Summary Basis of Decision for Movantik

Clinical Pharmacology

Movantik (naloxegol oxalate) is a peripherally acting μ-opioid receptor antagonist. Naloxegol is a pegylated derivative of the μ-opioid receptor antagonist naloxone and antagonizes opioid binding at the peripheral μ-opioid receptors. As a pegylated derivative of naloxone, the ability of naloxegol to cross the blood brain barrier is limited. Naloxegol acts primarily on the gut μ-opioid receptors and counteracts opioid-induced constipation (OIC) with limited impact on the opioid-mediated analgesic effects on the central nervous system (CNS) at the intended therapeutic doses.

The primary route of naloxegol elimination is via hepatic metabolism, with renal excretion playing a minimal role. In clinical studies, six metabolites were found in feces, urine, or plasma, none of which have been identified as unique or disproportionate human metabolites. The major plasma circulating species is naloxegol.

In vitro data indicate that naloxegol is a substrate for cytochrome P450 (CYP) 3A4 and that CYP3A is the major CYP enzyme responsible for the metabolism of naloxegol. Naloxegol is also a substrate of the P-glycoprotein (P-gp) transporter, which likely plays a significant role in limiting CNS exposure to naloxegol and in its disposition.

Drug-drug interaction studies established that concomitant use of strong CYP3A4 inhibitors lead to a significant increase in naloxegol plasma levels, which prompted the inclusion of a corresponding contraindication in the Product Monograph. Concomitant use of moderate and to a lesser extent weak CYP3A4 inhibitors also resulted in a significant increase in naloxegol plasma levels. A statement was included in the Warnings and Precautions section of the Product Monograph to not use Movantik with moderate inhibitors unless absolutely necessary and with careful risk-benefit considerations along with halving the daily dose to 12.5 mg. The use of weak CYP3A4 inhibitors also resulted in some increase in plasma levels and thus required a reduction of daily dosing to 12.5 mg. Finally, the use of strong CYP3A4 inducers resulted in a significant decrease of naloxegol exposure. This was also labelled accordingly such that concomitant use is discouraged.

A randomized, double-blind, placebo-controlled, open-label positive-controlled, 4-way single dose crossover electrocardiogram study in healthy subjects [number (n) = 51] revealed no effects at the therapeutic dose (25 mg), but a mild (approximately 4 ms) QTc prolongation effect was predicted on the basis of pharmacokinetic/pharmacodynamic modelling when strong CYP3A4 and/or P-gp inhibitors are co-administered.

For more information, refer to the Movantik Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The efficacy of Movantik (naloxegol oxalate) in the treatment of opioid-induced constipation (OIC) was assessed in two replicate, Phase III, multicentre, randomized, double-blind, placebo-controlled studies (KODIAC 4 and KODIAC 5). The studies were 12 weeks in duration and enrolled patients with OIC and non-cancer related pain. Patients were eligible to participate if they were taking a minimum of 30 morphine equivalent units of opioids per day for at least 4 weeks before enrolment and had self-reported OIC. Opioid-induced constipation was confirmed through a 2-week run-in period and defined as <3 spontaneous bowel movements (SBMs) per week on average with at least one or more symptoms of straining, hard/lumpy stools, and or sensation of incomplete evacuation/anorectal obstruction in at least 25% of bowel movements. Patients with possible clinically important disruption of the blood-brain barrier were excluded. Patients who had a QTcF >500 ms at screening, a recent history of myocardial infarction within six months before randomization, symptomatic congestive heart failure, or who had any other overt cardiovascular disease were also excluded from the clinical studies. In addition, patients with moderate or severe hepatic insufficiency were excluded.

The response to Movantik was evaluated over 12 weeks in patients who had an inadequate response to laxatives in the 2 weeks prior to enrolment. The laxative response status was determined at the screening visit using an investigator administered questionnaire (Stool Symptom Screener) about previous laxative use and constipation symptoms over the past 2 weeks. Patients categorized as laxative inadequate responder (LIR) reported using a minimum of one class of laxative for at least 4 days in the 14 days preceding the first study visit. In addition, LIR patients had at least one of the following OIC symptoms, described as moderate, severe, or very severe in intensity: incomplete bowel movements, hard stools, straining, or sensation of needing to pass a bowel movement but unable to do so.

Throughout the study, patients were prohibited from using laxatives with the exception of bisacodyl rescue laxative which was permitted if they had not had a bowel movement for 72 hours. An SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours.

