Regulatory Decision Summary for Viberzi

The efficacy of Viberzi in patients with irritable bowel syndrome with diarrhea (IBS-D) was primarily supported by two confirmatory Phase III pivotal clinical trials (studies 3001 and 3002) with durations of 6 and 12 months. The overall design of the studies was acceptable for the study objectives. The primary endpoint was the rate of composite responders over 26 weeks who had to meet a daily pain response criteria AND a daily stool consistency response criteria on ≥50% of the days. The rates of composite responders were statistically significantly larger with Viberzi as compared to placebo, with a difference of 10.3%, in the "week 1-12 analysis", and 11.5% in the "week 1-26 analysis". This is a moderate benefit given the benign nature of the condition and the symptomatic nature of the treatment.

The analysis of the individual components of the primary endpoint showed that the benefit of Viberzi on the "stool consistency" component was significant (difference in rates of ~13% vs. placebo), but less so for the "abdominal pain" component (difference in rates of ~4.5%, and around 7% if a more stringent pain criterion is applied. This benefit is considered to be modest hence the qualifying statement, "In clinical trials, VIBERZI improved abnormal stool consistency more prominently than abdominal pain" was added to the approved indication.

In patients 65 years of age and older, the efficacy of the 75 mg twice daily dosing appeared as large, and possibly larger than that of a dose of 100 mg twice daily. This finding and the apparent higher rates of adverse events (AEs) in this subpopulation prompted a dose-adjustment from 100 mg to 75 mg twice daily in elderly patients.

Serious AEs of pancreatitis and sphincter of Oddi spasm were reported in 0.8% (8/1032) of patients with Viberzi (none with placebo). However, these events occurred almost exclusively in patients with no gallbladder. Given the moderate treatment benefit of Viberzi, a contraindication was added for patients without a gallbladder.

In hepatic-impaired patients (mild-to-moderate), and in patients treated with organic anion-transporting polypeptide-P1B1 (OATP1B1) inhibitors, significant increases (4 to 6-fold) in systemic exposure to Viberzi were noted. Contraindications in patients with mild-to-moderate hepatic impairment, and in patients treated with potent OATP1B1 inhibitors were added. Furthermore, Viberzi is contraindicated in patients with biliary duct obstruction and sphincter of Oddi disease or dysfunction; without a gallbladder; with alcohol abuse or addiction; with a history of pancreatic conditions; with a history of chronic or severe constipation or sequelae from constipation, or known or suspected mechanical gastrointestinal obstruction.

Human and animal abuse potential studies showed that eluxadoline can produce psychological dependence. Viberzi tablets can be easily crushed, therefore, the potential for intravenous abuse of eluxadoline from crushed tablets in humans cannot be ruled out.

The nonclinical safety profile of Viberzi was established in a comprehensive investigational program that included in vitro and in vivo safety toxicity studies, genotoxicity, carcinogenicity, phototoxicity, antigenicity, and reproductive and developmental toxicity, and juvenile toxicity studies. Using the intravenous route, the margin of safety was smaller with toxicity findings in line with opioid agonist class effects (respiratory depression, lethargy, and other central nervous system effects). This reflects the low bioavailability of eluxadoline when taken orally. Orally-administered eluxadoline was excreted into the milk of lactating rats. Based on these nonclinical studies there are no major concerns that would predict unexpected AEs in patients treated with Viberzi at the recommended therapeutic dose.

Overall, Viberzi has a favorable benefit-harm-uncertainty profile in the treatment of IBS-D under the conditions of use described in the approved Product Monograph.