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Poster Session A - Sunday Afternoon

Category: Colon

A0090 - Naloxegol Provides Clinically Meaningful Symptom Improvement (PAC-SYM) in Patients With Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol

Sunday, October 23, 2022

5:00 PM – 7:00 PM ET

Location: Crown Ballroom

Has Audio

Presenting Author(s)

Darren M. Brenner, MD, FACG

Northwestern University Feinberg School of Medicine
Chicago, IL

Darren M. Brenner, MD, FACG¹, Carol Rockett, PharmD², Mansi Jamindar, PharmD³, Enoch Bortey, ⁴, June Almenoff, MD, PhD², Brooks D. Cash, MD, FACG⁵
¹Northwestern University Feinberg School of Medicine, Chicago, IL; ²RedHill Biopharma, Raleigh, NC; ³RedHill Biopharma Inc, Holly Springs, NC; ⁴Pharmaceutical Development Strategies LLC, Chapel Hill, NC; ⁵University of Texas Health Science Center, Houston, TX

Introduction: OIC affects 40-80% of patients taking chronic opioid therapy. Naloxegol (Movantik®), a peripherally acting mu-opioid receptor antagonist (PAMORA) is effective in treating OIC symptoms in adults with chronic non-cancer pain as shown in two pivotal phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This pooled analysis evaluated symptom improvement utilizing the Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM) in these two randomized, placebo-controlled trials.

Methods: PAC-SYM scores were collected during KODIAC 4/5 as supportive efficacy measures. Scores range from 0 (absence of symptoms) to 4 (very severe) for each domain (abdominal, rectal, and stool symptoms). Minimal clinically important difference (MCID) thresholds of 0.5 based on literature and naloxegol real world studies, and 0.8 based on anchor method assessment were used to identify responders and non-responders.

Results: 1337 patients (naloxegol (25mg, 12.5mg) or placebo (PBO)) were assessed in this analysis. The overall mean baseline values for PAC-SYM total, abdominal, rectal, and stool symptoms scores were 1.8, 1.7, 1.3, and 2.3, respectively, and were similar across groups.
For MCID ≥0.5, there was a significantly higher proportion of PAC-SYM responders with naloxegol (25 mg: 69.49%; 12.5 mg: 65.63%) vs PBO (57.66%) at week 12. Odds ratios (OR) were 1.776 (p=0.0010) for 25mg and 1.501 (p=0.0143) for 12.5mg vs PBO.
For MCID ≥0.8, higher proportions of PAC-SYM responders were also observed for naloxegol (25mg: 53.47%; 12.5mg: 45.74%) vs PBO (42.34%) at week 12. ORs were 1.709 (p=0.002) for 25mg and 1.217 (p=0.2368) for 12.5mg vs PBO
ORs were generally consistent between MCID >0.8 and 0.5 (Table 1). At 12 weeks for both MCID thresholds, patients receiving naloxegol 25mg were >70% more likely to achieve clinically meaningful symptom improvement than with PBO.
Subdomain analyses revealed dose-dependent responses; significantly greater responses in rectal and stool symptoms were achieved for 25mg vs. PBO (p< 0.05) at both MCID cut-offs (Figure 1a-d).

Discussion: OIC patients achieved clinically meaningful, constipation-related symptom improvement with naloxegol. These changes were dose dependent, with significant gains noted for 25mg at both MCID thresholds. Rectal and stool symptoms appear to drive these improvements consistent with the known effects of PAMORAs.

Figure: Figure 1a-d. Likelihood of Achieving PAC-SYM MCID at Week 12: Naloxegol vs. Placebo (KODIAC 4/5; ITT Population)

Placebo

(N=359)^a

n(%)

Naloxegol 12.5 mg

(N=352)^a

n(%)

Naloxegol 25 mg

(N=331)^a

n(%)

Naloxegol 12mg vs. Placebo

(95% CI)

p-value

Naloxegol 25 mg vs. Placebo

(95% CI)

p-value

Proportion of PAC-SYM Responders Achieving MCID ≥ 0.5

207 (57.66%)

231 (65.63%)

230 (69.49%)

1.501

(1.085, 2.078)

0.0143

1.776

(1.263, 2.497)

0.0010

Proportion of PAC-SYM Responders Achieving MCID ≥ 0.8

152 (42.34%)

161 (45.74%)

177 (53.47%)

1.217

(0.879, 1.687)

0.2368

1.709

(1.216, 2.401)

0.0020

^aNumber of analyzable subjects with complete PAC-SYM data for 12-wks

PAC-SYM, Patient Assessment of Constipation Symptoms questionnaire

MCID, minimal clinically important difference

OR, odds ratio

CI, confidence interval

Table: Table 1. PAC-SYM Total Score: Proportion of Responders Achieving MCID at Week 12 (KODIAC 4/5; ITT Population)

Disclosures:

Darren Brenner: Abbvie – Advisory Committee/Board Member, Consultant, Speakers Bureau. Alnylam – Advisory Committee/Board Member, Consultant. AlphaSigma – Advisory Committee/Board Member, Consultant. Ardelyx – Advisory Committee/Board Member, Consultant, Speakers Bureau. Arena – Advisory Committee/Board Member, Consultant. Bayer – Consultant. Gemelli – Advisory Committee/Board Member. International Foundation for GI Disorders (IFFGD) – Board of Directors. Ironwood – Advisory Committee/Board Member, Consultant, Speakers Bureau. Qol Medical – Advisory Committee/Board Member. Redhill – Advisory Committee/Board Member, Consultant, Speakers Bureau. Salix – Advisory Committee/Board Member, Consultant, Speakers Bureau. Takeda – Advisory Committee/Board Member, Consultant, Speakers Bureau. Vibrant – Advisory Committee/Board Member, Consultant.

Carol Rockett: RedHill Biopharma – Employee.

Mansi Jamindar: RedHill Biopharma – Employee.

Enoch Bortey: RedHill Biopharma – Consultant.

June Almenoff: RedHill Biopharma – Employee.

Brooks Cash: AbbVie – Consultant, Speakers Bureau. Ardelyx – Consultant, Speakers Bureau. RedHill – Consultant. Salix Pharmaceuticals – Advisory Committee/Board Member, Consultant, Speakers Bureau.

Darren M. Brenner, MD, FACG¹, Carol Rockett, PharmD², Mansi Jamindar, PharmD³, Enoch Bortey, ⁴, June Almenoff, MD, PhD², Brooks D. Cash, MD, FACG⁵. A0090 - Naloxegol Provides Clinically Meaningful Symptom Improvement (PAC-SYM) in Patients With Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol, ACG 2022 Annual Scientific Meeting Abstracts. Charlotte, NC: American College of Gastroenterology.