Mysimba is a sustained-release combination of naltrexone and bupropion. It is indicated as an adjunct to a reduced-calorie diet and increased physical activity for the management of weight in adults with an initial BMI of ≥30kg/m2 (obese), or ≥27kg/m2 to <30kg/m2 (overweight) in the presence of one or more weight-related co-morbidities, such as type II diabetes, dyslipidaemia, or controlled hypertension.
Combination treatment with sustained-release naltrexone and bupropion is thought to have complementary actions on CNS pathways regulating body weight.
Naltrexone is a μ-opioid antagonist and bupropion a weak inhibitor of neuronal dopamine and noradrenaline reuptake. Together these components affect two principal areas of the brain, the arcuate nucleus of the hypothalamus, and the mesolimbic reward system.
Bupropion stimulates pro-opiomelanocortin neurons in the arcuate nucleus, which influence appetite and energy balance. Naltrexone is thought to enhance this stimulation by blocking an opioid-mediated autoinhibitory feedback loop. The efficacy of naltrexone and bupropion in treating obesity may also derive from actions on dopaminergic reward pathways.
However, the exact neurochemical appetite suppressant effects of the combination are not fully understood.
Significant weight loss
The effect of sustained-release naltrexone/bupropion in conjunction with lifestyle modification on weight loss and weight maintenance was assessed in four double-blind, placebo-controlled phase III studies involving 4,536 obese and overweight individuals.
The CONTRAVE Obesity Research (COR)-I, COR-II and COR-BMOD studies included adults with a BMI of 30-45kg/m2 or a BMI of 27-45kg/m2 with dyslipidaemia and/or hypertension. Treatment was initiated with a three- or four-week dose escalation period and continued for up to 56 weeks.
In COR-I (n=1,742), patients were prescribed a mild hypocaloric diet and exercise and randomised to receive naltrexone 32mg/bupropion 360mg per day, naltrexone 16mg/bupropion 360mg per day, or placebo.
In the primary analysis population (n=1,453), weight loss in the naltrexone 32mg and 16mg groups at 56 weeks was significantly greater than in the placebo group (mean change in body weight -6.1% and -5.0%, respectively, vs -1.3%; p less than 0.0001 for both).
Weight loss of ≥5% was achieved by 48% and 39% of patients in the naltrexone 32mg and 16mg groups, respectively, compared with 16% of those in the placebo group (p less than 0.0001 for both). Weight loss in patients receiving naltrexone plus bupropion began in week 4 and was sustained for the 56 weeks of the study.
Similar findings were observed in the COR-II study (n=1,496). In the modified intent-to-treat (ITT) population, significantly greater weight loss was achieved in patients randomised to receive naltrexone 32mg/bupropion 360mg than in those receiving placebo, at both week 28 (co-primary endpoint; -6.5% vs -1.9%; p<0.001, n=1,281) and week 56 (-6.4% vs -1.2%; p<0.001, n=1,158). A significantly greater proportion of patients in the naltrexone group achieved ≥5% weight loss than in the placebo group at week 28 (co-primary endpoint; 55.6% vs 17.5%, p<0.001).
Patients in the COR-BMOD study (n=793) were randomised to receive naltrexone 32mg/bupropion 360mg as an adjunct to intensive behaviour modification (BMOD) or placebo plus BMOD. Patients in both groups were prescribed an energy-reduced diet and 28 group BMOD sessions.
As in COR-I and COR-II, patients receiving naltrexone/bupropion had lost significantly more weight at week 56 than those receiving placebo (ITT population [n=675], -9.3% vs -5.1%; p<0.001). In addition, a significantly greater proportion of patients in the naltrexone/bupropion group achieved ≥5% weight loss at week 56 (66.4% vs 42.5%, p<0.001).
Cardiometabolic risk factors
In all three studies naltrexone/bupropion was associated with improvements versus placebo in cardiometabolic risk markers (including waist circumference, triglycerides, HDL-C and LDL-C/HDL-C ratio), fasting insulin, patient-reported weight-related quality of life, and control of eating.
Patients with diabetes
The fourth study (n=505) assessed the effects of naltrexone/bupropion on body weight and glycaemic parameters in overweight and obese patients with type II diabetes, with or without background oral hypoglycaemics. In the ITT population (n=424), naltrexone 32mg/bupropion 360mg was associated with significantly greater weight loss (-5.0% vs -1.8%, p<0.001) and a greater proportion of patients achieving ≥5% weight loss (44.5% vs 18.9%, p<0.001) at week 56 compared with placebo.
Naltrexone/bupropion was also associated with improvements in glycaemic control, with an HbA1c reduction of -6.6mmol/mol (vs -1.1mmol/mol with placebo [-0.6% vs -0.1%], p<0.001) and 44.1% of patients achieving HbA1c <53mmol/mol (7.0%) (vs 26.3% with placebo, p<0.001). Modest improvements in cardiometabolic risk factors were also observed in the naltrexone/bupropion group.
Naltrexone/bupropion was generally well tolerated in clinical studies with the most frequently reported adverse effects including nausea, constipation, vomiting, dizziness and dry mouth. The combination was not associated with increased events of depression or suicidality versus placebo, although patients should nevertheless be monitored for these effects.