Tesomet for treatment of Prader-Willi Syndrome and Hypothalamic Obesity

Tesomet is a fixed-dose combination of tesofensine and metoprolol, currently in mid/late stages of development for the treatment of  clinical trials for treatment of Prader-Willi Syndrome and Hypothalamic Obesity.

PRADER-WILLI SYNDROME

Prader-Willi Syndrome is recognized as the most common genetic cause of life-threatening obesity. There are approx. 20,000 estimated patients in the U.S. and Europe who suffer from Prader-Willi Syndrome. The disease results from a deletion or loss of function of a cluster of genes on chromosome 15, which among other things leads to dysfunctional signalling in the brain’s appetite/satiety center (hypothalamus). Patients suffer from a constant, extreme, ravenous insatiable appetite, which persists no matter how much the patients eat. As a result, many of those affected with Prader-Willi Syndrome become morbidly obese and suffer significant mortality. Compulsive eating and obsession with food usually begin before the age of six. The food craving (Hyperphagia) affects the quality of life for the patients as well as their families.

Saniona has completed a Phase 2a proof-of concept study in Prader-Willi Syndrome and is currently planning for pivotal Phase 2b/3 studies. The Phase 2a study was an exploratory, randomized, double-blind, placebo-controlled trial in 18 patients with Prader-Willi Syndrome, which was divided into two parts; the first was performed in nine adult patients with Prader-Willi Syndrome and the second in nine adolescent patients. The primary efficacy endpoint was to examine the change in body weight with Tesomet compared to placebo. Secondary efficacy endpoints included eating behaviour and hyperphagia, body composition, lipids and other metabolic parameters.

The first part was successfully concluded and with data first reported in 2018. The results showed that Tesomet at 0.5 mg/daily for three months provided clinically meaningful weight loss and a significant reduction in hyperphagia in adult patients. The study results also suggested that the optimal dose of Tesomet in patients with Prader-Willi Syndrome may be lower than in other indications such as normal non-syndromic obese patients.

The second part of the study consisted of a 3-month double blind phase with adolescent patients followed by two 3-month open label extension phases (a total of 9 months study). The patients initially received Tesomet at a quarter of the Tesomet dose given to adult Prader-Willi Syndrome patients (0.125 mg daily) and in the last extension phase of the study, the dose was doubled (0.25 mg daily). The results were reported in September 2019.

The study showed that Tesomet appears to be safe and well tolerated at the lower doses with dose dependent effects on weight, BMI and hyperphagia consistent with the observations in adult patients at the higher dose. The study indicates a positive effect of Tesomet in this serious rare genetic disease and the data provide guidance for our planned pivotal Phase 2b/3 studies.

HYPOTHALAMIC OBESITY

Hypothalamic Obesity is a rare disease characterized by a constant craving for food with severe consequences for patients. Hypothalamic Obesity can be the result of damage to the hypothalamus e.g. from the growth or surgical removal of a rare brain tumor, and from other types of injury to the hypothalamus including stroke, brain trauma or radiation for cancer patients. The hypothalamus is a small nucleus in the brain that controls important biological functions including body temperature, hunger and body weight. A rare brain tumour, craniopharyngioma, or the treatment, is the most common cause of Hypothalamic Obesity. Hypothalamic Obesity is therefore sometimes also referred to as craniopharyngioma associated obesity.

A craniopharyngioma is a benign tumor, which most commonly affects children between 5-10 years of age, though onset can sometimes occur during adulthood. Craniopharyngioma is also a rare disease with an estimated prevalence of 1:50,000 in the US. The treatment involves surgical removal of the tumor in almost all patients. The procedure can lead to complications, including damage to the hypothalamus resulting in loss of appetite control, insatiable hunger and morbid obesity. A high frequency of Hypothalamic Obesity, between 30% and 77%, has been reported following treatment. Due to the Prader-Willi Syndrome-like insatiable hunger, Hypothalamic Obesity is sometimes referred to as “acquired Prader-Willi Syndrome”.

The condition reduces quality of life and there is no effective pharmacological treatment available today for appetite control in these patients.

Saniona is conducting a Phase 2 clinical study of Tesomet in Hypothalamic Obesity. 21 patients are participating in the study, which is conducted at Rigshospitalet in Copenhagen, Denmark. In this randomized, double-blind, placebo-controlled study, patients receive either Tesomet (Tesofensine 0.5 mg + metoprolol 50 mg daily) or matching placebo (2:1 randomization) for 24 weeks followed by an open-label extension study where all patients will receive Tesomet for 24 weeks, resulting in a total treatment period of 48 weeks.

On April 22nd, 2020 Saniona reported positive top-line results from its 24-week double blind, randomized, placebo-controlled Phase 2 trial evaluating the safety and efficacy of Tesomet in patients with hypothalamic obesity (HO). The study results showed that Tesomet was safe and well tolerated. Furthermore, robust efficacy data was also reported, with statistically significant improvements in body weight, waist circumference, and glycemic control observed with Tesomet treatment compared to placebo.

Highlights from top-line study data include:

  • Tesomet was found to be safe and well tolerated. Side effects seen more frequently in treated patients include sleep problems, dry mouth, and headache, which are well known side effects associated with tesofensine and/or metoprolol. There was a single case of Tesomet related anxiety/paranoia reported as a Serious Adverse Event (SAE), which improved after discontinuation of treatment.
  • There were no clinically meaningful differences in heart rate or blood pressure between treatment groups.
  • 18 of the 21 study participants completed the placebo-controlled part of the study (2 dropouts in placebo group; 1 dropout in treatment group) and have entered the open-label extension for an additional 24-week period.
  • Treatment with Tesomet led to a statistically significant 6.1% average reduction in body weight compared to placebo (p < 0.0001).
  • Average waist circumference of Tesomet treated patients was significantly reduced by 4.8% compared to placebo (p < 0.0001).
  • Tesomet treatment improved glycemic control as measured by a statistically significant 14.6% reduction in hemoglobin A1c (HbA1c) compared to placebo (p = 0.0153).