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 the clearance of tesofensine is much slower in this patient group than in the general population, and that PWS patients consequently should be given a lower dose to obtain the same blood concentration and effect as seen on normal obese patients.

In January 2019, an open label extension study in the second part of its Phase 2a study of Tesomet was initiated comprising nine adolescent patients with PWS. The treatment with a dose of 0.125 mg/day appeared to be well tolerated but did not achieve sufficient plasma levels known to be efficacious in previous Phase 2 and Phase 3 studies. Saniona has now filed and received approval to increase the dose to 0.25 mg/day in the Czech Republic; approval in Hungary is pending. The first patients are expected to be switched to the 0.25 mg dose in March and the study is scheduled to continue until the end of June.

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 is a rare disease that can occur from the growth or surgical removal of rare benign 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 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 these patients.

A clinical Phase 2a study with Tesomet was initiated in March 2019 in patients with hypothalamic obesity. The trial comprises a total of up to 25 patients and is conducted at Rigshospitalet in Copenhagen. In the exploratory randomized, double-blind, placebo-controlled study, patients will 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. Saniona expects to report the results from the double-blind part of the study in Q4 2019 and the full study in H1 2020.

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.