Poster Number-42 - Naloxegol Provides Clinically Meaningful Healthcare Related Quality of Life (HR-QOL) Improvement in Patients with Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol

Poster Abstracts

Author(s)

Charles McLeskey, MD

Vice President, Global Affairs
RedHill Biopharma Inc - Raleigh, NC
Raleigh, North Carolina
BC

Brooks Cash, MD, AGAF, FACG, FACP, FASGE

Chief of the Division of Gastroenterology, Hepatology, and Nutrition
University of Texas Health Science Center at Houston
Houston, Texas
Theresa Mallick-Searle, MS, PMGT-BC, ANP-BC

Nurse Practitioner–Pain Medicine
Sanford Pain Management
Redwood City, California
MJ

Mansi Jamindar, PharmD

Medical Director
RedHill Biopharma
Raleigh, North Carolina
CR

Carol Rockett, PharmD, RPh

Associate Vice President, Medical Affairs
RedHill Biopharma
Raleigh, North Carolina
EB

Enoch Bortey, PhD

Founder
Pharmaceutical Development Strategies LLC
Chapel Hill, North Carolina
DB

Darren Brenner, MD

Associate Professor of Associate Professor of Medicine (Gastroenterology and Hepatology) and Surgery
Northwestern Medicine
Chicago, Illinois

Naloxegol Provides Clinically Meaningful Healthcare Related Quality of Life (HR-QOL) Improvement in Patients with Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol

Purpose: The American Gastroenterological Association (AGA) reported that OIC affects 40-80% of patients taking chronic opioid therapy¹ which negatively impacts patients’ healthcare related quality of life (HR-QOL).² Naloxegol (Movantik®) is a peripherally acting mu-opioid receptor antagonist (PAMORA) which targets the GI tract to decrease the constipating effects of opioids. It was shown to be effective in treating OIC in adult subjects with non-cancer related pain in two pivotal Phase 3 Studies (KODIAC 4/5: NCT01309841/NCT01323790).³This study reports a pooled analysis of these two randomized, placebo-controlled trials which evaluates the efficacy of naloxegol in providing clinically meaningful HR-QOL improvements by utilizing the validated Patient Assessment of Constipation Quality of Life questionnaire (PAC-QOL).

Methods: Patient-reported scores from the PAC-QOL questionnaire were collected during KODIAC 4 and 5 as supportive efficacy measures of OIC HR-QOL improvement. Scoring ranged from 0 (absence of symptoms) to 4 (very severe) for each domain (Physical Discomfort, Psychosocial Discomfort, Worries/Concerns, and Satisfaction). Two Minimal Clinically Important Difference (MCID) thresholds were used to identify responders and non-responders. PAC-QOL MCID threshold of 0.5 is based on literature⁴ and naloxegol real-world studies in cancer patients with OIC.^5,6 MCID threshold of 0.8 is based on anchor method analysis of naloxegol phase 3 clinical trial data.

Results:

This pooled analysis included 1337 patients treated once daily with naloxegol (25mg, 12.5mg) or placebo (PBO). The overall baseline values for PAC-QOL Total, Physical Discomfort, Psychosocial Discomfort, Worries/Concerns, and Satisfaction scores were 2.0, 2.1, 1.3, 2.0, and 3.3, respectively.

For MCID >0.5, treatment with naloxegol 25mg and 12.5mg demonstrated a rapid, statically significant, and clinically meaningful improvement in HR-QOL vs. PBO (Proportion of PAC-QOL Responders 25mg: 63.9%; 12.5mg: 66.2; PBO:57.3%) at week 4. Odds ratios (ORs) at week 4 were 1.4 (p=0.038) for 25mg and 1.5 (p=0.013) for naloxegol 12.5mg vs. PBO. At week 12 there was a significantly higher proportion of PAC-QOL responders observed for naloxegol (25mg: 66.1%; 12.5mg: 68.5%) vs. PBO (59.0%). ORs at week 12 were 1.4 (p=0.047) for 25mg and 1.5 (p=0.017) for 12.5mg vs. PBO.

For MCID >0.8, treatment with naloxegol 25mg and 12.5mg demonstrated a rapid, statically significant, and clinically meaningful HR-QOL improvement vs. PBO (Proportion of PAC-QOL Responders 25mg: 50.4%; 12.5mg: 48.8; PBO: 39.7%) at week 4. Odds ratios (ORs) at week 4 were 1.7 (p=0.001) for 25mg and 1.4 (p=0.017) for naloxegol 12.5mg vs PBO. At 12 weeks, higher proportions of PAC-QOL responders were also observed for naloxegol (25mg: 52.7%; 12.5mg: 56.2%) vs. PBO (45.7%). ORs at 12 weeks were 1.4. (p=0.068) for 25mg and 1.5 (p=0.010) for 12.5mg vs. PBO.

ORs were generally consistent between MCID >0.8 and 0.5. At 4 weeks for both MCID thresholds, patients receiving naloxegol 25mg and 12.5mg were 40-70% more likely to achieve clinically meaningful symptom improvement than with PBO. At 12 weeks for both MCID thresholds, patients receiving naloxegol 12.5mg were 40-50% more likely to achieve clinically meaningful symptom improvement than with PBO.
A significantly greater proportion of patients receiving naloxegol 25mg and 12.5mg vs. PBO achieved clinically meaningful improvement in the PAC-QOL Satisfaction subdomain for both MCID thresholds at 12 weeks (p< 0.05 for both doses). Other subdomains also showed statistically significant and numerical improvements with naloxegol (25mg, 12.5mg) vs. PBO.

Conclusion: These data highlight the significant impact OIC has on patients' quality of life. In this pooled analysis of two phase 3 clinical trials, naloxegol 12.5mg and 25mg demonstrated rapid and clinically meaningful, constipation-related HR-QOL improvement in patients with OIC across MCID thresholds. Patient satisfaction appeared to drive these improvements, consistent with the known effects of PAMORAs. Such HR-QOL improvement may be an important clinical consideration in improving OIC management.

References: 1. AGA Institute Clinical Guidelines Committee. AGA Institute Guideline on the Medical Management of Opioid-Induced Constipation. Gastroenterology. 2019;156(1):218-226
2. Varrassi G et al. Impact and Consequences of Opioid-Induced Constipation: a Survey of Patients. Pain Med 2021 Dec;10(2):1139-1153
3. Chey WD, Webster L, Sostek M, Lappalainen J, Barker PN, Tack J. Naloxegol for opioid-induced constipation in patients with noncancer pain. N Engl J Med. 2014;370(25):2387-96.
4. Marquis P, De La Loge C, Dubois D, et al. Development and validation of the patient assessment of constipation quality of life questionnaire. Scand J Gastroenterol 2005;40:54
5. Lemaire A. et al. Effectiveness of naloxegol in patients with cancer pain suffering from opioid-induced constipation. Supportive care in Cancer. 2021 29:7577-7586
6. Cobo Dols M, et al. One-year efficacy and safety of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: KYONAL study. BMJ Supportive & Palliative Care 2021;0:1–9

Learning Objectives:

Describe the significant impact that opioid-induced constipation has on patients’ quality of life.
Understand naloxegol efficacy in providing rapid and clinically meaningful, constipation-related quality of life improvement in patients with opioid-induced constipation.
Provide holistic patient management including assessment and treatment of opioid-induced constipation.