PWS is a genetic disorder that begins in childhood. People with Prader-Willi syndrome always feel hungry, which can often lead to obesity and type 2 diabetes.
Tesomet is a fix-dosed combination of tesofensine and metoprolol. Tesofensine helps with weight loss in obese patients and also has the potential to reverse the progression of type 2 diabetes by reducing liver fat.
Tesofensine has been well tolerated in human clinical studies; however, an increase in heart rate has been reported.
The Phase 2a clinical trial (NCT03149445) enrolled nine adult patients with Prader-Willi syndrome, of which six patients received Tesomet and three received a placebo. A second part of the trial is expected to enroll 10-15 children with PWS.
Just four of the nine patients completed the trial (two on Tesomet treatment and two on placebo). Therefore, the results must be interpreted with caution, researchers highlighted.
Although the number of patients analyzed was small, researchers were able to observe a clinically meaningful weight loss over the course of the three-month study in patients treated with Tesomet compared to placebo.
The change in body weight was 6.76% in the Tesomet group compared to 0.75% in the placebo group; and the average waist circumference was reduced by 10 cm in patients treated with Tesomet compared to 6.5 cm in the placebo group.
A reduction in hyperphagia (abnormally increased appetite for food) was also observed at the end of the study. In fact, after one week of treatment, the total hyperphagia score fell from 10 at baseline to 5.67 in the group taking Tesomet, which is equivalent to a reduction of 43%. No hyperphagia was reported at the end of the study by the two final patients in the Tesomet group.
In interim results presented in January 2017, Tesomet was reported to lead to a significant reduction in heart rate, and to statistically significant reductions in body weight and waist circumference compared to placebo in patients with type 2 diabetes.
Now, researchers became more concerned with the side effects of the drug and the dropout rates observed.
The team found that plasma concentrations of tesofensine were two to four times higher in this study than researchers reported in other studies in obese and diabetic patients taking the same tesofensine dose.
This alone could explain the high dropout rate in the study and some of the observed side effects, the researchers suggested.
“The positive and convincing effectiveness data from this Phase 2a study is highly encouraging, as it indicates that Tesomet can provide a clinically meaningful reduction in weight and hyperphagia in patients with Prader-Willi syndrome,” Jørgen Drejer, CEO of Saniona, said in a press release.
“Side effects and dropout rates, however, were of concern. Now it turns out that plasma levels of tesofensine were dramatically and unexpectedly elevated in this population, which may explain the high incidence of side effects in the treatment group.
“We believe that by reducing the dose, it may be possible to reduce the plasma concentration to a level where tesofensine is better tolerated in this highly sensitive patient group, and at the same time remain efficacious, as demonstrated in other patient groups.” Drejer added.
In this 2018 analysis, however, heart rate and blood pressure did not vary significantly compared to placebo, despite the high concentration of tesofensine in patients receiving Tesomet.
“The results of this exploratory Phase 2a study supports further study of Tesomet in Prader-Willi syndrome, and we will discuss with key experts in the field how to pursue this opportunity,” Drejer concluded.