Tesofensine
Tesofensine is a drug candidate that acts on several sites and thereby increase the neurotransmission of three monoaminergic neurotransmitters, dopamine, noradrenaline and serotonin simultaneously(triple mode of action). Each of these transmitters exerts 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 “pleasure”-feeling of food. The two other transmitters act in the hypothalamus to increase metabolism and reduce appetite.
In September 2007, NeuroSearch concluded a Phase IIb Proof-of-Concept and dose finding study (“TIPO-1”) with tesofensine for the treatment of obesity with very positive results. Data from the study in 203 patients show that 24 weeks’ treatment with 0.25 mg, 0.5 mg and 1 mg tesofensine resulted in a dose-dependent average weight loss of 6.5%, 11.2% and 12.6%, respectively (against a weight loss of 2.0% in the placebo group). In all treatment groups, the primary endpoints were met with high statistical significance (p < 0.0001).
Secondary end-points, including relative change (reduction) in BMI (Body Mass Index (kg/m2)) as well as feeling of satiety and appetite were also met (p < 0.0001 for BMI). In the two highest dose groups (0.5 mg and 1.0 mg), treatment with tesofensine led to an average reduction in the patients’ BMI of 4.
Conclusions from the TIPO-1 study
The results of the TIPO-1 study show a clear dose-dependent weight reducing effect of tesofensine with a marked and clinically relevant effect already at the lowest dosing (0.25 mg).
The placebo adjusted weight loss of approx. 10% seen in both of the two highest dose groups (0.5 mg and 1.0 mg) is highly superior to the efficacy of any marketed drug for obesity management. The strong effect in both the low and the middle dose combined with a generally well-tolerated high dose leaves a highly promising therapeutic window for tesofensine.
The combined clinical safety data base from five individual studies with tesofensine now counts approximately 1,000 patients exposed to relevant therapeutic doses. This safety backing together with the breakthrough weight-loss results from the TIPO-1 study as well as weight-loss data from previous clinical studies support the preparation for a pivotal clinical Phase III programme with tesofensine within obesity with a clear guidance for final dosing regimes.
TIPO-1, Relative changes (%) in body weight:
Ongoing tesofensine-study (TIPO-4)
In July 2008, NeuroSearch reported positive key results of an nterim analysis after the first 24 weeks clinical Phase II extension study (TIPO-4) with tesofensine.
In TIPO-4, a total of 140 subjects having completed treatment in TIPO-1 with either tesofensine (0.25 mg, 0.5 mg or 1.0 mg) or placebo, have been enrolled after a wash-out period of two months to continue treatment with 0.5 mg tesofensine for an additional total of 48 weeks.
The interim analysis at 24 weeks of TIPO-4 shows the following key results:
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Patients previously treated in TIPO-1 with 0.5 mg tesofensine lost almost 4 kg in the subsequent treatment on 0.5 mg in TIPO-4. Taking into account the weight loss in TIPO-1 inclusive the weight gain during wash-out, the combined effect of TIPO-1 and TIPO-4 results in an average weight loss of 13 to 14 kg.
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Consistent with earlier clinical results, the 24 weeks safety data from TIPO-4 show that tesofensine is well-tolerated also over extended periods of administration. The most frequently reported adverse events are unchanged with dry mouth, insomnia and gastrointestinal disorders.
Further and more detailed analyses to integrate the efficacy and safety data of TIPO-1 and TIPO-4 are ongoing. In addition, the extension study continues as planned with expected reporting from the full 48 weeks extension treatment period by end 2008.
TIPO-2
TIPO-2 was a human metabolic study with tesofensine, designed as a randomised, double-blinded, placebo-controlled, parallel-group study, in which 32 overweight and obese subjects with a BMI (Body Mass Index (kg/m2)) of 28-35 were treated for 14 days with either tesofensine (with an accelerated daily dosing scheme of up to 1 mg exposure) or placebo. The aim of the study was to evaluate tesofensine’s effect on selected metabolic parameters by means of measurement of energy expenditure, fat oxidation and subjective appetite sensation (visual analogue scales (VAS) scores), DEXA scanning, and biochemical blood analyses.
The results showed that tesofensine significantly increases feelings of satiety and decreases the desire to eat while impacting favourably also on energy expenditure and fat metabolism in overweight and obese subjects. These synergistic effects are likely to help explain the outstanding efficacy of tesofensine in body weight management observed in both TIPO-2 (placebo-controlled mean weight loss of 1.8 kg after 14 days) and other clinical studies, including TIPO-1 (placebo-controlled mean weight loss of 9.2 kg after 24 weeks), and TIPO-4 (additional mean weight loss of approx. 4 kg after 24 weeks’ treatment extension to TIPO-1).
Main conclusions from the evaluation of tesofensine’s metabolic effects:
· Tesofensine reduces appetite sensations
In line with earlier clinical data from TIPO-1, the subjective appetite sensations measured after 14 days’ treatment in TIPO-2 showed that subjects in the tesofensine treated group had an increased feeling of satiety with less desire to eat than subjects in the placebo group (p<0.05).
· Tesofensine significantly increases fat oxidation and reduces fat tissue
In the tesofensine treated group, 24-hour fat oxidation was increased by 15% (p<0.05), while, reassuringly, 24-hour protein oxidation was lower compared with the placebo group (p<0.05). Also, results from DEXA scanning show a statistically significantly greater loss of fat tissue in the tesofensine treated subjects than under placebo (p<0.01).
· Tesofensine increases levels of adiponectin and improves insulin sensitivity
The significant loss of fat in the tesofensine-treated subjects was also reflected in a higher level of adiponectin in their blood. Adiponectin is a peptide hormone secreted exclusively by fat cells (adipocytes). Adiponectin decreases free fatty acids in the blood (plasma triglycerides) and increases glucose metabolism by improved insulin sensitivity, thereby also playing an important role in the treatment of type 2 diabetes.
· Tesofensine increases energy expenditure at rest
After 14 days, a significant increase of 6% in night time energy expenditure was observed in the tesofensine treated group compared with placebo (p<0.05). The observed increase could not be explained by differences in body weight or spontaneous physical activity, indicating a direct effect of tesofensine on energy expenditure at rest.
NeuroSearch holds all the rights to tesofensine.
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