Tesofensine

Tesofensine Benefits for Overall Health

• Fights obesity [6-23]
• Improves cognitive health [24-32]
• Improves mood [33-35]
• Improves blood sugar levels [36-38]
• Increases energy levels [35, 39]
• Treats sexual dysfunction [35, 40]
• Treats eating disorders [8, 41-45]
• Treats attention-deficit/hyperactivity disorder (ADHD) [46-49]
• Improves sleep quality [50-57]
• Fights alcohol addiction [58-62]

What is Tesofensine?

Tesofensine (NS2330) is a serotonin–noradrenaline–dopamine reuptake inhibitor or also known as a triple reuptake inhibitor, which means that it inhibits the reabsorption of the neurotransmitters (brain chemicals) serotonin, norepinephrine, and dopamine. This process increases the extracellular concentrations of these neurotransmitters. The therapeutic benefits of tesofensine are attributed to this effect because each of these neurotransmitters exerts an important function at different locations in the brain.

How Tesofensine Works?

Tesofensine works by boosting the levels of brain chemicals (neurotransmitters) such as dopamine, norepinephrine, and serotonin. Dopamine is associated with the regulation of motor function, mood, motivation, reward, cognitive function, and reproductive behaviours. Norepinephrine increases the force of the contraction of the skeletal muscle and the heart to ensure optimal body function. Serotonin is responsible for the regulation of mood, memory, sleep, and appetite.

Chemical Structure of Tesofensine

Research on Tesofensine

Fights Obesity

Tesofensine is widely known as a weight loss drug. Researchers believe that tesofensine may help treat obese and overweight patients because it boosts the levels of dopamine in the brain. A deficiency in this neurotransmitter has been shown to be linked with overeating and obesity. [1-5] An overwhelming body of human studies supports the fat-burning effect of tesofensine:

1. 1. The results of the 2018 phase 3 Viking study showed that obese patients who received both doses of oral tesofensine (0.25 and 0.50 mg once daily) had statistically and clinically significant weight loss with low incidence of adverse events at week 24. [6]
   2. The results of the Phase 2b trial (TIPO-1) showed that obese patients treated with tesofensine 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, suggesting that tesofensine has the potential to produce a weight loss twice that of currently approved drugs. [7]
   3. In the TIPO-2 trial, tesofensine administration in obese patients reduced their desire to eat and increased their satiety levels after 14 days of treatment. [8]
   4. In obese patients, tesofensine treatment at varying doses (0.25 mg, 0.5 mg or 1.0 mg) resulted in statistically significant and clinically relevant weight loss with positive effects on energy balance, appetite, physical activity, and quality of life. [9]
   5. In obese patients, tesofensine administration at a dose of 0.5 mg for 26 weeks produced weight loss twice that of anti-obesity agents such as sibutramine or rimonabant. [10]
   6. In overweight patients, tesofensine administration for 24 weeks is associated with enhanced appetite suppression and significant weight loss. [11]
   7. In phase II clinical trials with tesofensine in obese individuals, significant reductions in body weight, body fat and waist circumference were observed without any adverse side effects. [12]
   8. In obese patients, long-term tesofensine supplementation is well-tolerated and resulted in significant weight loss.[13]
   9. In patients with Parkinson’s or Alzheimer’s disease, tesofensine administration once daily for 14 weeks without any weight loss program induced weight loss of approximately 4%, which is similar to that of sibutramine. [14]
   10. In healthy males, multiple administration of tesofensine at doses of 0.125–1 mg induced a significant increase in dopamine levels, resulting in appetite suppression. [15]
   11. In the diet-induced obese rat, tesofensine administration resulted in appetite suppression and weight loss with reversal of low forebrain dopamine levels. [16-17]
   12. In a rat model of diet-induced obesity (DIO), administration of tesofensine (2.0mg/kg, s.c.) for 16 days significantly reduced body weights. [18]
   13. In diet-induced obese rats, tesofensine treatment at 2 mg/kg for 28 days decreased food intake and body weight. [19]
   14. In 203 obese persons, tesofensine 0.5 mg produced a weight loss twice that of currently approved anti-obesity drugs. [20]
   15. In obese patients, tesofensine administration resulted in a 10% average weight loss in 24 weeks. [21]
   16. A study showed that tesofensine showed a stronger weight-reducing effect than that of currently approved anti-obesity drugs. [22]
   17. In obese patients, tesofensine in combination with an energy-restricted diet effectively reduced the weight of the subjects. [23]

