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

Tesomet is a fixed-dose 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

In September 2019, Saniona reported positive Phase 2a clinical results in adolescent patients with PWS.

The study was designed as an exploratory randomized, double-blind, placebo-controlled Phase 2a trial. The primary endpoint of the study was to examine the change in bodyweight over 12 weeks of treatment with Tesomet compared to placebo. Secondary objectives included eating behavior and food craving (hyperphagia), body composition, lipids and other metabolic parameters. The study was divided into two parts.

The first part of this exploratory Phase 2a study in PWS had already demonstrated that Tesomet is highly efficacious in adult patients with PWS at a dose of 0.5 mg per day and suggested that patients would also benefit from a lower dose.

The second part nine-patient dose finding exploratory extension study in an adolescent population shows that Tesomet appear to be safe and well tolerated at lower doses (0.125 mg/day and 0.25 mg/day) and that it provides dose dependent effects on weight, BMI and hyperphagia consistent to what we observed in adult patients at the higher 0.5 mg/day dose. Saniona’s conclusion is that a broad spectrum of patients with PWS are likely to receive significant benefits on body weight, BMI and hyperphagia at a dose of 0.25 mg/day.

The completed Phase 2a study indicates a positive effect of Tesomet in this serious rare genetic disease and the data provide strong de-risking and guidance for the pivotal Ph2b/3 studies that we are now planning in PWS.

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 among other things leads to dysfunctional signaling 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 hyperphagia affects the quality of life for the patients as well as their families.

Published statistics from e.g. patient organizations indicate that there are about 20,000 known patients in the U.S. and Europe combined, equivalent to a prevalence of known and confirmed PWS patients of 1:40,000. There is no cure for this disease and there is no approved pharmacological treatment for the life-threatening hyperphagia and resulting obesity in these patients. The costs for payors are estimated to be 100–300 KUSD per patient per year in the U.S. (SVB Leerink) comprising assistance to families, residential homes in adulthood, medications as well as breathing devices and hospitalizations due to complications of hyperphagia and obesity.

There is a significant medical need for treatments that can reduce the hyperphagia and provide a weight loss in these patients. PWS is a significant commercial opportunity for Tesomet, with 20,000 patients in the U.S. and Europe combined and potential premium pricing as an orphan drug.

Hypothalamic obesity

Saniona is conducting a Phase 2a clinical study of Tesomet to treat hypothalamic obesity. The trial comprises a total of up to 25 patients and is conducted at Rigshospitalet in Copenhagen, Denmark. In this 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.

In November 2019, Saniona reported that the first patients have completed the double-blind part of the study and have now entered the open-label extension part. Saniona expects to report top line results from the double-blind part of the study in Q2 2020. It is believed that dose finding will be easier in hypothalamic obesity patients than in PWS patients. Therefore, if this trial is successful Saniona may be able to continue into pivotal Phase 2b/3 studies for hypothalamic obesity.

Like Prader-Willi syndrome, hypothalamic obesity is a rare disease characterized by a constant craving for food with severe consequences for the 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 tumor, 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 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 effective pharmacological treatment available today for appetite control in these patients.

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.