Two Treatments Show Early Promise for Hypothalamic Obesity

Mitchel L. Zoler, PhD

May 11, 2021

Two different agents showed potential for safely treating patients with hypothalamic obesity in two pilot studies with small numbers of patients.

One study prospectively randomized 21 adults with acquired hypothalamic obesity to treatment with placebo or Tesomet, a compound that combines the novel monoamine reuptake inhibitor tesofensine with metoprolol, a beta-blocker added to protect against adverse effects from tesofensine on heart rate and cardiac contractility. After 24 weeks of treatment, people on tesofensine/metoprolol had significant weight loss, compared with controls, while showing good tolerance with no significant effects on heart rate, blood pressure, or heart rhythm, Ulla Feldt-Rasmussen, MD, DMSc, reported at the annual meeting of the Endocrine Society.

The second report reviewed 18 children and adolescents with either acquired or genetic hypothalamic obesity who received open-label treatment with dextroamphetamine for an average of 20 months, and overall patients safely lost an average of 0.43 in their body mass index (BMI) standard deviation score, reported Jiska van Schaik, MD, in a separate talk at the meeting.

'A Supplement for Lost Satiety'

Patients with hypothalamic obesity face a dual problem from hypothalamic dysfunction that's addressed by tesofensine, the weight-loss agent in Tesomet that increases hypothalamic levels of dopamine, serotonin, and noradrenaline by blocking reuptake, and thereby dulls appetite and food craving while also increasing fat metabolism, explained Feldt-Rasmussen, a professor of medical endocrinology at the University of Denmark and Rigshospitalet in Copenhagen. No treatment currently has regulatory approval for treating any form of hypothalamic obesity.

Tesofensine works as "a supplement for lost satiety, and satiety is what is lost" in patients with hypothalamic obesity as well in patients as Prader-Willi syndrome, the two disorders for which tesofensine/metoprolol is currently undergoing testing. "That's the rationale, and it seems to work," she declared during her talk. The formulation contains 0.5 mg tesofensine and 50 mg metoprolol administered orally once daily.

The study, run at Rigshospitalet, randomized 21 patients aged 18-75 years and with a BMI of at least 27 kg/m2who all had acquired hypothalamic obesity secondary to hypothalamic damage following cancer treatment. Patients averaged about 45 years of age, three-quarters were women, and their average BMI was about 37, with 90% having a BMI of at least 30.

The study's design calls for 48-week follow-up; Feldt-Rasmussen presented the interim results after 24 weeks, with 18 of the 21 enrolled patients remaining in the study through 24 weeks. Three patients dropped out because of adverse events: one in the placebo arm, and two who received tesofensine/metoprolol.

Weight dropped by an average of 6.6 kg from baseline among the 11 patients who completed 24 weeks on tesofensine/metoprolol treatment, compared with no average change from baseline among the seven patients who completed the study on placebo, a significant difference. The researchers measured a validated, composite satiety score every 4 weeks, and found significantly more improvement among patients on tesofensine/metoprolol than in those on placebo during the study's first half, but subsequently average scores among the actively treated patients fell to the same level of modest improvement as in the placebo patients.

Despite this, average weight loss in the patients on tesofensine/metoprolol steadily increased throughout the full 24 weeks.

Safety measures of diastolic blood pressure, heart rate, and corrected QT interval showed no significant between-group difference. Systolic pressure showed a transient average rise of 4 mm Hg above baseline in the tesofensine/metoprolol group, compared with a small dip in the control patients, but by 24 weeks average systolic blood pressure had reverted closer to baseline levels in both subgroups and showed no significant between-group difference. Two patients on tesofensine/metoprolol developed serious adverse events. In one patient these were not treatment related. The other patient developed anxiety after 8 weeks that was possibly treatment related but remained on treatment. Other adverse effects on tesofensine/metoprolol included dizziness, sleep disorder, and dry mouth, but all of these were mild and patients were willing to tolerate them to achieve their weight loss, Feldt-Rasmussen said.

Repurposing an ADHD Treatment

Dextroamphetamine increases satiety and boosts resting energy expenditure, and is a common treatment for attention deficit hyperactivity disorder. van Schaik and coauthors reviewed 13 children and adolescents with acquired hypothalamic obesity and 5 with genetic hypothalamic obesity who received the treatment at either of two Dutch hospitals during 2014-2020. All 18 patients went on dextroamphetamine after other interventions had failed to produce improvement, said van Schaik, a researcher at University Medical Center and Wilhelmina Children's Hospital in Utrecht, the Netherlands. The patients averaged about 13 years of age.

In addition to an overall effect on weight across all 18 subjects, the researchers found they could subdivide the full cohort into 10 responders (56%), 4 (22%) with weight stabilization on treatment, and 4 nonresponders (22%) who continued to gain weight despite treatment. The 10 responding patients had an average drop in their BMI standard deviation score of 0.91. All 10 responders had acquired hypothalamic obesity, and they averaged a 12.5 percentage point rise in their resting energy expenditure level, compared with baseline, while on treatment. The four whose weight stabilized on treatment included three patients with genetic hypothalamic obesity. The four nonresponders split into two with acquired hypothalamic obesity and two with the genetic form.

Thirteen patients (72%) had improvements in hyperphagia, energy, and behavior, and no patient had a serious adverse effect. One patient stopped treatment after 1 month because of elevated blood pressure.

"Dextroamphetamine may be promising, especially for acquired hypothalamic obesity," van Schaik concluded, adding that prospective, controlled assessments are needed, and that a healthy lifestyle is the foundation of hypothalamic obesity treatment.

The Tesomet study was sponsored by Saniona, the company developing Tesomet. Feldt-Rasmussen is an advisor to Saniona, and some of the coauthors on the study are Saniona employees. van Schaik had no disclosures.

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