Poster Number-43 - Naloxegol Provides Clinically Meaningful Symptom Improvement in Patients with Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Global Phase 3 Studies of Naloxegol

The American Gastroenterological Association (AGA) reported that OIC affects 40-80% of patients taking chronic opioid therapy¹ and 58% of patients with OIC reported at least one severe or very severe constipation-related symptom.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 has demonstrated a rapid and predictable response and relief of OIC symptoms in patients treated with opioids for non-cancer pain in two phase 3 clinical trials (KODIAC 4/5: NCT01309841/NCT01323790).^3,4 This study reports a pooled analysis of these two randomized, placebo-controlled trials which evaluates the efficacy of naloxegol in providing clinically meaningful symptom improvement through utilizing the validated Patient Assessment of Constipation Symptoms questionnaire (PAC-SYM).

Methods: Data were pooled from the KODIAC 4 and 5 intent-to-treat population. 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). Two Minimal Clinically Important Difference (MCID) thresholds were used to identify responders and non-responders. PAC-SYM MCID threshold of 0.5 is based on literature^5,6 and naloxegol real-world studies in cancer patients with OIC.^7,8 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 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, treatment with naloxegol 25mg demonstrated a rapid, statically significant, and clinically meaningful improvement in symptoms vs. PBO (Proportion of PAC-SYM Responders 25mg: 65.6%; PBO: 57.3%) at week 4. Odds ratios (OR) at week 4 were 1.5 (p=0.006) for 25mg vs. PBO. At week 12, there was a significantly higher proportion of PAC-SYM responders with both naloxegol doses (25mg: 69.5%; 12.5mg: 65.6%) vs. PBO (57.7%). ORs at week 12 were 1.8 (p=0.001) for 25mg and 1.5 (p=0.014) for 12.5mg vs. PBO.

For MCID ≥0.8, higher proportions of PAC-SYM responders were also observed for both naloxegol doses (25mg: 53.5%; 12.5mg: 45.7%) vs. PBO (42.3%) at week 12. ORs at week 12 were 1.7 (p=0.002) for 25mg and 1.2 (p=0.237) for 12.5mg vs. PBO.

ORs were generally consistent between MCID >0.8 and 0.5. At 12 weeks for both MCID thresholds, patients receiving naloxegol 25mg were 70-80% more likely to achieve clinically meaningful symptom improvement in the PAC-SYM total score than with PBO.

Subdomain analyses revealed dose-dependent responses. At week 12, significant and clinically meaningful improvement in PAC-SYM rectal (ORs: MCID 0.5=1.7; MCID 0.8=1.9) and stool symptoms (ORs: MCID 0.5=2.0; MCID 0.8=2.0) subdomains were achieved for naloxegol 25mg vs. PBO (p< 0.05) at both MCID thresholds.

Conclusion: These data reinforce the high symptom burden at baseline experienced by patients with OIC. Naloxegol demonstrated clinically meaningful, constipation-related symptom improvement in patients with OIC. These improvements were dose dependent, with significant gains demonstrated for naloxegol 25mg at both MCID thresholds. Rectal and stool symptoms appear to drive these improvements, consistent with the known effects of PAMORAs. Such symptom improvement may be an important clinical consideration in improving OIC management and patient satisfaction.

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. Chey WD, Rockett CB, Bortey E, Almenoff J. Poster Presentation (Sa058): Rapid Onset of Time to First Spontaneous Bowel Movement (SBM) and Predictable Efficacy of Naloxegol: Pooled Analysis of Two Global Randomized Controlled Trials. Digestive Disease Week, May 21-23, 2021.
5. Frank L, Kleinman L, Farup C, et al. Psychometric validation of a constipation symptom assessment questionnaire. Scand J Gastroenterol 1999;34:870–7.
6. Yiannakou Y, Tack J, Piessevaux H et al. The PAC-SYM questionnaire for chronic constipation: defining the minimal important difference. Aliment Pharmacol Ther. 2017; 46(11–12):1103–1111.
7. 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
8. 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