Improves Cognitive Health

Research indicates that tesofensine helps preserve cognitive health by indirectly potentiating cholinergic neurotransmission, which is a process wherein nerve cells relay messages to each other. [24] This has been proven to have beneficial effects on various areas of cognitive health, including learning, memory, and thinking skills. The following studies support this effect:

1. 1. The first clinical results of two small 4-week phase IIa trials performed in patients with mild Alzheimer’s disease (AD) showed that tesofensine treatment induced significant improvement in cognitive function. [25-26]
   2. A growing body of research indicates that obesity is a major risk factor for cognitive impairment, especially in the older population. [27-30] With its anti-obesity effect, tesofensine may help protect against cognitive impairment.
   3. In a mouse model of Alzheimer’s disease, tesofensine administration decreased the brain concentrations of amyloid beta, which are abnormal protein aggregates and is the causative agent of the disease. [31]
   4. In patients with advanced Parkinson’s disease and motor fluctuations, low-dose tesofensine improved activities of daily living and motor function. [32]

Improves Mood

Sustained treatment with tesofensine has been shown to improve overall mood through its antidepressant effect. Studies show that tesofensine affects mood by:

1. 1. Increasing the levels of brain-derived neurotrophic factor (BDNF), thereby triggering an antidepressant effect. [33]
   2. Triggering an anti-anxiety effect in obese patients with comorbid depression and anxiety symptoms. [34]
   3. Increasing the levels of the neurotransmitters serotonin, noradrenaline, and dopamine. [35]

Improves Blood Sugar Levels

Tesofensine has also been found to have beneficial effects on blood sugar. Studies show that:

1. 1. In obese patients, administration of tesofensine at varying doses (0.25 mg, 0.5 mg, and 1.0 mg) resulted in a significant reduction in blood sugar levels and an improvement in quality of life. [36]
   2. In rodents, tesofensine also induced a significant reduction in blood sugar levels in addition to weight loss. [37-38]

Increases Energy Levels

Tesofensine treatment is also beneficial in improving one’s productivity by increasing energy levels. Evidence supports the energy-boosting effects of tesofensine:

1. 1. A study found that tesofensine can boost energy by increasing the levels of the neurotransmitters dopamine and norepinephrine, which are responsible for regulating motivation, energy, interest, and drive. [35]
   2. In one study, the administration of tesofensine in overweight and moderately obese men induced higher energy expenditure compared to a placebo. [39]

Treats Sexual Dysfunction

Because of its potent antidepressant effect, tesofensine has also been studied for its therapeutic benefits on sexual dysfunction, according to studies:

1. 1. Tesofensine has the capacity to increase the levels of dopamine, a neurotransmitter that contributes to the desire for sexual activity, erection, and ejaculation. [35]
   2. Tesofensine administration is effective in treating depression-related sexual dysfunction, suggesting that it can help ramp up sexual power. [40]

Treats Eating Disorders

Studies reported that triple reuptake inhibitor such as tesofensine also holds therapeutic potential for eating disorders:

1. 1. In obese patients, tesofensine administration reduced their desire to eat and increased their satiety levels after 14 days of treatment. [8]
   2. In patients with binge eating disorder, a condition in which a person eats large quantities of food when stressed, tesofensine administration has been shown to improve its symptoms, possibly due to tesofensine’s potent antidepressant effect. [41-44]
   3. In the diet-induced obese rat, tesofensine induced appetite suppression by indirect stimulation of α1 adrenoceptor and dopamine d1 receptor pathways. [45]

Treats Attention-Deficit/Hyperactivity Disorder (ADHD)

