ObesityWeek 2018:

Exploring Viable NonSurgical Treatment Options for Teens with Obesity

With Aaron S. Kelly, PhD, and Angela Fitch, MD

The increasing prevalence of obesity in adolescents, a multifactorial condition associated with concomitant comorbidities has heightened the urgency to identify effective developmentally appropriate therapeutic strategies.

In fact, the national obesity rate in children (ages 2 to 19 years) is currently 18.5%— more than triple the rate reflected in the 1980 National Health and Nutrition Examination Survey.1 Experts recommend pharmacological agents as adjunctive therapy, particularly to support long-term maintenance.2

Combination drug therapy appears safe at full dose for teens with obesity.

Evaluating Naltrexone/Bupropion for Weight Reduction in Teens

Giving the adult dose of the combination diet pill naltrexone/bupropion (Contrave, Nalprioprion Pharmaceuticals) to teenagers with obesity demonstrate safety from a pharmacokinetics perspective,3 according to research presented at ObesityWeek 2018 in Nashville, Tennessee. These findings will pave the way for further research to identify viable weight management options for adolescents.

"Overall, the data support progressing to a Phase 3 study in adolescents with the approved adult dose," says study author Aaron S. Kelly, PhD, associate professor of pediatrics at the University of Minnesota Medical School and co-director of the Center for Pediatric Obesity Medicine there.

The researchers selected 16 adolescents, stratified into two groups by age: (12-14 years) and (over 14-17 years) to receive one of two doses of the trial drug combination.3 The participants were randomized to receive either a low dose: 8 mg naltrexone/90 mg bupropion or a higher dose: 16 mg/180 mg. “These doses correspond to the half or full adult maintenance dose that would be taken at one time,” Dr. Kelly said.

The adolescents had a mean body mass index (BMI) of 32.0 (+-3.8 kg/m2) in which 75% of the participants were Caucasian, and the sexes were evenly split (50% female/50% male).3

After the teens received the single combination dose, the researchers collected multiple blood samples, starting 1/2 hour after the dose was taken, and continuing for 96 hours.3

"The single-dose pharmacokinetics of naltrexone/bupropion at the higher dose (16 mg/180 mg) —the approved full adult dose—responded similarly in adolescents as that of adults, supporting further clinical development of the adult dose [in teens]," Dr. Kelly told EndocrineWeb.

Favorable Review of Side Effects Profile Demonstrated

Exposure to the drugs or the active metabolites was lower than or similar to that observed in adult studies looking at the pharmacokinetics of these individual medications, he said. Only two participants reported adverse events (AE), with 10 events reported in all.3

One adolescent reported two of the 10 complaints, and the eight remaining adverse events were reported by the second teen. The reported adverse events, none of them serious, included: palpitations, eye irritation, diarrhea, nausea, pyrexia, muscle spasms, myalgia, throat tightness, and pruritis.3

"Because there were so few AEs and there was no difference in frequency between those that were related and unrelated, all AEs were listed," Dr. Kelly said. "However, eye irritation, pyrexia, and palpitations were considered unrelated to the study drug."

None of the adolescents reported any psychiatric incidents while taking this obesity treatment, Dr. Kelly said. This is important to point out because the drug combination ''has a boxed warning for suicide because it contains bupropion;4 however, in our study it was reassuring to see that no psych AEs were reported."

However, it was a single-dose study so that needs to be studied further in the phase 3 trial, Dr. Kelly said. That is in the planning stages, but the start date is not yet known.

Seeking to Expand Armamentarium Given Urgent Need

The researchers noted that in addition to concerns about obesity directly, comes a higher risk of weight-related conditions ranging from type 2 diabetes and hypertension to dyslipidemia, nonalcoholic fatty liver disease, and sleep apnea.5

In the phase 3 trials with adults,6-8 more than 53% of people lost 5% or more of their body weight, compared with about 21% of those on placebo. 

The combination of naltrexone and bupropion is thought to work on the hypothalamic hunger system, according to Dr. Kelly, specifically bupropion increases the firing rate of proopiomelanocortin neurons in vitro, suppressing appetite. Naltrexone blocks the B-endorphin negative feedback loop on POMC neurons, which enhances the appetite suppressing effect.

Contrave was approved by the FDA in 2014 for weight management in adults.4  It holds an indication as an adjunct therapy to a reduced calorie diet and increased physical activity for chronic weight management in adults with an initial BMI of 30 or 27 or higher with a weight-related comorbidity such as diabetes or dyslipidemia.4

Among the warnings are that all patients being treated with antidepressants for any indication should be monitored and observed, especially during the initial few months or after dose changes, for the possibility of suicidal thoughts. 

The researchers did not look at the effect of the bupropion on teen depression but in response to a question EndocrineWeb posed about the increasing occurrence of depression in teens, particularly among those with obesity, Dr. Kelly said. ”This drug combination could potentially help with that.”

"However, the weight loss efficacy of bupropion alone is very modest," he said. And as there is limited data in the pediatric population regarding treating obesity and depression he said, "it definitely would not be a recommendation yet but it might be a reasonable approach."

Expanding Therapeutics to Better Manage Obesity in Teens

"This work on kinetics validates that we can feel confident that the children we prescribe bupropion and naltrexone to for obesity are likely getting the same dose response as adults with a similar side effect profile," said Angela Fitch, MD, FACP, FOMA, associate director of the Massachusetts General Hospital Weight Center and assistant professor of medicine at Harvard Medical School. She reviewed the findings for EndocrineWeb and was not involved in the study.

At her facility, these medications are used off-label in treating adolescents for obesity, she said.  "As with any medication, we always need to weigh the risks and benefits, so this type of study validates that the risk is manageable and use in an adolescent may offer good benefit," Dr. Fitch told EndocrineWeb.

She too acknowledges the significant challenge faced by any clinicians who are treating children with obesity. "We need further studies in children with these and all anti-obesity medications so we can manage the disease of obesity more effectively and earlier," she said.

Raising the stakes, adolescents with obesity are at higher risk of asthma, sleep apnea, bone and joint problems, type 2 diabetes, cardiovascular disease, and stroke, and the list goes on. In addition, childhood obesity also comes the risks of social isolation, lower self-esteem, and depression.9

"Currently, bariatric surgery is really the only effective treatment modality for severe childhood obesity. Having efficacious, non-surgical options would be greatly beneficial, particular as the incidence of severe pediatric obesity is increasing and in increasingly younger children." More so because we know that obesity in childhood is predictive of adult obesity; Dr. Fitch said, "Treating of obesity more effectively and earlier is of utmost importance."

Financial disclosures: Dr. Kelly served as an unpaid consultant to Orexigen, the former maker of the drug. Other coauthors on the research are employees of Nalpropion Pharmaceuticals, formerly Orexigen Therapeutics. The study was funded by Nalpropion. Dr. Fitch has no conflicts to report.

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Sustained Weight Loss Viable with Diet/Drug Combination Therapy
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