OPIOID-INDUCED CONSTIPATION (OIC)

Opioids, such as morphine, are highly effective in the treatment of moderate-to-severe pain, which could include pain associated with or as a result of back pain, arthritis, cancer and other pain conditions.

Mu-opioid receptors in the gastrointestinal (GI) tract regulate functions such as motility, secretion and absorption. Stimulation of these GI mu-opioid receptors by morphine, or other opioid analgesics, disrupts normal gut motility resulting in non-propulsive contractions of the bowel wall, ultimately delaying transit time of intestinal contents. This is the primary mechanism underlying OIC.

OIC can be distressing for patients, causing a significant burden of illness and reduced quality of life. Some patients receiving long-term opioid treatment for pain would rather endure their pain than the constipation that opioids may cause.

Cubist is developing CB-5945 to treat OIC. This compound is a small-molecule, potent, peripherally-acting mu-opioid receptor antagonist intended to block the adverse effects of opioid analgesics on the GI tract without affecting analgesia.

CB-5945 Overview

Clinical Status

During 2010, an initial clinical evaluation of CB-5945 was conducted. The single-dose and multiple-ascending-dose studies of CB-5945 enrolled both healthy volunteers and chronic non-cancer pain patients on long-term opioid therapy with OIC. At target therapeutic doses, the compound was well-tolerated and, in the patients with OIC, produced greater increases (over baseline) in weekly average number of spontaneous bowel movements (SBMs) as compared with placebo. The most commonly reported adverse events were dose-dependent and primarily GI related, including abdominal cramping and nausea, the majority of which were of mild severity. There were no serious adverse events reported.

In August 2011, two Phase 2 studies of CB-5945 in chronic non-cancer pain patients suffering from OIC were completed. Study 242 evaluated two doses of CB-5945 (0.10 mg and 0.25 mg) given twice daily versus placebo over a 4-week, double-blind treatment period, with approximately 130 patients enrolled (n = 43/treatment group). Study 243 also evaluated CB-5945 (0.25 mg) in patients suffering from OIC and had a similar study design to Study 242; however, once-daily dosing was evaluated with approximately 80 patients (n = 40/treatment group) enrolled. The primary endpoint of the studies was the change from baseline in the weekly average number of SBMs over the 4-week treatment period. Both Phase 2 trials of CB-5945 demonstrated statistically significant and clinically relevant efficacy in patients suffering from OIC and CB-5945 was well tolerated in both studies. There was no evidence of drug-related central opioid withdrawal or reversal of analgesia in any of the CB-5945 treatment groups across both studies.