ADHD is characterized by short attention span, hyperactivity and impulsivity, and is common in children and even adults. Evidence suggests that tesofensine may have beneficial effects on this mental condition:

1. 1. Studies show that ADHD is strongly linked with low levels of dopamine and serotonin and that tesofensine can have beneficial effects on this condition by increasing the levels of these neurotransmitters. [46-48]
   2. A study reported that tesofensine can lower the risk of ADHD associated with obesity. [49]

Improves Sleep Quality

Studies suggest that tesofensine’s ability to increase the levels of certain neurotransmitters can help improve sleep quality:

1. 1. A deficiency in the neurotransmitter serotonin has been linked to insomnia and various sleeping difficulties. [50-55]
   2. Studies reported that increasing the levels of serotonin through selective serotonin reuptake inhibitors treatment has been shown to improve objective and subjective sleep quality in patients with sleeping difficulties – an effect similar to tesofensine. [56-57]

Fights Alcohol Addiction

There’s also evidence suggesting that tesofensine can cure alcohol addiction via its ability to boost neurotransmitter levels:

1. 1. Studies show that low dopamine levels are associated with alcohol addiction – with tesofensine’s ability to increase dopamine levels, it may help reduce excessive alcohol intake along with its symptoms. [58-61]
   2. In ethanol-preferring rats, triple reuptake inhibitor administration reduced alcohol consumption without decreasing food or water consumption. [62]

Associated Side Effects of Tesofensine

Tesofensine side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on tesofensine. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of tesofensine. Despite this, it was listed as a side effect associated with tesofensine even though these associated side effects are very uncommon.

Side effects associated with tesofensine may include the following:

• Constipation
• Diarrhea
• Dry mouth
• Headache
• Increased blood pressure
• Increased heart rate
• Insomnia
• Nausea

Reference

1. Mahapatra A. Overeating, Obesity, and Dopamine Receptors. ACS Chemical Neuroscience. 2010;1(5):346-347. doi:10.1021/cn100044y. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368677/.
   View Summary +

   Dopamine is a type of neurotransmitter. It is naturally produced by your body and used by your nervous system in relaying messages between nerve cells. It plays a key role in the brain reward circuit, executive function, motor control, motivation, arousal, and reinforcement. In other words, it allows you to feel pleasure, satisfaction, and motivation. While eating, your dopamine level increases as you enjoy the food and look forward in eating more in the future.

   Recent studies have shown the involvement of dopamine in food intake in obese patients. In positron emission tomography (PET) scan studies, it was shown that obese individuals have reduced striatal dopamine D2 receptors (dopamine in the brain) compared to non-obese patients. In addition, it was also shown that these obese individuals tend to overeat to compensate for this effect.

   D2 Receptor Levels and Obesity in Rats

   For the first set of experiments, rats of the same sizes were prepared for brain stimulation reward procedures. Stimulation electrodes were then implanted to their brains to record their brain activities. The rats were then divided into three groups. For the span of 40 days, the first group of rats had access to only standard laboratory chow, the second set had access to chow and one-hour access to palatable, energy-rich food such as bacon, sausage, and cake, and lastly, the third group had extended access to both chow and high-fat food. As the experiment goes on, the group of rats who had extended access to energy-rich food had gained approximately twice as much weight as the rats that had access to only chow or chow and limited amounts of energy-rich food.

   Another set of rats were tested to know whether overeating had any effect on D2 receptor levels in the striatum (a brain region responsible for motor and action planning). Just like the first experiment, the rats were divided into three groups and were given access to chow only, chow and limited access to high-fat food, and extensive access to high-fat food. After significant changes in weight were noted, the rats were killed to examine their D2 receptor levels in the striatal complex. It was found that the fatter the rat, the lower the density of D2 receptors in the brain.

   Conclusion

   In the presence of low levels of dopamine receptors, the brain tells people to eat more than normal to achieve contentment and satisfaction. Tesofensine is an inhibitor of neuronal reuptake of dopamine. These dopamine reuptake inhibitors increase the levels of dopamine in the brain. Thus, these results show that taking tesofensine may help prevent overeating as compensation for the low density of D2 receptors in the brain.

