ORIGINAL CONTRIBUTIONS 1 see related editorial on page x Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea Brooks D. Cash , MD 1 , Brian E. Lacy , MD, PhD 2 , Philip S. Schoenfeld , MD 3 , Leonard S. Dove , PhD 4 and Paul S. Covington , MD 4 OBJECTIVES: Eluxadoline is a mixed μ -opioid receptor (OR) and κ -OR agonist and δ -OR antagonist, approved for the treatment of irritable bowel syndrome with diarrhea (IBS-D). This analysis evaluated the safety and tolerability of eluxadoline 75 and 100 mg twice daily (BID) in one Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) studies. METHODS: Adults with IBS-D (Rome III criteria) were randomized to placebo or eluxadoline (75 or 100 mg) BID for 12 (IBS-2001), 26 (IBS-3002), or 52 (IBS-3001) weeks. Safety data were pooled. Adverse events (AEs) were assessed, with special focus on opioid-related AEs, including suspected sphincter of Oddi spasm (SOS) events. RESULTS: 2,776 patients were included in the enrolled set; the safety set comprised 2,814 patients, based on FUNCTIONAL GI DISORDERS actual treatments received. The most frequent AEs in the placebo and eluxadoline 75 and 100 mg groups were constipation (2.5, 7.4, and 8.1%, respectively) and nausea (5.0, 8.1, and 7.1%, respectively); discontinuation due to constipation was uncommon (0.3, 1.1, and 1.5%, respectively). Ten SOS events (10/1,839; 0.5%) occurred in eluxadoline-treated patients, manifesting as acute abdominal pain with elevated aminotransferases or lipase, or pancreatitis; all occurred in patients without a gallbladder. Eight of these events occurred with the higher dose of eluxadoline, within 1 week of initiation of therapy, and all resolved with eluxadoline discontinuation. There were fi ve events independently adjudicated as pancreatitis not associated with SOS, three of which were associated with heavy alcohol use. CONCLUSIONS: Eluxadoline was well tolerated in Phase 2 and 3 trials, with constipation and nausea the most common AEs. Consistent with the known adverse effects of opioid agonists, clinically apparent SOS events were observed in eluxadoline-treated patients. All occurred in patients without a gallbladder and the majority were observed in patients on the higher dose of eluxadoline, suggesting a possible association. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg Am J Gastroenterol advance online publication, 6 December 2016; doi: 10.1038/ajg.2016.542 INTRODUCTION use of health-related resources and reduced work productivity Irritable bowel syndrome (IBS) is a chronic functional gastro- ( 7–10 ). intestinal (GI) disorder characterized by recurrent abdominal Dietary and lifestyle changes oft en comprise fi rst-line manage- pain or discomfort and altered bowel movements in the absence ment strategies for patients with IBS-D ( 1 ), although the durability of structural, infl ammatory, or biochemical abnormalities ( 1 ). of these interventions remains unproven. Approved pharmaco- IBS global prevalence ranges from ~5 to 15% ( 2–4 ) and approxi- logic therapies for IBS-D include alosetron, a serotonin antagonist mately one-third of all cases meet criteria for IBS with diarrhea used for the treatment of severe IBS-D in women who have not (IBS-D) ( 3,5 ). IBS-D is associated with impaired quality of life responded to conventional therapy ( 11 ), and rifaximin, a non- ( 6 ) as well as a marked socioeconomic impact through increased systemic antibiotic ( 12 ). Both alosetron ( 13,14 ) and rifaximin ( 15 ) 1 Department of Medicine, University of South Alabama , Mobile , Alabama , USA ; 2 Dartmouth-Hitchcock Medical Center , Lebanon , New Hampshire , USA ; 3 University of Michigan School of Medicine , Ann Arbor , Michigan , USA ; 4 Furiex Pharmaceuticals, Inc., an affi liate of Allergan plc , Parsippany, New Jersey , USA . Correspondence: Brooks D. Cash, MD, Department of Medicine, University of South Alabama, 6000 University Commons, 75 University Boulevard , Mobile , Alabama 36688 , USA . E-mail: [email protected] Received 22 June 2016 ; accepted 13 October 2016 Offi cial journal of the American College of Gastroenterology The American Journal of GASTROENTEROLOGY 2 Cash et al. have demonstrated improvement in global IBS symptoms and Phase 3 trials abdominal pain. IBS-3001 and IBS-3002 were randomized, double-blind, placebo- Loperamide, an over-the-counter μ -opioid receptor (OR) ago- controlled, parallel-group, multicenter studies conducted across nist, is an eff ective antidiarrheal agent commonly used to manage 556 centers in the US, Canada, and the UK ( 23 ). In both trials, the disturbed defecation of IBS-D, although evidence to support patients were randomized to receive eluxadoline (75 or 100 mg) its use is minimal ( 16 ). In addition, loperamide