Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Kyowa Kirin Holdings B.V., Bloemlaan 2, 2132NP, Hoofddorp, The Netherlands
Pharmacotherapeutic group: Drugs for constipation, peripheral opioid receptor antagonists
ATC code: A06AH03
Naloxegol is a PEGylated derivative of the mu-opioid receptor antagonist naloxone. PEGylation reduces naloxegol’s passive permeability and also renders the compound a substrate for the P-glycoprotein transporter. Due to poorer permeability and increased efflux of naloxegol across the blood-brain barrier, related to P-gp substrate properties, the CNS penetration of naloxegol is minimal.
In vitro studies demonstrate that naloxegol is a full neutral antagonist at the mu-opioid receptor. Naloxegol acts by binding to mu-opioid receptors in the GI tract targeting the underlying causes of OIC (i.e. reduced GI motility, hypertonicity and increased fluid absorption resulting from long-term opioid treatment).
Naloxegol functions as a peripherally-acting mu-opioid receptor antagonist in the gastrointestinal tract, thereby decreasing the constipating effects of opioids without impacting opioid-mediated analgesic effects on the central nervous system.
The efficacy and safety of naloxegol was established in two replicate double-blind, placebo-controlled studies in patients with OIC and non-cancer related pain (Kodiac 4 and Kodiac 5). Patients taking a minimum of 30 morphine equivalent units (meu) of opioids per day for at least 4 weeks before enrolment and self-reported OIC were eligible. OIC was confirmed through a two week run in period and defined as <3 spontaneous bowel movements (SBMs) per week on average with constipation symptoms associated with at least 25% of bowel movements. Patients were prohibited from using laxatives other than bisacodyl rescue laxative if they had not had a bowel movement for 72 hours. SBM was defined as a bowel movement without rescue laxative taken within the past 24 hours. Patients with mean Numeric Rating Scale (NRS) pain scores equal to or higher than 7 were not studied due to the risk of confounding the efficacy result as a result of uncontrolled pain. Patients who had a QTcF >500 msec at screening, had a recent history of myocardial infarction within 6 months before randomization, had symptomatic congestive heart failure, or had any other overt CV disease were excluded from the clinical studies. In a thorough QT/QTc study, as defined by the ICH E14 Guideline, there were no clinically important changes in HR, RR, QT, PR or QRS intervals or T wave morphology observed. In addition, no safety and tolerability concerns were identified in this study up to the highest dose given (150 mg). According to the ICH E14 Guideline, this is considered a definitively negative thorough QT/QTc study. Patients with moderate or severe hepatic insufficiency (Child’s-Pugh Class B or C) were excluded from the Phase III studies (Kodiac 4 and 5). Therefore, naloxegol has not been studied in OIC patients with moderate or severe hepatic impairment. Both studies were powered and stratified so that at least 50% of patients randomized to each treatment arm met baseline criteria to be categorized as a laxative inadequate responder (LIR).
To qualify as LIR, in the two weeks prior to first study visit patients had to have reported concurrent OIC symptoms of at least moderate severity while taking at least one laxative class for a minimum of four days during the pre study period.
Efficacy and durability of effect were measured in the primary end-point as response over the 12-week treatment period to naloxegol as defined by ≥3 SBMs per week and a change from baseline of ≥1 SBM per week for at least 9 out of the 12 study weeks and 3 out of the last 4 weeks. The first of three multiplicity protected secondary endpoints was the 12-week responder rate in the LIR subgroup.