2. Blum K, Thanos PK, Gold MS. Dopamine and glucose, obesity, and reward deficiency syndrome. Frontiers in Psychology. 2014;5:919. doi:10.3389/fpsyg.2014.00919. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166230/.
   View Summary +

   Obesity has been accurately considered to be a world-wide epidemic as a result of overeating and a number of eating disorders. Numerous neurochemical and genetic studies provided strong evidence that food addiction is similar to psychoactive drug addiction. A concept known as Reward Deficiency Syndrome (RDS) was published in relation to this issue. RDS is a form of sensory deprivation of the pleasure and reward mechanisms as a result of the person’s neurochemical inability to feel pleasure from simple, everyday activities. It causes hypo-dopaminergic function which then results in abnormal craving behavior that is associated with obesity. To compensate for this lack of dopamine function, the patient with RDS will find a way to supplement his need for pleasure, in which in the case of obesity, consuming more food before feeling contented or satisfied.

   What is Dopamine?

   Dopamine is a very powerful feel-good neurotransmitter in the brain that modulates motivation and reward circuits. It plays a vital role in letting you feel pleasure, satisfaction, and happiness in many pleasurable behaviors like sex, drug use, and eating. Several studies with rats about the relationship of dopamine level and obesity showed that the fatter the rat, the lower the density of dopamine receptors in the brain. This shows that as a compensation for the low level of dopamine, the subject need to eat more than normal before feeling satisfied.

   How Dopamine works on Appetite?

   Most of people like drinking a cup of coffee every morning to jump start their day. While caffeine helps in increasing energy levels, having a cup of coffee is a pleasant experience that results in the release of high levels of dopamine. This rise of dopamine level enables them to feel happy while drinking until they are satisfied. After finishing the cup of coffee, dopamine level decreases until it is again low enough to trigger the urge for another cup or to eat your next meal.

   As the previous studies showed, fatter rats had lower density of dopamine receptors in the brain which caused them to gain too much weight that has led to obesity. This happens because lower level of dopamine receptors means that it is harder to trigger dopamine release. In other words, people with lower levels of dopamine will need to eat a larger amount of food than people with normal dopamine levels to satisfy their cravings.

3. Karlsson HK, Tuominen L, Tuulari JJ. Obesity is associated with decreased μ-opioid but unaltered dopamine D2 receptor availability in the brain. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2015; 35(9):3959-65. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/25740524.
   View Summary +

   Opioid System and Obesity

   Obesity is one of the greatest challenges in human health worldwide due to its association with serious medical conditions such as type 2 diabetes, coronary heart disease, and stroke. Food reward is driven by functionally distinct neurochemical mechanisms in the brain promoting incentive motivation (“wanting”) and hedonic impact (“liking”) when food is consumed. Evidence suggests that obesity is related to altered neurochemistry of the reward circuitry of the brain which makes obese individuals prone to overeating. Obesity’s unique neurobiological association with the reward circuit of the brain is more similar to opioid addiction than to other addictive disorders. The opioid system regulates motivation and reward processing, and low μ-opioid availability may promote abnormal eating behavior or overeating as a response to compensate for the decreased hedonic responses in this system. Thus, the development of behavioral and pharmacological strategies in recovering opioidergic function would be a critical step in keeping the obesity epidemic in check

   To assess the association between μ-opioid and dopamine, 13 morbidly obese women with a body mass index (BMI) range of 37.1–49.3 kg/m2 were recruited in a study. The obese subjects were compared with 14 healthy non-obese female subjects that were age and height matched with the obese subjects. Clinical screening included history, physical examination, anthropometric measurements, and laboratory tests. Their D2 and μ-opioid receptor availability were measured using positron emission tomography (PET) scan. Then, they were injected with raclopride and carfentanil in separate scans on separate days. After injection, radioactivity in brain was measured. The results revealed that morbidly obese patients had significantly lower level of μ-opioid receptor availability without alterations in D2 receptor.

