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Background: Structural damage to the hypothalamus often results in hypothalamic obesity characterized by rapid and severe weight-gain with increased risk of cardiovascular and metabolic morbidity and mortality. Currently, there are no approved or effective pharmacological treatments and conventional weight management remains largely ineffective. Objective: This RCT investigated safety and efficacy of Tesomet (co-administration of 0.5mg tesofensine and 50mg metoprolol) in hypopituitary patients with acquired hypothalamic obesity. Methods: Twenty-one (16 females) hypopituitary adults with hypothalamic obesity were randomized to Tesomet or placebo (2:1) for 24 weeks (NCT03845075). Subjects also received diet and lifestyle counselling. Primary endpoint was safety evaluated by change in heart rate, blood pressure and adverse events. Secondary endpoints included changes in anthropometric measures, body composition, corrected QT-interval and arrythmias. Results: Subjects had a median (range) age of 50 (25; 70) years and 90% had a BMI ≥30 kg/m2. Almost half (48%) had a history of craniopharyngioma, 86% had undergone pituitary/hypothalamic surgery, and 52% had irradiation therapy. All received one or more anterior pituitary hormone replacements; 52% had diabetes insipidus. In total, 18/21 subjects completed the study, one without investigational treatment. Three serious adverse events (SAE) were recorded in 2 subjects randomized to Tesomet. Adverse events were otherwise mostly mild (58%), frequently reported were sleep disturbances (62%), dry mouth (46%) and dizziness (46%), known side effects of tesofensine or metoprolol. Four subjects, two in each group, discontinued treatment. Tesomet discontinuation was secondary to anxiety (n=1) or dry mouth (n=1). No significant differences in heart rate or blood pressure were observed between the two groups. At week 24, compared to placebo (weight-loss: -0.3%), Tesomet treatment resulted in additional mean weight-loss of -6.3% (95CI [-11.3%; -1.3%], p=0.017); increase in the proportion of patients achieving &amp;gt;5% reduction in body weight (Tesomet 8; Placebo 1, OR 11.2 [1.0; 120.4], p=0.046); and reduction in waist circumference of -5.7cm ([-11.5; 0.1], p=0.054). Tesomet-induced weight loss was primarily correlated to a reduction in mean (SD) fat mass -5.3kg (5.3) (r2=0.9, P=0001) and to lesser extent a reduction in lean tissue mass -2.9kg (1.9) (r2=0.4, P=0.03). Treatment did not affect corrected QT-interval; mean change from placebo was -1.1ms (95CI [-16.0; 13.9], p=0.882), nor were arrythmias registered during the trial period. Conclusions: Tesomet was generally well-tolerated, did not affect heart rate, blood pressure or QTc-interval, and resulted in significant reductions in body weight compared to placebo in this cohort of hypopituitary patients with acquired hypothalamic obesity. The study was sponsored by Saniona A/S

Weight Loss, Improved Body Composition and Fat Distribution by Tesomet in Acquired Hypothalamic Obesity