Clinical Trials

Date: 2018-01-08

Type of information: Results

phase: 2a

Announcement: results

Company: Saniona (Denmark)

Product: Tesomet® (tesofensine)

Action mechanism:

• monoamine uptake inhibitor. Tesofensine, a monoamine uptake inhibitor, is focused on obesity. Pathological overeating and obesity can be caused by decreased dopamine function in the reward centre of the brain. Dopamine transporter proteins are inhibited by tesofensine, so the dopamine receptors are stimulated for a longer period after activation and the brain's reward system is amplified. With a similar mechanism of action tesofensine also increases levels of two other monoamines, serotonin and noradrenaline. Each of these transmitters exert an important function on appetite and metabolism at different locations in the brain. Dopamine acts in the nucleus accumbens of the forebrain to modulate reward and the "pleasure"-feeling of food. The two other transmitters act in the hypothalamus to increase metabolism and reduce appetite. The unique efficacy of tesofensine in obesity may be explained by reversal of blunted dopamine response in obese patients. In obese individuals, the brain centre (striatum) controlling consummatory food reward dopamine receptors are reduced relative to lean individuals. It has been found that in the relevant brain region more than 70% of obese individuals have a blunted dopamine response to food intake.
• Tesofensine has been evaluated in Phase 1 and Phase 2 human clinical studies with the aim of investigating treatment potential with regards to obesity, Alzheimer’s disease and Parkinson’s disease. Tesofensine demonstrated strong weight reducing effects in Phase 2 clinical studies in obese patients. In general, tesofensine was well tolerated in humans. However, blood pressure and heart rate increased at therapeutic doses of tesofensine. A recent patent application covering the combination of tesofensine and metoprolol has been filed. The patent claims are based on the demonstration in preclinical studies that the robust weight reduction seen with tesofensine is maintained when co-treatment with a beta-blocker was used to eliminate heart rate and blood pressure increase by tesofensine.

Disease: Prader-Willi syndrome

Therapeutic area: Rare diseases - Genetic diseases - Metabolic diseases

Country:

Trial details:

Latest news:

• • On January 8, 2018, Saniona announced  results from its exploratory Phase 2a clinical trial for Tesomet® in patients with Prader-Willi syndrome. 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. We did, however, observe a clinically meaningful weight loss as well as a remarkable reduction in hyperphagia over the course of the 3-month study. 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 exploratory, double-blind, randomized, placebo-controlled Phase 2a trial enrolled a total of nine adult patients with Prader-Willi syndrome, of which six patients received Tesomet® and three patients received placebo. A total of four patients completed the trial (two on treatment and two on placebo). A total of seven patients completed eight weeks of the study (five on treatment and two on placebo). Overall, the results must be interpreted with caution.
• Based on the data, the following observations can be made:
• The clinical trial achieved a positive outcome on the primary endpoint with a clinically meaningful reduction in weight for patients treated with Tesomet compared to placebo. After 8 weeks the mean change in body weight was 5.00 % (n=5) for patients receiving Tesomet compared to 0.46 % (n=2) for patients receiving placebo. After 13 weeks the change in body weight was 6.76% (n=2) for patients receiving Tesomet compared to 0.75 % (n=2) for patients receiving placebo. The average weight reduction was 4.78 kg (n=5) after 8 weeks and 7.95 kg (n=2) after 13 weeks for patients receiving Tesomet. There was significant variance in weight loss between patients.
• The average waist circumference was reduced by 7.2 cm (n=5) after 8 weeks and 10 cm (n=2) after 13 weeks for patients treated with Tesomet and by 4 cm (n=2) and 6.5 cm (n=2) for the two timepoints respectively in the placebo group.
• There was a remarkable reduction in the observed numbers for craving for food in patients treated with Tesomet. The total score measured by the validated hyperphagia questionnaire for clinical trials, fell from 10.00 (n=6) at baseline to 1.00 (n=5) after 8 weeks and to 0.00 (n=2) after 13 weeks where a score of 0 is equivalent to no signs of hyperphagia as measured by the hyperphagia questionnaire. After one week of treatment the total score fell from 10 at baseline to 5.67 (n=6), which is equivalent to a reduction of 43%. The observed hyperphagia score in the placebo group varied over time due to the low number of subjects. After 13 weeks the total score was 9.50 (n=2) compared to a baseline of 11.67 (n=3).
• The plasma concentration of tesofensine in patients treated with Tesomet was on average two to four times higher than anticipated when compared to the plasma concentration in other patient groups from previous clinical trials who were given the same dose. The observed plasma concentration may be explained in part by a lower metabolic rate and clearance of tesofensine in Prader-Willi patients and their high body fat percentage.
• The cardiovascular parameters such as heart rate and blood pressure did not vary significantly compared to placebo despite the high concentration of tesofensine in patients receiving Tesomet.
• There were no reports of serious adverse events in the trial. However, there were reports of adverse events in all patients participating in the trial, which is typical in clinical trials in this patient group. Of the reported adverse events, 67 % of the placebo group and 83 % of the treatment group were qualified as possible or probably treatment related. In the treatment group, the adverse events included an exacerbation of already occurring behavioral problems and CNS disorders, which were reversed after the completion of the study or in two cases where patients were offered a temporary reduction in dose during the study.
• Saniona will go on data analysis of this trial to  evaluate potential follow up studies using a lower dose of Tesomet® for this complex patient group. In parallel, Tesomet® studies in other indications continue as planned.
• • On October 26, 2017, Saniona announced that nine out of a planned ten adult patients with Prader-Willi syndrome have 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. Some patients discontinued the study due to adverse effects, which might be drug related. This interim analysis will last about 2-3 months and based on the results Saniona will decide on the next steps for Tesomet in Prader-Willi syndrome.
• The actual assignment of patients to respective treatment arms is currently unknown since the placebo controlled study is still blinded. The indications of a reduction in weight and craving for food are encouraging whereas the discontinuation of five patients due adverse effects, potentially drug related, may indicate that we have used a too high dose in this study.
• • On April 3, 2017, Saniona announced that it has initiated a Phase 2a clinical study in Czech Republic and Hungary for Tesomet® in patients with Prader-Willi syndrome (PWS). The first three patients have been randomized to either receive Tesomet® or placebo. It is an exploratory study in a limited number of patients and includes an interim safety review. The study is expected to take approximately a year from initiation.
• The objectives of this Phase 2a study are to examine the efficacy, tolerability, safety, and pharmacokinetics of Tesomet in patient with PWS. This exploratory randomized, double-blind, placebo-controlled study may ultimately include up to 30 patients where patients will either receive Tesomet (tesofensine 0.5 mg + metoprolol 50 mg daily) or matching placebo (3:2 randomization) for a total of 12 weeks. The study is divided into two parts. The first part of the study will include 10-15 adult patients with PWS. After having established safety in the adult patients, the second part of the study may potentially include 10-15 adolescents with PWS. Saniona expects to report the results from the trial about one year from initiation.
• The primary endpoint is change in body weight over 12 weeks of treatment compared to placebo. The secondary objectives are to examine eating behavior, food craving, body composition, lipids and other metabolic parameters. The study also includes comprehensive assessments of tolerability, safety and pharmacokinetic parameters in this patient population.

Is general: Yes