There was a statistically significant difference for the 25 mg dose versus placebo for the LIR subgroup responder rate in Kodiac 4 (p=0.002) and Kodiac 5 (p=0.014). Under multiplicity testing procedure, statistical significance for the 12.5 mg treatment group versus placebo in the LIR subgroup was observed in Kodiac 4 (p=0.028) but not in Kodiac 5 (p=0.074). In Kodiac 4, response rates in the placebo, 12.5 mg and 25 mg groups in the LIR subgroup were 28.8%, 42.6% and 48.7%, while in Kodiac 5, the corresponding response rates were 31.4, 42.4% and 46.8%. In the pooled data from Kodiac 4 and Kodiac 5, responder rates in the LIR subgroup were 30.1% for placebo, 42.5% for the 12.5 mg dose, and 47.7% for the 25 mg dose, with the relative risk (95% CI) for treatment effect versus placebo of 1.410(1.106, 1.797) and 1.584(1.253, 2.001) for the 12.5 mg and 25 mg groups, respectively.
Response to naloxegol over 12 weeks was tested in the sub-group of patients with inadequate response to at least two laxative classes, approximately 20% of the patients randomized. In a pooled analysis of Kodiac 4 and Kodiac 5 (90, 88 and 99 patients in the placebo, 12.5 mg and 25 mg groups respectively), higher response rates in this population was observed for the 25 mg dose group compared with placebo (p=0.040). The responder rates in this population were placebo 30.0%, 12.5 mg 44.3% and 25 mg 44.4%.
The time to first SBM in the LIR subgroup after taking the first dose was shorter for the 25 mg dose as compared to placebo in Kodiac 4 (p<0.001) and Kodiac 5 (p=0.002). The 12.5 mg dose in the LIR subgroup also demonstrated shorter time to first post-dose SBM as compared to placebo in Kodiac 4 (p=0.002) and Kodiac 5 (p<0.001). In Kodiac 4, placebo, 12.5 mg and 25 mg dose had median time to first post dose SBM of 43.4, 20.6, and 5.4 hours, respectively. In Kodiac 5 the corresponding times to first post dose SBM were 38.2, 12.8, and 18.1 hours, respectively.
There was an increase in the mean number of days per week with at least one SBM in the LIR subgroup for the 25 mg dose in Kodiak 4 and Kodiac 5 (p<0.001 in both studies) and also for the 12.5 mg dose (p=0.006 in both studies).
The 25 mg dose in the LIR subgroup improved rectal straining (Kodiac 4 p=0.043, Kodiac 5 p<0.001). Stool consistency in the LIR subgroup as measured by the Bristol stool scale improved in Kodiac 5 versus placebo (p<0.001) but not in Kodiac 4 (p=0.156). The 25 mg dose in the LIR subgroup increased mean days per week compared with placebo with at least 1 complete spontaneous bowel movement (CSBM) in both studies (Kodiac 4 p=0.002, Kodiac 5 p<0.001).
A “symptom responder” was defined as meeting both the 12-week responder criteria and demonstrating improvement in pre-specified OIC symptoms and no deterioration in symptoms. In the LIR subgroup, the 25 mg dose increased the symptom responder rates in both studies as compared to placebo (Kodiac 4 p=0.001, Kodiac 5 p=0.005). The LIR subgroup symptom responder rates in Kodiac 4 for placebo, 12.5 mg and 25 mg arms were 24.6%, 36.5% and 45.3% and the symptom responder rates in Kodiac 5 were 25.6%, 33.6% and 42.7%.
Naloxegol 25 mg dose in the LIR subgroup resulted in a greater improvement (change from baseline) of patient assessment of constipation symptoms (PAC-SYM) total scores compared with placebo in both studies at 12 weeks (Kodiac 4 p=0.023, Kodiac 5 p=0.002). The 12.5 mg dose in the LIR subgroup also resulted in greater improvement in total PAC SYM at week 12 compared with placebo in both studies (p=0.020 and p=0.001 respectively). Naloxegol 25 mg dose, compared with placebo, also resulted in greater improvement (change from baseline) of week 12 PAC-SYM rectal domain scores in both studies (p=0.004 and p<0.001, Kodiac 4 and 5, respectively) and for the stool domain scores in Kodiac 4 (p=0.031) and Kodiac 5 (p<0.001). There was no relevant impact on abdominal symptoms in either study (p=0.256 and p=0.916, Kodiac 4 and 5, respectively).
