P2479 - An Open-Label Comparison Study of Eluxadoline in Participants with Irritable Bowel Syndrome with Diarrhea Who Have Evidence of Bile Acid Malabsorption

Tuesday, October 26, 2021

10:30 AM – 4:00 PM PT

Location: Shoreline Exhibit Hall

Has Audio

Presenting Author(s)

MC

Michael Camilleri, MD

Mayo Clinic
Rochester, MN, United States

Michael Camilleri, MD¹, Priya Vijayvargiya, MD¹, Margaret Breen-Lyles, BS¹, Sara Linker Nord, ¹, Daniel Maselli, MD¹, Irene Busciglio, BS¹, Ramesh Boinpally, PhD², Anna Muslin, MBA³, Timothy Carrothers, PhD³
¹Mayo Clinic, Rochester, MN; ²AbbVie Inc., Madison, NJ; ³AbbVie, Inc., Madison, NJ

Introduction: Eluxadoline, a peripherally acting, mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, is approved for the treatment of adults with irritable bowel syndrome-diarrhea (IBS-D). About a third of IBS-D patients has bile acid malabsorption (BAM); opioid agonists may stimulate TGR5 (bile acid) receptors and may conceivably aggravate diarrhea in the presence of stimulated colonic BA mechanisms mediated by TGR5. Our aim was to evaluate the efficacy on altered bowel functions and safety of eluxadoline in IBS-D patients with and without BAM.

Methods: In a single-center, phase IV, parallel-group, open-label study in participants with IBS-D (Rome IV criteria) with (cohort 1) or without (cohort 2) evidence of BAM, all participants were treated with eluxadoline, 100mg tablets BID, with food for 4 weeks. Participants recorded bowel functions by electronic daily diary. BAM was based on fasting serum 7αC4 ( > 52.5ng/mL) or concurrent criteria of total and primary fecal BAs excreted in 48 hours. We assessed the efficacy on treatment compared to baseline in the 2 cohorts. Primary outcome measures were change from baseline in average stool consistency score and safety. We also evaluated the pharmacokinetics (PK) of eluxadoline as determined from plasma concentration data extrapolated from dried blood sample analysis.

Results: The mean changes from baseline in cohorts 1 and 2 (data presented in this order) were similar for: Bristol Stool Form Scale score averaged over 4 weeks of treatment (-1.25 and -1.09); daily bowel movement frequency (-1.48 and -0.79); daily urgent bowel movements (-0.52 and -0.80); IBS-QoL (5.9 and 13.6); and serum 7αC4 (-5.59 and -8.78ng/mL). Overall, the derived PK parameters (Cmax, Cmin, AUCtau, and Tmax) showed relatively high interindividual variation (% CV > 80%), but they were comparable between subjects with and without evidence of BAM and with no variations attributed to weight, sex, and gender. There were no deaths, serious treatment-emergent adverse events or discontinuations due to adverse events during the study. The cohort with evidence of BAM had an overall slightly higher number of participants with gastrointestinal adverse events (n=9 vs. n=7) and dizziness or headaches (n=2 vs. n=0).

Discussion: Eluxadoline is efficacious for the treatment of IBS-D, with or without BAM, and appears to be safe and efficacious as documented in the large clinical trials of patients with IBS-D.

Data: median (IQR), or number (%)

