Tesofensine
Encyclopedia
Tesofensine 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.
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.
) 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%).
.
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.
Serotonin-noradrenaline-dopamine reuptake inhibitor
A serotonin–norepinephrine–dopamine reuptake inhibitor , or triple reuptake inhibitor , is a drug that acts simultaneously as a reuptake inhibitor for the monoamine neurotransmitters, serotonin , norepinephrine and dopamine , by blocking the action of the serotonin transporter , norepinephrine...
from the phenyltropane
Phenyltropane
Phenyltropanes were originally developed to reduce cocaine addiction and dependency. In general these compounds act as inhibitors of the plasmalemmal monoamine reuptake transporters. Although RTI holds a strong position in this field, they are not the only researchers that have prepared these...
family of drugs, which is being developed for the treatment of obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
. 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 diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, 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
Overweight
Overweight is generally defined as having more body fat than is optimally healthy. Being overweight is a common condition, especially where food supplies are plentiful and lifestyles are sedentary...
or obese
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
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 (CYP3A4CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
) 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 groupPlacebo-controlled studies
A Placebo-controlled study is a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect...
.
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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) for the treatment of obesity.
NeuroSearch has also reported interim results from a 48-week, open-label
Open-label trial
An open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....
, 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.