Tesofensine

Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the phenyltropane family of drugs, which is being  developed for the treatment of obesity. The right to develop and market tesofensine is held by NeuroSearch, a Danish pharmaceutical company.

History
Tesofensine was originally investigated for the treatment of Alzheimer's disease and Parkinson's disease,  and was subsequently dropped from development for these applications  after early trial results showed limited efficacy for treatment of these  diseases. However, weight loss was consistently reported as an adverse event in the original studies,  especially in overweight  or obese  patients. Therefore, it was decided to pursue development of tesofensine for the treatment of obesity.

Tesofensine primarily acts as an appetite suppressant, but possibly also acts by increasing resting energy expenditure. Phase 2 trials for the treatment of obesity have been successfully completed.

Pharmacology
Tesofensine has a long half-life  of about 9 days (220 h)  and is mainly metabolized by cytochrome P4503A4 (CYP3A4) to the N-desmethyl-metabolite  NS2360. NS2360 is the only metabolite detectable in human plasma. It has a longer half-life than tesofensine, i.e. approximately 16 days (374 h) in humans, and has an  exposure of 31–34% of  the parent compound at steady state. In vivo data indicate that NS2360 is responsible for approximately 6% of the activity of tesofensine. As in animals, the kidney appears to play only a minor role in the clearance of tesofensine in humans (about 15–20%).

Clinical trials
Phase 2b trial (TIPO-1) results reported in The  Lancet showed levels of weight loss over a 6-month period that were significantly greater than those achieved with any currently available drugs. Patients lost an average of 12.8 kg on the 1 mg dose, 11.3 kg on the 0.5 mg dose and 6.7 kg on the 0.25 mg dose, compared with a 2.2 kg loss in the placebo group.

All participants were instructed to follow a diet with a 300 kcal deficit and to increase their physical activity gradually to 30–60 minutes of exercise per day. The placebo-subtracted mean weight losses were 4.5%, 9.2% and 10.6% in the 0.25 mg, 0.5 mg and 1 mg dose groups, respectively. This is approximately twice the weight loss produced by medications currently approved by the US Food and Drug Administration (FDA) for the treatment of obesity.

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.

Adverse events
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.