A total of 652 patients in KODIAC 4 and 700 patients in KODIAC 5 were randomized to receive 12.5 mg or 25 mg of Movantik or placebo once daily for 12 weeks. The mean age of the patients was 52 years, 62% were women, 79% were white, and 11% were 65 years of age or older. The mean daily opioid morphine equivalent dose was 138 mg/day and patients had been taking opioids for an average of 3.6 years for the current episode of pain. Back pain (57%) and arthritis (10%) were the most common reasons for pain. Laxative use within the 2 weeks prior to enrolment was reported by 71% of patients. Eighty-four percent (84%) of patients reported using laxatives within 6 months prior to enrolment. Patients were stratified based on their response to laxative use (LIR, Laxative Adequate Responders, and Laxative Unknown Responders) and were randomly assigned to one of the three treatment groups in a 1:1:1 ratio.

The primary efficacy endpoint was the response over the 12-week treatment period, defined by ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 treatment weeks including 3 out of the last 4 treatment weeks.

Issuance of a Notice of Non-Compliance and Response

The efficacy of Movantik was not supported in the overall study population by the efficacy data from the two pivotal studies submitted by the sponsor. The rate of response over 12 weeks was 42% in the Movantik-treatment arm versus (vs.) 29% in the placebo-treatment arm. This resulted in a statistically significant difference of 13% between groups based on data pooled from both studies; however, the magnitude of this difference was of unclear clinical relevance, especially given the nature of the efficacy endpoint that was chosen [that is (i.e.) SBM] and given the fact that the sponsor had pre-specified the studies to detect a significant difference of 25%. Furthermore, using the more appropriate, and internationally recommended clinical endpoint of complete spontaneous bowel movement (CSBM) for the definition of responders, the difference in responders' rates was even lower at only 6.2%. Such a treatment effect is considered to be of little clinical significance since 16 patients would have to be treated to expect one patient to benefit from Movantik i.e., number needed to treat (NNT) of 16.

Given the availability of other drugs in the peripherally acting μ-opioid receptor antagonist class for treating OIC, and given the minimal efficacy demonstrated by Movantik in the overall population, the risk-benefit profile of Movantik was not considered to be favourable based on the data submitted and a Notice of Non-Compliance (NON) was issued to the sponsor on August 20, 2014 citing a lack of clear, clinically relevant efficacy in the study population of the two pivotal studies.

In the response to the NON, the sponsor proposed to restrict the indication to the pre-specified sub-group of LIR patients based on the 14-day period prior to study treatment. The screening tool used to determine the status of response to laxative was not adequately validated for this purpose. However, in response to the NON, the sponsor showed that LIR and non-LIR patients were most likely different populations and the risk of misclassification of LIR as non-LIR was remote. In a clinical practice setting, LIR patients would likely be an important target population in whom Movantik will be prescribed (i.e., those who have failed common laxative treatments). Therefore, after careful consideration, it was concluded that restricting the indication to the LIR subgroup would be acceptable.

Overall Efficacy Analysis

The primary efficacy endpoint was the response over the 12-week treatment period, defined by ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 treatment weeks including 3 out of the last 4 treatment weeks. When taking into consideration only the LIR patients in the pooled pivotal studies (Movantik 25 mg, n = 241, and placebo, n = 239), the results for the primary efficacy endpoint using SBM showed that the proportion of responders was 48% with Movantik 25 mg, and 30% with the placebo, for a statistically significant difference of 18%. This difference in rates corresponds to a NNT of 5.7 patients.

Using pooled responder rates from KODIAC 4 and KODIAC 5 based on the more stringent CSBM, the proportion of responders was 21% with Movantik 25 mg, and 10% with the placebo, for a difference of 11%. Given the relatively stringent nature of the primary efficacy endpoint which required a sustained response for 9 out of the 12 weeks (including 3 out of the last 4 weeks), the difference in rates of responders based on SBM (18%) or on CSBM (11%) was moderate but was considered to be of clinical relevance as a second line therapy in LIR patients.

For more information, refer to the Movantik Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

There are two main known potential safety issues with opioid antagonists:

1. The possible inhibition of the centrally mediated effects of opioids drugs thus reversing the analgesic effect of opioids, and/or
2. Eliciting an opioid withdrawal syndrome (OWS) which can lead to serious safety outcomes.

The safety profile of Movantik was based primarily on data from the overall study population of the two 12-week pivotal placebo-controlled Phase III studies described in the Clinical Efficacy section. In these studies, a combined total of 441 patients received Movantik 12.5 mg and 446 patients received Movantik 25 mg.

