Tesomet for treatment of Prader-Willi syndrome

Tesomet is a combination of tesofensine and metoprolol, which currently is being tested in a Phase 2a study for treatment of 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.

Administration of tesofensine has previously been investigated in a Phase 2 study in obese patients where it demonstrated a highly statistically and clinically meaningful weight loss. It is believed that this large magnitude of weight loss is driven by the triple mode of action including normalization of the appetite, reduction in the craving for food and an increase in metabolic rate. Due to the mode of action of Tesomet, Saniona believes that it potentially may be used for treatment of a number of metabolic syndromes including obesity, type 2 diabetes and fatty liver diseases including NASH and eating disorders including Prader-Willi syndrome and binge eating,

Tesofensine has been tested in more than 1,300 patients. It is very well tolerated, and a full and favourable safety package is available. Apart from an increase in heart rate at therapeutic dose, the adverse effect profile does not differ significantly from placebo when tesofensine is administered as monotherapy. The fixed dose combination, Tesomet, has been tested in a Phase 1 study in healthy volunteers and in a Phase 2 study in type 2 diabetes. These studies support that Tesomet is well tolerated and that metoprolol can eliminate the increase in heart rate caused by tesofensine while maintaining the weight loss properties of tesofensine.

Saniona initiated a small explorative double-blind placebo controlled Phase 2a study for Tesomet in Prader-Willi syndrome in April 2017, to be potentially followed by a study in 10-15 adolescents. In October 2017, Saniona announced that nine adult patients with Prader-Willi syndrome had completed or discontinued from the Phase 2 clinical study, and initiated a full interim analysis to decide on the next steps for Tesomet in Prader-Willi syndrome.

Top line results from the exploratory Phase 2a clinical trial for Tesomet in patients with Prader-Willi syndrome was presented in January 2018, and revealed a positive outcome on the primary endpoint with a clinically meaningful weight loss as well as a remarkable reduction in hyperphagia (i.e. craving for food) over the course of the 3-month study. However, the small number of patients in the study (n=9) and the failure of one placebo and four treated patients to complete the study preempts statistical evaluation. Surprisingly, plasma concentrations of tesofensine were found to be two to four times higher in this study compared to previous studies in obese and diabetic patients with the same tesofensine dose. This may explain the high dropout rate in the study and some of the observed side effects.

The results of this exploratory Phase 2a study supports further study of Tesomet in Prader-Willi syndrome. Saniona is now carefully analyzing the data and will confer with key experts in the field to evaluate potential follow up studies using a lower dose of Tesomet for this complex patient group.

Tesomet is covered by several patent applications and certain issued patents which together may provide patent protection until 2036.