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.
Conclusions from the TIPO-1 study 
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.
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.
TIPO-1, Relative changes (%) in body weight:
Conclusions from the TIPO-4 study
NeuroSearch has also reported interim results from a 48-week, open-label, extension trial (TIPO-4) in which 140 patients who completed the 24-week phase 2b trial (TIPO-1) were re-enrolled after an average of 3 months’ wash-out. All were initially treated with 0.5 mg tesofensine once daily but up-titration to 1.0 mg once daily was allowed in the first 24 weeks of the extension study. At this time point, all subjects were continued on the 0.5 mg dose for an additional 24 weeks. The 24-week interim results for those who were previously treated with tesofensine 0.5 mg in TIPO-1 showed a total mean weight loss of between 13 kg and 14 kg over 48 weeks of treatment. Furthermore, TIPO-4 confirmed the TIPO-1 results since those patients who were previously treated with placebo lost approximately 9 kg in the first 24 weeks of the TIPO-4 study.
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.
Safety profile
In general, the safety profile of tesofensine is similar to currently approved medications for the treatment of obesity. The most commonly reported side effects in the obese population were dry mouth, headache, nausea, insomnia, diarrhoea and constipation. A dose-dependent pattern was observed for dry mouth and insomnia. The overall withdrawal rate due to adverse events in clinical trials in the obese population was 13% with tesofensine and 6% with placebo. Blood pressure and heart rate increases with the therapeutically relevant doses of tesofensine (0.25 mg and 0.5 mg) were 1–3 mmHg and up to 8 bpm, respectively.
Conclusion
The combined clinical safety data with tesofensine now counts approximately 1,300 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.
Phase III strategy and plans
At a meeting with the FDA in mid-2009, the data package on tesofensine was presented, and a Phase III development plan was endorsed by the authorities. In early 2010, NeuroSearch also obtained FDA approval of the protocol for the first Phase III study which included an existing anti-obesity drug, sibutramine, as an active comparator.
Subsequently, however, the efficacy and safety profile of sibutramine was questioned, and the product was withdrawn from the European market.
As a consequence, NeuroSearch in the spring decided to revise the development strategy and the Phase III plan for tesofensine. In relation hereto, NeuroSearch is awaiting the outcome of a scheduled FDA hearing regarding sibutramine and is also closely following the authorities' evaluation of other new anti-obesity drugs for which marketing authorisation has been applied. It is expected that a new Phase III plan for tesofensine can be ready for discussion with the authorities in the US and Europe within 2010.
Concurrently, NeuroSearch will continue the dialogue with potential collaboration partners with the aim of signing a licensing agreement before the initiation of Phase III.
NeuroSearch holds all the rights to tesofensine.
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