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,

Saniona initiated a small explorative double-blind placebo controlled Phase 2a study for Tesomet in Prader-Willi syndrome in April 2017 comprising a total of up to 10 adult patients, 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. Some patients showed indication of weight loss and reduced craving for food, the key efficacy endpoints. Five of the nine patients discontinued the study. The patients were typical discontinued because the patients either did not fulfil the inclusion criteria for participating in the trial (e.g. due to introduction of other type of medications) or due to a potential worsening of existing behavioural problems.

It is not uncommon that there is a relative high dropout rate in Prader-Willi clinical studies. This may in particular be the case in trials comprising adult patients who have a higher incidence of behaviour problems. The participation in a clinical study also represents a disturbance to the daily routine, which by itself may increase such behaviour problems.  

It is currently not known whether the discontinued patients have received placebo or Tesomet. Therefore, it cannot be ruled out that some of the relative high number of discontinued patients in this trial are drug related despite that tesofensine monotherapy and Tesomet have proven to be well tolerated in large patients’ groups in a number previous clinical trials in the past.

Based on these overall observations, Saniona has decided to perform a full interim analysis of the results in adult patients before potentially continuing the study in adolescents. There has been collected blood samples during the trial for each individual patient. These blood samples need to be analysed and the results to be included in the database before Saniona can un-blind the study and analyse data on individual patient's drug exposure in relation to observed efficacy and safety signals. This interim analysis will consequently last about 2-3 months.

The future strategic decisions for Saniona in relation to continuing the development of a treatment option for patients with Prader-Willi syndrome, will not have any impact on the potential use of Tesomet in other indications.

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.

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