   Conclusion

   Cerebral μ-opioid receptor availability was lowered in morbidly obese patients in brain regions implicated in reward processing while D2 receptor availability remained unaltered. Altered μ-opioid receptor availability was also associated with alterations in affect-driven eating, as indicated by elevated self-reported food addiction and restrained eating behavior. Also, food addiction and restrained eating were significantly associated with the level of μ-opioid receptor availability. This information suggests that lowered μ-opioid receptor availability is directly linked with the tendency to compulsively eat regardless of internal state of hunger or satiety.

   Drugs that may modulate opioid system function could be a good strategy in treating obesity. Several studies have already shown that tesofensine, a serotonin–noradrenaline–dopamine reuptake inhibitor, offers clinically significant weight-lowering effects by increasing the D2 receptors availability. Thus, understanding its effects in the opioid system in association with obesity is important.

4. Wang GJ, Volkow ND, Logan J. Brain dopamine and obesity. Lancet (London, England). 2001; 357(9253):354-7. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/11210998.
   View Summary +

   Obesity and Health

   Obesity, the condition of having too much body fat, is a serious health problem that is associated with poor mental health outcomes, low quality of life, and even death in more serious cases. Obesity is associated with several health problems – most of these medical conditions are life-threatening. Obese people are prone to heart diseases, stroke, diabetes, high blood pressure, arthritis, some types of cancer, gallbladder and gallstone diseases, and breathing problems such as sleep apnea and asthma.

   To treat obesity, a low-calorie diet and regular exercise is important. By eating low-calorie foods, you enable your body to absorb less calories that you need to burn to lose weight or maintain weight loss. Also, performing exercise regularly lets you burn your excess calories faster than diet alone. Burning more calories than you take is the best way to lose weight. However, recent studies showed that weight-loss drugs could offer additional weight reduction effects in obese patients

   Function of Dopamine

   Dopamine is a type of neurotransmitter. It is naturally produced in the body and is used by your nervous system in relaying messages between nerve cells. It plays a key role in the brain reward circuit, plays executive function, motor control, motivation, arousal, and reinforcement. In other words, it allows you to feel pleasure, satisfaction, and motivation.

   Brain Dopamine D2 Receptors and Obesity

   The brain mechanisms behind the behaviors that lead to pathological overeating and obesity are not yet fully understood. However, dopamine which modulates motivation and reward circuits, is likely to be involved. To test the hypothesis, abnormalities in the brain dopamine activity in obese individuals were recorded and the availability of dopamine D2 receptors in their brain was measured. Obese individuals were selected from a pool of people with a BMI greater than 40 kg/m2. Their brain dopamine D2 receptor availability was measured with positron emission tomography (PET) scan and raclopide was used as a measure of dopamine D2 receptor availability. Brain glucose metabolism was also assessed.

   The results showed that striatal dopamine D2 receptor availability was significantly lower in the ten obese individuals than in controls. The body mass index (BMI) of obese individuals was negatively correlated with the measures of their D2 receptors wherein the patient with the highest BMI has the lowest D2 values.

   Conclusion

   The availability of dopamine D2 receptor was significantly lower in obese individuals in relation to their BMI. Dopamine regulates motivation and reward circuits, therefore dopamine deficiency in obese individuals may result in pathological eating as a way to compensate for the decreased activation of these circuits. Therefore, strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals. Tesofensine is an inhibitor of neuronal reuptake of dopamine that works by increasing the levels of dopamine in the brain which may help prevent pathological eating.

5. Benton D, Young HA. A meta-analysis of the relationship between brain dopamine receptors and obesity: a matter of changes in behavior rather than food addiction? International Journal of Obesity (2005). 2016;40(Suppl 1):S12-S21. doi:10.1038/ijo.2016.9. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4819757/.
   View Summary +

   Addiction to a wide range of substances of abuse has been suggested to reflect a reward deficiency syndrome. Drugs are said to stimulate the reward mechanisms too much that the density of dopamine D2 receptors (DD2R) significantly decreases. To compensate, increased intake is needed to experience the same degree of reward or satisfaction. Without this additional intake, cravings and withdrawal symptoms usually occur.

