Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity

Abstract

Context: Hypothalamic injury often leads to rapid, intractable weight gain causing hypothalamic obesity, which is associated with increased risk of cardiovascular and metabolic morbidity and mortality. There are no approved or effective pharmacological treatments for hypothalamic obesity, and conventional lifestyle management remains ineffective. Objective: Investigate the safety and efficacy of Tesomet (0.5mg tesofensine/50mg metoprolol) in adults with hypothalamic obesity. Methods: Twenty-one adults with hypothalamic obesity (16 females) were randomized to Tesomet (0.5mg/50mg) or placebo for 24 weeks. Patients also received diet/lifestyle counselling. The primary endpoint was safety; secondary endpoints included measures of body weight, appetite-scores, quality of life, and metabolic profile. Results: Eighteen patients completed 24-weeks. Consent withdrawal, eligibility, and serious adverse events (SAE) unrelated to treatment resulted in dropouts. One patient experienced a Tesomet-related SAE of exacerbated pre-existing anxiety leading to treatment discontinuation. Tesomet-related adverse events were otherwise mostly mild, and included sleep disturbances (Tesomet 50%, Placebo 13%), dry mouth (Tesomet 43%, Placebo 0%), and headache (Tesomet 36%, Placebo 0%). No significant differences in heart rate or blood pressure were observed between groups. Compared to placebo, Tesomet resulted in additional mean (95% CI) weight change of -6.3% ([-11.3; -1.3]; p=0.017), increased the number of patients achieving ≥5% weight loss (Tesomet 8/13, Placebo 1/8; p=0.046), and tended to augment the reduction in waist circumference by 5.7cm ([-0.1; 11.5]; p=0.054). Conclusion: Tesomet was well-tolerated, did not affect heart rate or blood pressure, and resulted in significant reductions in body weight compared to placebo in adults with hypothalamic obesity.

Acquired hypothalamic obesity: A clinical overview and update

“…In a recent randomized, doubleblind, placebo-controlled Phase 2 trial testing Tesomet versus placebo in 21 adults with HO, Tesomet produced significant reductions in body weight, waist circumference and glucose levels as compared to placebo. 117 Tesomet was overall safe and well tolerated; drug-related adverse events included mild sleep disturbances, dry mouth, and headache. There were no significant differences in heart rate or blood pressure between Tesomet and placebo.…”

“…The addition of the β‐blocker is intended to decrease potential adverse effects due to adrenergic stimulation. In a recent randomized, double‐blind, placebo‐controlled Phase 2 trial testing Tesomet versus placebo in 21 adults with HO, Tesomet produced significant reductions in body weight, waist circumference and glucose levels as compared to placebo 117 . Tesomet was overall safe and well tolerated; drug‐related adverse events included mild sleep disturbances, dry mouth, and headache.…”

“…There were no significant differences in heart rate or blood pressure between Tesomet and placebo. 117 A larger clinical trial has not yet been performed testing Tesomet in HO, but planning may be underway.…”

Current and upcoming methods of pharmacotherapy of obesity

“…Badania te nie zostały jednak opublikowane; obecnie na stronie producenta znajduje się informacja, że prace nad lekiem zostały wstrzymane z powodu braku funduszy 29 . W maju 2022 roku zostały natomiast opublikowane wyniki badań III fazy przeprowadzonych przez producenta w Danii; tesofensyna została tutaj połączona z metoprololem, dodanym w celu zniesienia skutków ubocznych terapii tesofensyną 30 . Zbadany został wpływ leku na leczenie otyłości podwzgórzowej, trwające 24 tygodnie badanie ukończyło 18 z 21 uczestników; dodatkowy spadek masy ciała względem placebo wyniósł 6,3%.…”

“…Autorzy zwracają uwagę, że jeden z uczestników wycofał się z badania ze względu na stany lękowe; badacze stwierdzili, że choć mógł je spowodować metoprolol, to bardziej prawdopodobny jest wpływ tesofensyny. Inne, istotnie częstsze względem placebo, skutki uboczne występujące wśród uczestników badania to suchość w ustach, bóle głowy i bezsenność 30 . Wydaje się, że lek, choć obiecujący, wymaga dalszych badań, zwłaszcza w zakresie owych działań ubocznych oraz dalszych badań u pacjentów z innymi niż podwzgórzowe, przyczynami otyłości, a także stworzenia większych grup badawczych.…”