The clinical safety data showed a higher rate of adverse events (AEs) with Movantik 25 mg (64%) as compared to Movantik 12.5 mg (52%) and placebo (51%). This was mainly driven by abdominal pain (reported in 16% of patients receiving Movantik 25 mg), diarrhea (reported in 9% of patients receiving Movantik 25 mg), and nausea (reported in 8% of patients receiving Movantik 25 mg). Back pain, pain in extremity, and hyperhidrosis were more frequently reported with Movantik 25 mg (4.3%, 2.2%, 2.9%, respectively) as compared to placebo (2.0%, 0.7%, 0.2%, respectively). This may indicate some degree of opioid withdrawal syndrome, however, opioid withdrawal syndrome as an adverse event (AE) was uncommonly reported (≤1%).

Serious adverse events (SAEs) were reported in 3.4% (n = 15) of patients administered Movantik 25 mg, 5.7% (n = 25) of patients receiving Movantik 12.5 mg, and 5.2% (n = 23) of patients administered placebo. The most frequently reported SAEs were infections (n = 12) followed by neurological (n = 6) and gastrointestinal (n = 6) events across treatment groups. Overall, no clear significant trend or safety signals emerged for SAEs, except possibly for few cases of changes in blood pressure. Two cases of severe hypertension (malignant or accelerated) were reported in the Movantik 25 mg treatment group. One case of hypertension and one case of hypotension were reported in the Movantik 12.5 mg treatment group. No cases were reported in the placebo treatment group. Due to the potential for gastrointestinal perforation, Movantik is contraindicated in patients with (or at increased risk of) gastrointestinal obstruction.

Treatment-related AEs (as judged by the investigator) were also reported more frequently with Movantik 25 mg (32.5%) as compared to Movantik 12.5 mg (20.6%) and placebo (16.2%). This difference was mainly due to more treatment-related events of the gastrointestinal tract in the Movantik 25 mg group. The proportion of patients who discontinued due to AEs in KODIAC 4 and KODIAC 5 was higher in the Movantik 25 mg group (10.3%) than in the Movantik 12.5 mg (4.8%) and placebo (5.4%) groups, driven predominantly by differences in the incidence of diarrhea and abdominal pain.

The pooled data from studies KODIAC 4, KODIAC 5, and KODIAC 7 (supportive extension study) suggested a possible small imbalance in the rates of AEs related to blood pressure changes, such as increased blood pressure (2.9% with Movantik 25 mg vs. 2.3% with Movantik 12.5 mg vs. 1.1% with placebo), decreased blood pressure (1.3% vs. 0.5% vs. 0.7%), and syncope (0.4% vs. 0.5% vs. 0%). These findings were not replicated in the 52-week study, except possibly for syncope, and therefore, these few cardiovascular findings are not considered to be a clinically significant issue at this time. Patients who had a QTcF >500 ms at screening, a recent history of myocardial infarction within six months before randomization, symptomatic congestive heart failure, or who had any other overt cardiovascular disease were excluded from the clinical pivotal studies. 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.

The sponsor did not report any significant differences in the safety profile of Movantik in the LIR population as compared to the overall study population.

As per the Canadian Risk Management Plan, the sponsor was requested to provide results of any incoming post-market safety data, especially, but not limited to, data from a planned cardiovascular safety study required by the United States Food and Drug Administration (FDA) as a post-market commitment.

Supportive Studies

One additional double-blind, placebo-controlled, randomized, 12-week safety extension study (KODIAC 7) included 291 patients who were rolled over from the KODIAC 4 study (97 treated with Movantik 25 mg, 94 with Movantik 12.5 mg, and 100 with placebo). Overall 188 patients were exposed to >24-weeks of treatment (63 patients with Movantik 25 mg, 56 with Movantik 12.5 mg, and 63 with placebo groups).

In addition, KODIAC 8 was a Phase III, 52-week, multicentre, open-label, randomized parallel group, safety and tolerability study of Movantik 25 mg taken daily versus usual care (flexible laxative treatment regimen determined by the investigator according to his/her best clinical judgement) in the treatment of OIC in patients with non-cancer-related pain. The overall population was comparable to that enrolled in the pivotal studies. A total of 804 patients were included in the safety set (534 treated with Movantik 25 mg), and 270 treated with ‘usual care' at the discretion of the investigator.

Frequencies and patterns of AEs in the 12-week blinded safety extension study (KODIAC 7) and in the 52-week long-term open-label safety study (KODIAC 8) were generally consistent with those in the pivotal studies, as were the patients' reasons for requiring opioid medication.

For the KODIAC 8 Study, the incidence and pattern of discontinuations due to AEs in the Movantik 25 mg group was comparable to those seen in the pivotal studies.

For more information, refer to the Movantik Product Monograph, approved by Health Canada and available through the Drug Product Database.