Regulatory Decision Summary for Movantik

The safety and efficacy of Movantik was studied in two 12-week, multicentre, double-blind, randomized, placebo-controlled, parallel-group studies in patients with OIC treated with opioids for at least 4 weeks for non-cancer pain [number of patients (n) = 1,337]. The mean age of patients was 52 years old, and 62% of them were women. The efficacy for Movantik was not demonstrated in the overall study population from these two studies, therefore, only the efficacy data from the subgroup of patients who were inadequate responders to laxative treatments (LIR) were considered. This was acceptable because this subgroup analysis in LIR patients was pre-specified in the study design, and accounted for in the statistical analysis plan. Patients in the LIR subgroup (n = 720) received a daily dose of Movantik 25 mg (n = 241), Movantik 12.5 mg (n = 240), or placebo (n = 239). The primary efficacy endpoint was the response over the 12-week treatment period, defined by ≥3 spontaneous bowel movements (SBM) per week and a change from baseline of ≥1 SBM per week. The results showed that in the pooled pivotal studies, the proportion of responders in the LIR subgroup was 47.7% with Movantik 25 mg, and 30.1% with the placebo, for a statistically significant difference of 17.6%. Using the same analysis based on the more stringent and relevant endpoint of complete spontaneous bowel movement (CSBM), the proportion of responders was 20.7% with Movantik 25 mg, and 9.6% with the placebo, for a difference of 11.1%. Given the relatively stringent nature of the primary efficacy endpoint which required a sustained response in 9 out of the 12 weeks (including 3 out of the last 4 weeks), the difference in rates of responders based on SBM (17.6%) or on CSBM (11.1%) was moderate but considered to be of clinical relevance as a second line therapy in LIR patients. Other secondary efficacy parameters were generally in support of the primary endpoint analyses.

The clinical safety data from the pooled overall study populations showed a higher rate of adverse events (AEs) with Movantik 25 mg (64%) as compared to placebo (52%), mainly driven by abdominal pain, diarrhea and nausea. An imbalance was reported regarding pain (abdominal, pain in extremity), and hyperhidrosis which were more frequently reported with Movantik as compared to placebo. These may indicate some degree of opioid withdrawal syndrome, which was uncommonly reported.

The data suggested a possible small imbalance in the rates of AEs related to blood pressure (BP) changes, such as increased BP (2.9% with Movantik 25 mg, 1.1% with placebo), decreased BP [1.3% versus (vs.) 0.7%], and syncope (0.4%, vs. 0%). These findings were not replicated in another 52-week safety study, except possibly for syncope, and therefore, these few cardiovascular findings are not considered to be a significant clinical issue. In the pivotal clinical trials however, cardiac patients were originally excluded, therefore, as a mitigating measure, a Warning was included in the Product Monograph to limit the use of Movantik in patients with pre-existing cardiovascular conditions. A thorough electrocardiogram study (including QT) revealed no issues at the therapeutic dose (25 mg), but a mild QT prolongation effect was predicted when strong cytochrome P450 (CYP) 3A4/P glycoprotein inhibitors are co-administered. An increase in Movantik plasma levels with concomitant use of strong CYP3A4 inhibitors was confirmed in drug-drug interaction studies; consequently, a corresponding contraindication was included in the Product Monograph. A statement to avoid the concomitant use of moderate inhibitors (unless absolutely necessary and with halving the daily dose to 12.5 mg) was included in the Warnings and Precautions section of the Product Monograph. Other warnings included patients with disruptions of the blood-brain barrier, and in those using methadone treatments as they may be at higher risk of opioid withdrawal and/or reversal of analgesia.

There was no significant difference in the safety profile of Movantik in the LIR population as compared to the overall studied population.

The overall benefit-to-risk profile of Movantik was found acceptable for the treatment of OIC in adult patients with non-cancer pain who have had an inadequate response to laxative(s).

For more information on Health Canadas decision, please view the Summary Basis of Decision.