There were no clinically relevant differences between naloxegol 12.5 mg, 25 mg, and placebo in average pain intensity, daily opioid dose or in opioid withdrawal scores over the 12-week study.
In the 12-week studies (Kodiac 4 and 5), the frequency of back pain AEs was 4.3% for naloxegol 25 mg versus 2.0% for placebo, and the frequency of extremity pain AEs was 2.2% for naloxegol 25 mg, versus 0.7% for placebo. In a long-term safety study (Kodiac 8), the frequency of AE reports of back pain was 8.9% for naloxegol 25 mg versus 8.8% for usual care. For extremity pain, the rate for naloxegol 25 mg was 3.5% versus 3.3% for usual care.
Kodiac 7 was a 12-week safety extension that allowed for patients from Kodiac 4 to continue the same blinded treatment from Kodiac 4 for an additional 12 weeks (placebo, naloxegol 12.5 mg or 25 mg daily). The primary objective was to compare safety and tolerability among the three treatment groups for an additional 12 weeks (beyond that observed in Kodiac 4) using descriptive statistics. In this study, naloxegol at doses of 12.5 mg and 25 mg was generally safe and well tolerated as compared with placebo in the treatment of OIC patients with non-cancer-related pain.
In all treatment groups, including placebo, improvements in PAC-SYM domains observed in Kodiac 4 were maintained for patients continuing in Kodiac 7.
Kodiac 8 was a Phase III, 52-week, multi-center, open-label, randomized, parallel group, safety and tolerability study of naloxegol versus usual care in the treatment of OIC in patients with non-cancer-related pain. The primary objective was to assess long-term safety and tolerability for naloxegol 25 mg and to compare with usual care treatment using descriptive statistics.
Eligible patients were randomized in a 2:1 ratio to receive either naloxegol 25 mg daily (qd) or usual care treatment for OIC for 52 weeks. Patients assigned to usual care followed a laxative treatment regimen for OIC determined by the investigator according to best clinical judgment, excluding peripheral mu-opioid receptor antagonists.
Of the 844 patients who were randomized, 61.1% completed the study (defined as completing the 2-week follow-up visit after the 52-week treatment period). Overall 393 and 317 patients had at least 6 and 12 months exposure to naloxegol 25 mg, respectively, in this study, which met the specified exposure requirements.
Long-term exposure to naloxegol 25 mg, up to 52 weeks, was generally safe and well tolerated in the treatment of OIC patients with non-cancer-related pain. During the 52-week treatment period there were no important unexpected differences in the safety and tolerability findings between the naloxegol 25 mg treatment group and the usual care treatment group.
The European Medicines Agency has deferred the obligation to submit the results of studies with Moventig in one or more subsets of the paediatric population in opioid induced constipation (see section 4.2 for information on paediatric use).
Following oral administration, naloxegol is absorbed rapidly, with peak concentrations (Cmax) achieved at less than 2 hours. In a majority of subjects, a secondary plasma concentration peak of naloxegol was observed approximately 0.4 to 3 hours after the first peak. Enterohepatic recirculation may be an explanation as extensive biliary excretion was seen in the rat.
A high-fat meal increased the extent and rate of naloxegol absorption. The Cmax and area under the plasma concentration-time curve (AUC) were increased by approximately 30% and 45%, respectively.
Naloxegol as a crushed tablet mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to the whole tablet, with a median tmax of 0.75 and 1.50 hours (range 0.23 to 5.02 hours) for the crushed tablet given orally and the crushed tablet given via NG tube, respectively.
The mean apparent volume of distribution during the terminal phase (Vz/F) in healthy volunteers ranged from 968 to 2,140 L across dosing groups and studies. Results from a QWBA (Quantitative Whole Body Autoradiography) study in the rat and the lack of antagonism of CNS opiate effects in humans at naloxegol doses less than 250 mg, indicate minimal distribution of naloxegol into the CNS. Plasma protein binding of naloxegol in humans was low and the fraction unbound ranged from 80% to 100%.
