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Tesofensine, NS2330 (Tesofensine)

Tesofensine is a serotonin–noradrenaline–dopamine reuptake inhibitor developed by NeuroSearch. Tesofensine was originally investigated for the treatment of Alzheimer's and Parkinson's disease, but early testing of the product for these diseases found it to be limited in effectiveness for them. What the researchers found instead was remarkable results in weight loss.

Studies indicate that obesity is associated with lower dopamine D2 receptor availability, which may be related to disturbed regulation of food intake. However, since tesofensine will block dopamine from binding to the D2 receptors it will help increase D2 receptor availability and thus lead to decreased food intake. Although tesofensine primarily acts as an appetite suppressant there is also evidence that the reduction in weight is due to a combined synergistic effect of appetite suppression, increased energy expenditure and fat oxidation.

Another study was conducted where sibutramine and rimonabant were used as reference comparators. It was found that tesofensine worked twice as well as previously published information on sibutramine and rimonabant. While all compounds exhibited a significant inhibitory effect on food intake that gradually wore off, the hypophagic (reduced food intake) effect of tesofensine was longer lasting than sibutramine and rimonabant. In an oral glucose tolerance test, only tesofensine significantly suppressed the plasma insulin response, indicating that tesofensine further improved glycemic control.

A phase 2b trial (TIPO-1) that lasted 24 weeks was launched where 161 out of 203 people completed the study. The volunteers were placed on a diet with a 300 kcal deficit and asked to perform 30–60 minutes of exercise per day. The volunteers were divided into four groups. The first group was given 1.0 mg per day and they lost an average of 12.8Kg or 10.6% of their bodyweight. The second group was given 0.5 mg and they lost an average of 11.3kg or 9.2% of their bodyweight. The third group was given 0.25 mg and they lost an average of 6.7Kg or 4.5% of their bodyweight. The last group was a placebo group and they only lost an average of 2.2kg or 2% of their bodyweight.

After the completion of the phase 2b trial (TIPO-1) a three-month break was taken before 140 of the original volunteers were re-enrolled to do a 48-week extension trial (TIPO-4). This time the trail was divided into two 24-week phases. For the first 24-week phase all were initially treated with 0.5 mg tesofensine once daily but up-titration to 1.0 mg once daily was allowed. At the end of the first 24-week phase those who were previously treated with tesofensine 0.5 mg in the phase 2b trial (TIPO-1) showed a total mean weight loss of between 13 kg and 14 kg over the 48 weeks of treatment. For the second 24-week phase all subjects were continued on the 0.5 mg dose. Furthermore, TIPO-4 confirmed the TIPO-1 results since those patients who were previously treated with placebo during TIPO-1 lost approximately 9 kg in the first 24 weeks of the TIPO-4 study.

Approval from the FDA (Food and Drug Administration) and the EMA (European Medicines Agency) regarding the development of Tesofensine has resulted in NeuroSearch planning a phase 3 program including two obesity studies of one year each. This phase 3 program must also include a study for more than a two-year period in order to determine the drug’s cardiovascular safety profile. This particular two-year part of the testing requires between 5 and 7 thousand patients.

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, diarrhea and constipation. A dose-dependent pattern was observed for dry mouth and insomnia. Blood pressure and heart rate increases with the 0.25 mg and 0.5 mg doses of tesofensine were 1–3 mmHg and up to 8 bpm, respectively. The initial positive findings suggest that tesofensine may be a well-tolerated long-term treatment for obesity.

Since tesofensine is still undergoing medical testing it’s impossible to obtain it through a pharmacy.