   Food addiction was suggested to decrease DD2R in a similar manner to that of the drug abuse. The role of DD2R in obesity was therefore assessed by examining the association between body mass index (BMI) and the Taq1A polymorphism, as the A1 allele is associated with a lower number of DD2R, and is a risk factor for drug addiction. If a lower density of DD2R is an indication for physical addiction, it was hypothesized that if food addiction occurs, those with the A1 allele should have a higher BMI. To check if this hypothesis is correct, a systemic review was conducted to compare the BMI of those individuals who did and did not have A1 allele.

   Searches for studies were made both electronically and quotations from relevant papers. Several databases were searched using the search terms used as inclusion criteria. After the collection of studies, duplicates were removed while retaining human studies that related Taq1 allele to BMI, and studies that compared these alleles in groups differing in BMI. Those of different ages and different ranges of BMI were distinguished to establish whether any effect depended on these parameters. The selection of search terms reflected a precise and focused objective and an interest in a single outcome measure. The abstracts of the studies initially identified were examined for duplicates and were filtered for those that potentially met the inclusion criteria. The full article of those that remained was then read to establish whether they met the inclusion criteria. In total, 33 studies were found that related Taq1A to BMI. For all the studies that were included for the review, the BMI of those with the various alleles were listed. When those who were obese were compared with a control group of lesser weight, the frequency of the various alleles in these two groups was recorded.

   The results of comparing those with or without various alleles showed that there was no difference in BMI. It was therefore concluded that there was no support for a reward deficiency theory of food addiction. In contrast, there are several reports that those with the A1 allele are less able to benefit from an interventions that aimed to reduce weight. Also, it showed the role of dopamine in reward mechanisms and its influence in other aspects of behavior that could contribute to weight gain.

6. Retrieved from https://globenewswire.com/news-release/2018/12/17/1667781/0/en/Saniona-s-tesofensine-meets-primary-and-secondary-endpoints-in-Phase-3-obesity-registration-trial.html.
   View Summary +

   Obesity, the state of having too much body fat, is a serious health problem that is associated with poor mental health outcomes, low quality of life, and even death in more serious cases. This is different from being overweight since a person’s weight may come from muscle, bone, fat, and/or body water. Obesity is associated with several health problems with others having some of the highest mortality rates worldwide. Obese people are prone to heart diseases, stroke, diabetes, high blood pressure, arthritis, some types of cancer, gallbladder and gallstone diseases, and breathing problems such as sleep apnea and asthma.

   Although the difficulty of treating obesity differs for everyone, there are some things that you can do to help reduce your weight such as:
   •Eating a low-calorie diet: Following a low-calorie diet can help lose weight by reducing the calories that you need to burn to prevent weight gain. Foods like oats, eggs, fish, berries, and soup are some of the best foods for weight reduction. Avoid sugary and high-fat foods.
   •Performing regular exercise: Regularly performing exercise everyday is important in weight loss and maintaining weight loss. Exercise increases your metabolism and the calories that you burn in a day.
   •Taking weight-lowering medicines: Some doctors prescribe weight-lowering medicines to their patients to help reduce their weight and some obesity-related health problems.
   Tesofensine, a serotonin–noradrenaline–dopamine reuptake inhibitor can help prevent obesity by regulating the levels of brain chemicals that are involved in satiety and food intake. A 24-week double-blinded, randomized, placebo-controlled trial was conducted to investigate the safety and efficacy of once-daily administration of both 0.25 and 0.50 mg oral tesofensine in 372 obese patients. [1] Aside from the treatment, all patients involved in the study followed the same reduced-calorie diet and the same exercise program. The primary endpoint of the study was the average percentage of changes in body weight compared to placebo. Secondary endpoint included the percentage of patients who experienced weight loss of at least 5% and 10% of baseline body weight.

