Physiol Gastrointest Liver Physiol. 2017; 3: G505-G510Crossref Scopus (23) Google Scholar without retardation of gastric emptying; and tradipitant has demonstrated efficacy in the treatment of motion sickness.5Polymeropoulos V.M. Czeisler M.É. Gibson M.M. et al.Tradipitant in the treatment of motion sickness: a randomized, double-blind, placebo-controlled study.Front Neurol. 2020; 1: 563373Crossref Scopus (2) Google Scholar 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: NCT04849559). Tradipitant (85 mg bid), has been tested in a multicenter, double-blind, placebo-controlled trial of 152 adults with gastroparesis treated for 4 weeks.3Carlin J.L. Lieberman V.R. Dahal A. et al.Efficacy and safety of tradipitant in patients with diabetic and idiopathic gastroparesis in a randomized, placebo-controlled trial.Gastroenterology. 2021; 1: 76-87.e4Abstract Full Text Full Text PDF Scopus (8) Google Scholar Symptoms were assessed by means of the Gastroparesis Cardinal Symptom Index (GCSI) daily diary and other patient-reported questionnaires. There was a >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. 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 that relamorelin accelerated gastric emptying, in pharmacodynamic studies based on scintigraphic measurements in type 1 and type 2 diabetes, as well as stimulated postprandial antral motility in healthy participants. Relamorelin (30–100 μg subcutaneously), has been in development for treatment of gastroparesis in the past decade. As summarized elsewhere,6Chedid V. Camilleri M. Relamorelin for the treatment of gastrointestinal motility disorders.Expert Opin Investig Drugs. 2017; 2: 1189-1197Crossref Scopus (16) Google Scholar relamorelin shows promise in treating diabetic gastroparesis, with a reduction in core symptoms. It appears to be effective and well tolerated with low risk of neurologic or cardiovascular adverse effects. An analysis of phase 2a and 2b trial data7Camilleri M. Lembo A. McCallum R. et al.Overall safety of relamorelin in adults with diabetic gastroparesis: analysis of phase 2a and 2b trial data.Aliment Pharmacol Ther. 2020; 5: 1139-1148Crossref Scopus (6) Google Scholar has recently documented safety, other than increased HbA1c and fasting blood glucose that 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 (ClinicalTrials.gov: NCT03285308; NCT03426345). Felcisetrag is a highly selective and potent 5-HT4 receptor agonist with prokinetic activity throughout the gastrointestinal tract in experimental models.8Beattie D.T. Armstrong S.R. Vickery R.G. et al.The pharmacology of TD-8954, a potent and selective 5-HT4 receptor agonist with gastrointestinal prokinetic properties.Front Pharmacol. 2011; 2: 25Crossref PubMed Scopus (26) Google Scholar After intravenous 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.9Chapman M.J. Jones K.L. Almansa C. et al.Blinded, double-dummy, parallel-group, phase 2a randomized clinical trial to evaluate the efficacy and safety of a highly selective 5-hydroxytryptamine type 4 receptor agonist in critically ill patients with enteral feeding intolerance.J Parenter Enteral Nutr. 2021; 4: 115-124Crossref Scopus (7) Google Scholar Felcisetrag (0.1 mg, 0.3 mg, or 1.0 mg intravenously) 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, and the medication was well tolerated with no clinically significant adverse events on clinical laboratory, vital signs, or electrocardiography. 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. μ-Opioid-receptor (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 FDA 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 pharmacologic effects, including analgesic properties and studies of respiratory depression in preclinical models, have been described in detail.10Azevedo Neto J. Costanzini A. de Giorgio R. et al.Biased versus partial agonism in the search for safer opioid analgesics.Molecules. 2020; 2: 3870Crossref Scopus (19) Google Scholar The analgesic actions of PZM21 have also been documented in nonhuman primates,11Ding H. Kiguchi N. Perrey D.A. et al.Antinociceptive, reinforcing, and pruritic effects of the G-protein signalling–biased mu opioid receptor agonist PZM21 in nonhuman primates.Br J Anaesth. 2020; 1: 596-604Abstract Full Text Full Text PDF Scopus (10) Google Scholar and those of SR-17108 in mice.12Grim T.W. Schmid C.L. Stahl E.L. et al.A G-protein signaling–biased agonist at the μ-opioid receptor reverses morphine tolerance while preventing morphine withdrawal.Neuropsychopharmacol. 2020; 4: 416-425Crossref Scopus (29) Google Scholar An alternative smart approach to achieve analgesia with μ-OR activation and low risk of respiratory depression is provided by NFEPP, a fluorinated fentanyl molecule13Spahn V. del Vecchio G. Labuz D. et al.A nontoxic pain killer designed by modeling of pathological receptor conformations.Science. 