is well known to or placebo BID for 52 weeks in IBS-3001 and 26 weeks in IBS- precipitate constipation to the point that is has been used in animal 3002. Key inclusion criteria were: patients 18−80 years of age with and human models to reliably produce constipation ( 17,18 ), con- IBS-D (Rome III criteria ( 24 )), with an average worst abdominal sistent with the eff ects of unopposed agonism of the μ -OR ( 19 ). pain score of >3.0, an average BSFS score of ≥5.5, ≥5 days with a Eluxadoline is a peripherally active, mixed μ -OR and κ -OR ago- BSFS score of ≥5, and an average IBS-D global symptom score of nist and δ -OR antagonist ( 20 ) that was recently approved by the ≥2.0 (scale of 0 (no symptoms) to 4 (very severe symptoms)). Key US Food and Drug Administration for the treatment of IBS-D in exclusion criteria were: a history of infl ammatory bowel disease, adults. Enteric neurons in the GI tract express μ -, δ -, and κ -ORs, celiac disease, or alcoholism; abnormal thyroid function; pancre- which regulate GI motility and visceral sensation ( 21 ). Although atitis, sphincter of Oddi (SO) dysfunction, or post-cholecystec- there is potential for the mixed pharmacological profi le of elux- tomy biliary pain; and cholecystitis within the previous 6 months. adoline (local agonistic targeting of μ - and κ -ORs) to be associ- ated with the known class eff ects of μ -OR agonists, the likelihood Safety assessments of these eff ects may be reduced through simultaneous μ -/δ -OR Th e safety and tolerability of eluxadoline were evaluated in each of binding ( 20 ). these Phase 2 and Phase 3 studies, and safety assessments included Th e effi cacy of eluxadoline was initially evaluated in a dose- adverse event (AE) reporting, clinical laboratory results, 12-lead FUNCTIONAL GI DISORDERS ranging Phase 2 study (IBS-2001) that demonstrated that elux- electrocardiograms, vital signs, and physical examinations. Con- adoline 100 mg twice daily (BID) could simultaneously improve comitant medication use was collected throughout the study. abdominal pain and stool consistency over the full 12-week dura- Special focus was directed on AEs related to the opioid pharma- tion of the study ( 22 ). Subsequently, two large Phase 3 trials (IBS- cologic class, including constipation and SO spasm (SOS). In addi- 3001 and IBS-3002) demonstrated the effi cacy of eluxadoline in tion to traditional AE reporting, constipation was also evaluated patients with IBS-D ( 23 ). retrospectively based on patient electronic diary (interactive voice Herein we report the pooled safety and tolerability data from the response system) entries. Diary-confi rmed constipation as pro- Phase 2 and 3 clinical studies for the approved doses of eluxado- spectively defi ned in the protocol was confi rmed retrospectively line, 75 and 100 mg. using two of the electronic diary measurements: BSFS score and number of bowel movements. Constipation using the BSFS score was defi ned as an average score <2 over any study week. Constipa- METHODS tion using the number of bowel movements was defi ned as zero Th e Phase 2 (IBS-2001; ClinicalTrial.gov identifi er: NCT01130272) bowel movements for ≥4 consecutive days. and Phase 3 (IBS-3001 and IBS-3002; NCT01553591 and As the known class eff ects of μ -OR agonists on the SO can be NCT01553747, respectively) studies described herein were con- diffi cult to diagnose ( 25 ), a safety-focused adjudication committee ducted with the approval of each investigator’s institutional review comprising three independent experts (the Hepatobiliary and Pan- board or independent ethics committee, and the studies were con- creatitis Adjudication Committee) was established outside of the ducted in accordance with the principles of Good Clinical Prac- Phase 3 study protocol in order to evaluate suspected pancreatitis tice guidelines. All patients provided written informed consent. and SOS events. For all cases adjudicated, the committee reviewed a treatment-blinded dossier of primary medical records, labora- Phase 2 trial tory reports, radiology reports, and case narratives to determine IBS-2001 was a randomized, double-blind, parallel-group, pla- whether the events met pre-specifi ed case defi nitions for acute cebo-controlled study conducted at 263 primary and tertiary care pancreatitis of any etiology or an acute hepatobiliary event, and centers in the US, the design and results of which have been pre- whether SOS was the precipitating etiology based on a decision viously reported ( 22 ). Patients were randomized to receive elux- algorithm ( Supplementary Figure S1 ). adoline (5, 25, 100, or 200 mg) or placebo BID for 12 weeks. Key Th e committee used the Atlanta criteria for the diagnosis of eligibility criteria