Eluxadoline, 100 mg BID

Parameter	Cohort 1 with BAM	Cohort 2 without BAM
Number in each cohort	12	12
Demographics
Age, years	39.5 (37.0, 47.5)	37.5 (33.0, 46.0)
Gender (M=male, F=female)	5M, 7F	3M, 9F
Race (W=white, B=Black or African American	12W	11W, 1B
BMI, kg/m²	36.34 (31.81, 40.75)	28.85 (24.06, 31.16)
Number with history of anxiety/depression/panic disorder at baseline	5	6
Bowel Functions
BSFS baseline	5.96 (5.54, 6.11)	5.96 (5.54, 6.11)
BSFS average over Rx period	4.44 (3.83, 5.46)	4.30 (3.73, 4.73)
Change in BSFS on Rx minus baseline	-1.08 (-1.70, -0.57)	-1.09 (-1.86, -0.72)
Daily BM frequency at baseline	3.23 (1.93, 5.29)	2.81 (1.99, 3.25)
Change in daily BM frequency average on Rx minus baseline	-0.84 (-2.21, -0.41)	-0.80 (-0.99, -0.44)
Daily urgent BM frequency at baseline	1.43 (0.63, 2.65)	0.96 (0.85, 1.42)
Change in daily urgent BM frequency average on Rx minus baseline	-0.31 (-0.79, -0.18)	-0.69 (-0.99, -0.53)
Number with experience of fecal incontinence during baseline	3 (25%)	3 (25%)
Number with experience of fecal incontinence on Rx	4 (33%)	4 (33%)
Scores of Worst Daily Abdominal Pain and Bloating
Worst daily abdominal pain average score at baseline	1.17 (0.61, 2.54)	1.08 (0.82, 2.62)
Change in worst daily abdominal pain average score on Rx minus baseline	0.00 (-0.68, 0.46)	-1.22 (-1.65, -0.44)
Worst daily abdominal bloating average score at baseline	1.00 (0.46, 4.83)	3.30 (2.35, 6.12)
Change in worst daily bloating average score on Rx minus baseline	-0.40 (-1.57, 0.48)	-1.04 (-2.31, -0.35)
Quality of Life
IBS-QoL total score at baseline	78.3 (65.8, 87.1)	74.3 (61.0, 77.9)
Change in IBS-QoL score on Rx minus baseline	5.9 (2.6, 10.3)	13.6 (5.1, 17.6)
Serum 7αC4 (ng/mL)
Serum 7αC4 baseline	39.95 (23.25, 58.60)	30.30 (20.2, 36.50)
Serum 7αC4 at end of Rx	29.30 (16.50, 64.20)	20.05 (13.20, 26.40)
Change in serum 7αC4 at end of Rx minus baseline	-1.40 (-22.50, 12.70)	-8.20 (-18.10, -0.80)
Pharmacokinetics: plasma parameters expressed as mean (% coefficient of variation)
Cmax (ng/mL)	1.40 (96)	0.91 (88)
Tmax (hr) median (minimum, maximum)	1.50 (1.00, 2.50)	2.00 (1.00, 3.00)
AUCtau (hr*ng/mL)	9.22 (92)	7.75 (109)

Table: Effects of 4 weeks' treatment with eluxadoline on bowel functions, abdominal pain, bloating, and IBS-QoL. Note there are no numerical differences in changes from baseline for all bowel function parameters. Rx=treatment; BM=bowel movement; BSFS=Bristol Stool Form Scale score; IBS=irritable bowel syndrome; QoL=quality of life; BAM=bile acid malabsorption; IQR=interquartile range

Disclosures:
Michael Camilleri: Allergan – Grant/Research Support.
Priya Vijayvargiya indicated no relevant financial relationships.
Margaret Breen-Lyles indicated no relevant financial relationships.
Sara Linker Nord indicated no relevant financial relationships.
Daniel Maselli indicated no relevant financial relationships.
Irene Busciglio indicated no relevant financial relationships.
Ramesh Boinpally: AbbVie, Inc. – Employee.
Anna Muslin: AbbVie, Inc. – Employee.
Timothy Carrothers: AbbVie, Inc. – Employee.

Michael Camilleri, MD¹, Priya Vijayvargiya, MD¹, Margaret Breen-Lyles, BS¹, Sara Linker Nord, ¹, Daniel Maselli, MD¹, Irene Busciglio, BS¹, Ramesh Boinpally, PhD², Anna Muslin, MBA³, Timothy Carrothers, PhD³. P2479 - An Open-Label Comparison Study of Eluxadoline in Participants with Irritable Bowel Syndrome with Diarrhea Who Have Evidence of Bile Acid Malabsorption, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.