Tesomet for treatment of Prader-Willi syndrome, hypothalamic obesity, and metabolic diseases

Tesomet is a combination of tesofensine and metoprolol, which currently is being tested in late-stage clinical trials for treatment of Prader-Willi syndrome, hypothalamic obesity, and metabolic diseases. Tesomet is covered by several patent applications and certain issued patents which together may provide patent protection until 2036.

Prader-Willi syndrome

Prader-Willi syndrome is recognized as the most common genetic cause of life-threatening obesity. The disease results from a deletion or loss of function of a cluster of genes on chromosome 15, which 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 age 6 and currently there is no cure for this disease. Besides the physical and eating problems, Prader-Willi syndrome is characterized by maladaptive behaviour including temper tantrums, impulsivity, mood fluctuations, difficulty with changes in routine, skin picking, stubbornness, self-destruction and aggression. The behavioural problems are reported to worsen with age and is pronounced in adulthood. The patients also tend to have cognitive impairment, usually mild to moderate mental retardation.

The first part of Saniona’s Phase 2a in PWS was initiated in April 2017 and enrolled nine adult patients. The results from the first part of the study revealed that Tesomet may provide clinically meaningful weight loss and a significant reduction in hyperphagia. The study also revealed that patients with PWS should be given lower doses of Tesomet compared to other patient groups.

In the second part of the study, adolescent patients received either Tesomet or placebo at a 3:2 randomization. The primary endpoint of the study is to examine the change in bodyweight over 12-weeks of treatment with Tesomet compared to placebo. Secondary objectives include eating behavior and food craving (hyperphagia), body composition, lipids and other metabolic parameters. The study will also comprehensively assess tolerability, safety and pharmacokinetic parameters in this patient population.

The trial was completed in January 2019 and topline results from this placebo-controlled Phase 2a trial is expected in the first quarter of 2019. Based on support from the Primary Investigators, an open label extension study for an additional 24-weeks of treatment has been initiated to obtain longer-term treatment data relevant for future regulatory interactions.

Hypothalamic obesity

Hypothalamic obesity is, in analogy with Prader-Willi syndrome, a rare disease characterized by a constant craving for food with severe consequences for the patients. The hypothalamus is a small nucleus in the brain that controls important biological functions including body temperature, appetite/satiety/hunger and thereby body weight.

Hypothalamic obesity can occur from damage to the hypothalamus e.g. from the growth or surgical removal of rare brain tumors and from other types of injury to the hypothalamus including stroke, brain trauma or radiation for cancer patients. The surgical removal of a rare brain tumor, craniopharyngioma, 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 old, 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”. As in Prader-Willi syndrome, the condition reduces quality of life and there is no pharmacological treatment available today for appetite control in these patients.

Saniona has planned a clinical Phase 2a study with Tesomet in patients with hypothalamic obesity in collaboration with leading academic groups around the Danish national hospital (Rigshospitalet).

Metabolic diseases (obesity, Type 2 diabetes, NASH)

In 2016, Saniona performed a Phase 2a clinical trial for Tesomet in type 2 diabetes patients. Top line data from this clinical trial was presented in January 2017. The clinical trial achieved a positive outcome on the primary endpoint with a statistically significant reduction in heart rate for patients treated with Tesomet compared to placebo. Furthermore, the key secondary and exploratory endpoints regarding body weight and waist circumference also showed statistically significant reductions compared to placebo. Glycemic secondary endpoints were not statistically significantly different from placebo in this rather short 12-weeks study.

The more recent data together with data from previous clinical studies with tesofensine, supports the use of Tesomet as a safe and effective weight loss drug in patients with metabolic disorders like type 2 diabetes and obesity. Furthermore, the statistically significant reduction in weight loss and the numeric reduction in liver fat achieved in the Phase 2a type 2 diabetes study suggests that Tesomet may provide a clinically relevant reduction in glycemic parameters over a longer period and thereby represent an interesting potential new treatment principle for type 2 diabetes and NASH (non-alcoholic steatohepatitis).

Type 2 diabetes is considered as a progressive chronic disease today. However, recent published research concludes that large patient populations may undergo long-term remission if they achieve a substantial weight loss through reduced food consumption. According to Datamonitor, the market for type 2 diabetes is estimated to grow from US $ 23 billion in 2014 to 43 billion USD in 2023 of which weight-reducing therapy options will be the major value driver.