2017; 3: 966-969Crossref Scopus (120) Google Scholar that is activated selectively in acidic environments, such as in sites of inflammation. In mice with 2.5% dextran sodium sulphate–induced colitis,14Jiménez-Vargas N.N. Yu Y. Jensen D.D. et al.Agonist that activates the μ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.Gut. 2021 Mar 30; ([E-pub ahead of print])Crossref PubMed Scopus (6) Google Scholar 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 G protein–coupled receptor (GPCR) pathway without activating β-arrestin, NFEPP (in addition to activation of the opioid GPCR signaling pathway) actually recruits β-arrestins and evokes μ-OR 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.15Gottesman-Katz L. Latorre R. Vanner S. et al.Targeting G protein–coupled receptors for the treatment of chronic pain in the digestive system.Gut. 2021; 70: 970-981Crossref PubMed Scopus (4) Google Scholar Studies in humans with these novel μ-OR 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 models14Jiménez-Vargas N.N. Yu Y. Jensen D.D. et al.Agonist that activates the μ-opioid receptor in acidified microenvironments inhibits colitis pain without side effects.Gut. 2021 Mar 30; ([E-pub ahead of print])Crossref PubMed Scopus (6) Google Scholar show that an average tissue pH acidification by 0.33 units is sufficient to activate NFEPP. Olorinab, a CBR2 receptor agonist, reduced pain as it reduced visceromotor response to colorectal distension in a rat model of 2,4,6-trinitrobenzene sulfonic acid–induced colitis and in a mouse model of chronic visceral hypersensitivity.16Castro J. Garcia-Caraballo S. Maddern J. et al.Olorinab (APD371), a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2, reduces colitis-induced acute and chronic visceral hypersensitivity in rodents.Pain. 2021 Apr 13; ([E-pub ahead of print])Crossref Scopus (1) Google Scholar 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.17Yacyshyn B. Ginsberg D.C. Gilder K. et al.Safety and efficacy of olorinab, a peripherally restricted, highly selective, cannabinoid receptor 2 agonist in a phase 2A study in chronic abdominal pain associated with Crohn’s disease.Gastroenterology. 2019; 156: S665Abstract Full Text PDF Google Scholar In a recent announcement,18Taylor N.P. Arena's pain drug fails phase 2b, prompting review of ‘strategic options.’.Fierce Biotech. Mar 3, 2021; (Available at:)https://www.fiercebiotech.com/biotech/arena-s-pain-drug-fails-phase-2b-prompting-review-strategic-optionsGoogle Scholar the company reported that in a phase 2b clinical trial (NCT04043455), olorinab administered orally 3 times daily at 3 separate doses to 273 patients with IBS missed its primary end point (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 with placebo. The future development of this medication for visceral pain is unclear. Approximately 15% of patients with IBS with constipation 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.19Vijayvargiya P. Busciglio I. Burton D. et al.Bile acid deficiency in a subgroup of patients with irritable bowel syndrome with constipation based on biomarkers in serum and fecal samples.Clin Gastroenterol Hepatol. 2018; 1: 522-527Abstract Full Text Full Text PDF Scopus (36) Google Scholar In these patients, lower levels of excretion of bile acids into feces correlated with slower colonic transit. As reviewed elsewhere,20Khanna L. Camilleri M. Elobixibat: a novel treatment for chronic constipation.Aliment Pharmacol Ther. 2021; 5: 234-242Google Scholar elobixibat accelerated colonic transit in several species, including humans, and 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 increased secretory bile acids in the colon as measured by stool bile acid content21Misawa N. Higurashi T. Takatsu T. et al.The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota.Aliment Pharmacol Ther. 2020; 5: 821-828Crossref Scopus (7) Google Scholar without significant alterations in the microbiome. Elobixibat (up to 10 mg/day) is approved in Japan for the treatment of chronic constipation. Multiple placebo-controlled RCTs 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.20Khanna L. Camilleri M. Elobixibat: a novel treatment for chronic constipation.Aliment Pharmacol Ther. 2021; 5: 234-242Google Scholar The drug is effective in the treatment of constipation, including severe constipation, and is safe and well tolerated. Farnesoid X receptor (FXR) agonists stimulate the synthesis and subsequent release of fibroblast growth factor 19 from ileal epithelial cells and inhibit bile acid synthesis by hepatocytes. This results in reduced intraluminal concentration of bile acids in the colon, relieving the diarrhea. It is estimated that up to a third of adults with symptoms consistent with functional diarrhea or IBS with diarrhea have increased fecal bile acid excretion or serologic markers of increased bile acid synthesis.1Vijayvargiya P. Camilleri M. Current practice in the diagnosis of bile acid diarrhea.Gastroenterology. 2019; 1: 1233-1238Abstract Full Text Full Text PDF Scopus (22) Google Scholar Although this class of medications is being developed predominantly for the treatment of nonalcoholic fatty liver disease22Shah R.A. Alkhouri N. Kowdley K.V. Emerging drugs for the treatment of nonalcoholic steatohepatitis: a focused review of farnesoid X receptor agonists.Expert Opin Emerg Drugs. 2020; 2: 251-260Crossref Scopus (4) Google Scholar,23Shah R.A. Kowdley K.V. Current and potential treatments for primary biliary cholangitis.Lancet Gastroenterol Hepatol. 2020; 5: 306-315Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar 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 2 FXR agonists, obeticholic acid24Walters J.R. Johnston I.M. Nolan J.D. et al.The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid.Aliment Pharmacol Ther. 2015; 4: 54-64Crossref Scopus (102) Google Scholar (6-ethyl chenodeoxycholic acid, approved for the treatment of primary biliary cholangitis) and tropifexor25Camilleri M. Nord S.L. Burton D. et al.Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.Aliment Pharmacol Ther. 2020; 5: 808-820Crossref Scopus (7) Google Scholar (a nonbile acid), which respectively improved stool index and slowed ascending colon emptying in patients with BAD. Several novel medications for functional and motility gastrointestinal disorders are promising, and with formal proof of efficacy and safety in patients, they should enhance care of patients.