Safety of Eluxadoline in Patients with Irritable Bowel Syndrome with Diarrhea

Abstract

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 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 five 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.

Figure 1

Incidence of (a) AEs and (b) SAEs by time interval: pooled analysis for eluxadoline Phase 2 and 3 studies (safety set). For the Phase 2 study (IBS-2001) events were nominally reported up to the end of treatment visit at week 12 only (and not through the last follow-up visit at week 14), while for the Phase 3 studies events were counted up to the last visit (up to the week 54 visit in IBS-3001 and the week 30 visit in IBS-3002). AE, adverse event; BID, twice daily; SAE, serious adverse event.

Figure 2

Incidence of constipation AEs by time:^a,b pooled analysis for eluxadoline Phase 2 and 3 studies (safety set). ^aEach 3-month interval was defined as a 13-week period, starting from the date of the first dose of study drug; ^bIncidence was defined as number of patients with at least one constipation event, and for the patient-level summary, multiple occurrences of constipation within a patient are counted once only. All occurrences of constipation were included in the total number of constipation events. Percentages were based on patients being in the study for ≥1 day within a period (overall, each quarter). Patients receiving >1 treatment are included in summaries of each treatment. AE, adverse event; BID, twice daily.