Movantik for Opioid-Related Esophageal Disorders

Background MOVANTIK™ (Naloxegol) can alleviate the adverse effects associated with frequent opiate use. The GI system is a common site for their unintended effects of opiate use, but literature suggests that peripherally acting opioid agonist may provide relief in the instance of GI dysfunction. (Holzer 2007) Toxicology and pharmacology summary

14 Phase I studies were completed with 439 health volunteers participating. MOVANTIK™ (Naloxegol) has been tested in a standard range of safety pharmacology studies including an absorption, distribution, metabolism and excretion study, a QTc (corrected QT interval) study, several PK (pharmacokinetic) studies, and a study to determine its central and peripheral pharmacodynamics effects. MOVANTIK™ (Naloxegol) is metabolized primarily by cytochrome P450 enzyme (CYP)-3A4 and CYP3A5 and is a substrate for a P-glycoprotein transporter. Drug-drug interaction studies were performed for a strong and a moderate CYP3A4 inhibitor, a CYP3A5 inhibitor and P-glycoprotein transporter inhibitor.

Clinical Safety summary MOVANTIK™ (Naloxegol) was initially tested in 439 healthy volunteers across 14 Phase I studies. Ascending-dosing studies were performed with first dose ranging from 8-1000 mg, followed by twice daily dosing ranging from 25-250 mg, all administered intravenously. Another ascending dose study was completed in older volunteers (age 65 and older) in Japan to determine the effects of advanced age on PK values. Phase IIb and II studies exposed 1497 patients to dosages ranging from 5 mg to 50 mg for periods of time varying from 24 to 52 weeks. MOVANTIK™ (Naloxegol) has shown acceptable safety profile and was well-tolerated at 5 mg and 25 mg. The 50 mg cohort had shown increased frequency of GI adverse events (abdominal pain, nausea and diarrhea) when compared to the 25 mg and 5 mg cohorts. The 25 mg dose was the maximum used across the 5 phase III studies. Two 12 week placebo-controlled double-blind studies were completed to confirm safety and efficacy, as well as a 12 week double-blind safety extension, a randomized 52-week open-label parallel group, long-term safety study and a placebo-controlled, double-blind study in patients with cancer-related pain. The efficacy studies demonstrated the therapeutic effect of MOVANTIK™ (Naloxegol) was independent of age, gender, race, body mass index, region, use of anticholinergics, response to previous laxative use, type of opioid, or dose of opioid. Phase III studies demonstrated that MOVANTIK™ (Naloxegol) is generally safe and well tolerated at doses up to 25 mg once daily in patients with OIC (opioid-induced constipation) up to 52 weeks of treatment.

Acute and chronic use of opioids is associated with a variety of adverse effects on the gastrointestinal tract. The effect of opioids on gastric, small bowel, and colonic motility has been well characterized. The main esophageal abnormalities seen were impaired LES (lower esophageal sphincter) relaxation. Recently a large retrospective study assessing the effect of opioids on esophageal motility using, for the first time, HREM and the Chicago classification of esophageal motility disorders v3.0 found that Esophageal motor dysfunction are common in chronic opioid users whether studied on opioids and off opioids. (K raichely 2010) However, opioid use within 24 h of manometry was associated with increased EGJ ( Esophagogastric junction) outflow obstruction and other spastic esophageal motor abnormalities. In addition, current opioid users also had significantly higher integrated relaxation pressure and manometric patterns consistent with type III achalasia.

Benefit/risk and ethical assessment Preliminary data suggests a relationship between opioid use and esophageal dysfunction. The decline in quality of life associated with esophageal disorders may discourage patients from taking opioids, subjecting them to unwarranted pain. MOVANTIK™ (Naloxegol) is an opioid antagonist specifically designed to work outside of the central nervous system. This allows relief from undesired peripheral effects of opioids without disrupting analgesic effects. The use of MOVANTIK™ (Naloxegol) has the potential to mediate esophageal dysfunction while preserving vital pain relief.