Viberzi (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year oral carcinogenicity studies have been conducted with eluxadoline in CD-1 mice at doses up to 1500 mg/kg/day (about 14 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) and in Sprague Dawley rats at oral doses up to 1500 mg/kg/day (about 36 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg). Oral administration of eluxadoline for 104 weeks did not produce tumors in mice and rats.

Mutagenesis

Eluxadoline was negative in the Ames test, chromosome aberration test in human lymphocytes, in the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test and in the in vivo rat bone marrow micronucleus test.

Impairment of Fertility

Eluxadoline at oral doses up to 1000 mg/kg/day (about 10 times the human AUC of 24 ng.h/mL after a single oral dose of 100 mg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

14 CLINICAL STUDIES

The efficacy and safety of VIBERZI in IBS-D patients was established in two randomized, multi-center, multi-national, double-blind, placebo-controlled trials (Studies 1 and 2). A total of 1281 patients in Study 1 and 1145 patients in Study 2 received treatment with VIBERZI 75 mg, VIBERZI 100 mg or placebo twice daily [overall, patients had a mean age of 45 years (range 18 to 80 years with 10% at least 65 years of age or older), 66% female, 86% white, 11% black, and 27% Hispanic].

All patients met Rome III criteria for IBS-D (loose [mushy] or watery stools ≥25% and hard or lumpy stools <25% of bowel movements) and were required to meet both of the following criteria:

  • an average of worst abdominal pain scores in the past 24 hours of >3.0 on a 0 to 10 scale over the week prior to randomization.
  • an average daily stool consistency score (Bristol Stool Scale or BSS) of ≥5.5 and at least 5 days with a BSS score ≥5 on a 1 to 7 scale over the week prior to randomization.

Pertinent exclusion criteria included: prior pancreatitis, alcohol abuse, cholecystitis prior 6 months, sphincter of Oddi dysfunction, inflammatory bowel disease, intestinal obstruction, gastrointestinal infection or diverticulitis within prior 3 months, lipase greater than 2 xULN, ALT or AST greater than 3 xULN.

Study 1 and Study 2 included identical 26-week double-blind, placebo-controlled treatment periods. Study 1 continued double-blinded for an additional 26 weeks for long-term safety (total of 52 weeks of treatment), followed by a 2-week follow-up. Study 2 included a 4-week single-blinded, placebo-withdrawal period upon completion of the 26-week treatment period. During the double-blind treatment phase and the single-blinded placebo withdrawal phase, patients were allowed to take loperamide rescue medication for the acute treatment of uncontrolled diarrhea, but were not allowed to take any other antidiarrheal, antispasmodic agent or rifaximin for their diarrhea. Additionally, patients were allowed to take aspirin-containing medications or nonsteroidal anti-inflammatory drugs, but no narcotic or opioid containing agents.

Efficacy of VIBERZI was assessed in both trials using an overall composite responder primary endpoint. The primary endpoint was defined by the simultaneous improvement in the daily worst abdominal pain score by ≥30% as compared to the baseline weekly average AND a reduction in the BSS to <5 on at least 50% of the days within a 12-week time interval. Improvement in daily worst abdominal pain in the absence of a concurrent bowel movement was also considered a response day. Results for endpoints were based on electronic daily diary entries by patients.

The proportion of composite responders over 12 weeks is shown in Table 4. In both trials, the proportion of patients who were composite responders to VIBERZI was statistically significantly higher than placebo for both doses. The proportion of patients who were composite responders to VIBERZI was similar for male and female patients in both trials.

Table 4: Efficacy Results in Randomized Clinical Trials
Study 1 Study 2
VIBERZI 100mg twice daily n=426 VIBERZI 75mg twice daily n=427 PBO n=427 VIBERZI 100mg twice daily n=382 VIBERZI 75mg twice daily n=381 PBO n=382
Composite 1 Response o ver 12 weeks
Responder rates 25% 24% 17% 30% 29% 16%
Treatment difference 8%2 7%4 13%3 13%3
95% CI (%) (2.6, 13.5) (1.4, 12.2) (7.5, 19.2) (6.8, 18.5)
Composite Response over 26 weeks
Responder rates 29% 23% 19% 33% 30% 20%
Treatment difference 10% 4% 13% 10%
95% CI (%) (4.7, 16.1) (-1.0, 9.9) (6.4, 18.8) (4.2, 16.4)
Abdominal Pain Response Improved ≥30% over 12 weeks
Responder rates 43% 42% 40% 51% 48% 45%
Treatment difference 4% 3% 6% 3%
95% CI (%) (-3.0, 10.2) (-3.8, 9.4) (-1.3, 12.8) (-4.3, 9.8)
BSS <5 Response over 12 weeks
Responder rates 34% 30% 22% 36% 37% 21%
Treatment difference 12% 8% 15% 16%
95% CI (%) (6.3, 18.2) (2.1, 13.8) (8.4, 21.0) (9.7, 22.4)

1 Composite= Simultaneous improvement of Worst Abdominal Pain (WAP) by ≥30% and Bristol Stool Score (BSS) < 5 on the same day for ≥ 50% of days over the interval

2 P <0.01

3 P <0.001

4 P <0.05

Additionally, the proportion of patients who were composite responders to VIBERZI at each 4-week interval was numerically higher than placebo for both doses as early as month 1 through month 6 demonstrating that efficacy is maintained throughout the course of treatment.

During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose.

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