Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor from the

phenyltropane Phenyltropanes (PTs) 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, ...

family of drugs, which is being developed for the treatment of

obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...

. Tesofensine was originally developed by a Danish biotechnology company, NeuroSearch, who transferred the rights to Saniona in 2014. As of 2019, tesofensine has been discontinued for the treatment of Alzheimer's and Parkinson's disease but is in

phase Phase or phases may refer to: Science *State of matter, or phase, one of the distinct forms in which matter can exist *Phase (matter), a region of space throughout which all physical properties are essentially uniform * Phase space, a mathematic ...

III

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

for obesity.

History

Tesofensine was originally investigated for the treatment of Alzheimer's disease and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, 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 Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...

patients. Therefore, it was decided to pursue development of tesofensine for the treatment of obesity. Tesofensine primarily acts as an

appetite suppressant An anorectic or anorexic is a drug which reduces appetite, resulting in lower food consumption, leading to weight loss. By contrast, an appetite stimulant is referred to as orexigenic. The term is (from the Greek ''ἀν-'' (an-) = "without" ...

, but possibly also acts by increasing resting energy expenditure. Phase II clinical trials for the treatment of obesity have been successfully completed.

Pharmacology

Metabolism and half-life

Tesofensine has a long half-life of about 9 days (220 h) "and is mainly metabolized by cytochrome P4503A4 ( CYP3A4) to its desalkyl metabolite M1" 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%).

Transporter selectivity

Originally it had been reported that Tesofensine has IC₅₀ of 8.0, 3.2 and 11.0nM at the DAT, NAT and 5HTT. More recently, though, the following data was submitted: IC₅₀ (nM) NE 1.7, SER 11, DA 65. ref name=Larsen> cited in The revised IC₅₀'s would adequately explain the lack of efficacy in treating

, i.e. insufficient DRI potency relative to the SERT and the NET. This could also help account for why Tesofensine is not reliably self-administered by human stimulant abusers since it has been believed to be the case that DAT inhibition is necessary for this and not NET inhibition. Tesofensine also indirectly potentiates

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word " choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cati ...

neurotransmission Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...

proven to have beneficial effects on cognition, particularly in learning and memory. Sustained treatment with tesofensine has been shown to increase

BDNF Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

levels in the brain, and may possibly have an antidepressant effect.

Clinical trials

Phase IIB 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 Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dieta ...

. 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 The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) for the treatment of obesity. NeuroSearch has also reported interim results from a 48-week,

open-label An open-label trial, or open trial, is a type of clinical trial in which information is not withheld from trial participants. In particular, both the researchers and participants know which treatment is being administered. This contrasts with a do ...

, extension trial (TIPO-4) in which 140 patients who completed the 24-week phase IIB 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, diarrhea 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. At the conclusion of phase II clinical trials, Saniona announced that tesofensine was well tolerated with low incidence of adverse events, low increase in heart rate and no significant effect on blood pressure.

References

{{Phenyltropanes Anorectics Antiobesity drugs Serotonin–norepinephrine–dopamine reuptake inhibitors Tropanes Sympathomimetic amines Chlorobenzenes