In a mass balance study in humans, a total of 6 metabolites were identified in plasma, urine and faeces. These metabolites represented more than 32% of the administered dose and were formed via N-dealkylation, O-demethylation, oxidation and partial loss of the PEG chain. None of the metabolites were present in > 10% of the plasma concentrations of parent or total parent and metabolite related material.
Following oral administration of radiolabelled naloxegol, 68% and 16% of total administered dose were recovered in the faeces and urine, respectively. Parent naloxegol excreted in the urine accounted for less than 6% of the total administered dose. Thus renal excretion is a minor clearance pathway for naloxegol. In clinical pharmacology studies, the half-life of naloxegol at therapeutic dose ranged from 6–11 hours.
Across the range of doses evaluated peak plasma concentration and AUC increased in a dose-proportional, or approximately dose proportional, manner.
There is a small effect of age on the pharmacokinetics of naloxegol (approximately 0.7% increase in AUC for every year increase in age). No dose adjustment is recommended for elderly patients. Patients over 65 years of age have been represented in the phase III studies. Clinical studies of naloxegol did not include sufficient numbers of patients aged 75 years or over to determine whether they respond differently than younger patients, however, based on the mode of action of the active substance there are no theoretical reasons for any requirement for dose adjustments in this age group. For dose recommendations for patients with moderate or severe renal insufficiency, see section 4.2. There is no gender effect on the PK of naloxegol.
The effect of race on the pharmacokinetics of naloxegol is small (approximately 20% decrease in the AUC of naloxegol when other groups are compared to Caucasian) and, therefore, no dose adjustment is necessary.
Naloxegol exposure was found to increase with increased weight, however, the differences in exposure were not considered clinically relevant.
As renal clearance is a minor route of elimination for naloxegol, regardless of severity (i.e. moderate, severe and end stage renal failure), the impact of renal impairment on the pharmacokinetics of naloxegol was minimal in most subjects. However, in 2 out of 8 patients (in both the moderate and severe renal impairment groups but not in the end stage renal failure group) up to 10-fold increases in the exposure of naloxegol were observed. In these patients renal impairment may adversely affect other clearance pathways (hepatic/gut drug metabolism, etc.) resulting in higher exposure. The starting dose for patients with moderate or severe renal insufficiency is 12.5 mg. If side effects impacting tolerability occur, naloxegol should be discontinued. The dose can be increased to 25 mg if 12.5 mg is well tolerated by the patient (see section 4.2). Exposure of naloxegol in end-stage renal disease (ESRD) patients on haemodialysis was similar to healthy volunteers with normal renal function.
Less than 20% decrease in AUC and 10% decrease in Cmax were observed in patients with mild and moderate hepatic impairment (Child-Pugh Class A and B). Effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of naloxegol was not evaluated. Use in patients with severe hepatic impairment is not recommended.
The pharmacokinetics of naloxegol in the paediatric population has not been studied.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and fertility.
Embryo-foetal development studies were conducted in rats and rabbits. A potentially treatment-related increased incidence of the skeletal variant bipartite vertebral centrum and a single foetus with anorchism was seen at the highest dose tested in the rat embryo-foetal development study. A possible treatment-related foetal skeletal malformation of fused arches was noted at highest dose tested in the rabbit embryo-foetal development study, in the absence of maternal toxicity. In a separate pre- and post-natal development study in rats, body weights were lower for male pups following maternal administration at the high dose. All these effects were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Carcinogenicity studies of naloxegol were conducted in rats and mice. In male rats, a dose-related increase in Leydig cell adenomas and interstitial cell hyperplasia was observed at exposures considered sufficiently in excess of the maximum human exposure. The observed neoplastic changes are well known hormonal and centrally mediated effects in the rat which are not relevant for humans.
Studies in suckling rats have shown that naloxegol is excreted in the milk.
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