   At week 24, patients who received both tesofensine treatments showed significant reductions in all endpoints compared to placebo. The positive results included average percentage and absolute change in body weight, reduction in body mass index (BMI), and the proportion of patients experiencing weight loss of at least 5% and 10% of baseline body weight.

   The data also showed significant reductions in obesity-related risk factors in tesofensine-treated participants compared to those who received placebo. These factors include waist circumference, hip circumference, body fat, visceral fat, bad cholesterol, triglycerides, and insulin.

   In conclusion, both 0.25 and 0.50 mg oral tesofensine treatments were effective in inducing statistically and clinically significant weight loss in obese patients. With low incidence of adverse effects, both treatments were considered to be safe and well tolerated.

7. Astrup A, Madsbad S, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet (London, England). 2008; 372(9653):1906-1913. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18950853.
   View Summary +

   Obesity

   Obesity is the state in which a person’s body weight is significantly higher than what’s considered as healthy for his/her height as a result of having too much fat. It is a serious health problem as it can cause life-threatening diseases and complications. Obese people are prone to heart diseases, stroke, diabetes, high blood pressure, arthritis, some types of cancer, gallbladder and gallstone diseases, and breathing problems such as sleep apnea and asthma.

   To treat obesity, a low-calorie diet and regular exercise are important. By eating low-calorie foods, you enable your body to absorb fewer calories that you need to burn to lose weight or maintain weight loss. Also, performing exercise regularly lets you burn your excess calories faster than diet alone. Burning more calories than you take is the best way to lose weight. However, recent data show that tesofensine, a potential weight-loss drug, can offer additional weight reduction effects in obese patients when combined with diet and exercise.

   Tesofensine in Obesity

   Weight-loss drugs were successful in inducing 3 to 5 kilograms of additional weight reduction in obese patients. This additional weight loss is higher than that of diet and placebo alone over the span of 6 months. To assess the efficacy of tesofensine, an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin which works primarily as an appetite suppressant, a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres was initiated. The subjects were obese patients. After a 2-week run-in phase, 203 obese patients with a body-mass index of 30-40 kg/m2 were instructed to follow an energy-restricted diet. They were also randomly treated with 0.25 mg, 0.5 mg, or 1.0 mg dosage of tesofensine, or placebo once a day for 24 weeks. The primary outcome was the percentage of change in body weight which was measured in the patients after 24 weeks.

   Seventy-nine percent (161 specifically) of participants successfully completed the study. After the measurement and analysis of the results, it was found that the mean weight loss induced by diet and placebo was 2%. On the other hand, 0.25 mg, 0.5 mg, and 1.0 mg dosage of tesofensine with diet produced a mean weight loss of 4.5%, 9.2%, and 10.6%, respectively, significantly greater than the weight reduction induced by diet and placebo. The most common reported adverse events associated with tesofensine administration were dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia. No significant increase in systolic and diastolic blood pressure was observed in subjects treated with 0.25 mg and 0.5 mg tesofensine compared to placebo. These results show that the 0.5 mg dosage of tesofensine has the potential to offer weight loss effects twice that of currently approved weight-loss drugs.

8. Retrieved from https://www.drugdevelopment-technology.com/projects/tesofensine/.
   View Summary +

   Obesity is characterized by a significant increase in body fat. To be considered obese, a person’s body mass index (BMI) must be 30 and above. A BMI of 25.0-29.9 is considered overweight. Obesity is now the most common nutritional disorder in western industrialized countries. According to the data from the World Health Organization’s MONICA project, in some parts of Europe over 70% of men aged 55–64 years are clinically obese or overweight (BMI >25), and almost 70% of women in this age group

   In all American populations, the data shows that there is 1 obese in every 5 persons and 1 in every 3 is overweight. These data are alarming because studies have shown that obesity is greatly associated with an increased risk of cardiovascular disease and diabetes and possibly some types of cancers, like breast and colorectal cancer. The significant rise in incidences of diabetes is because of the increased prevalence of obesity. In addition, increases in body weight lead to changes in blood lipid and cholesterol levels, predisposing to increased risk of atherosclerosis. The increase in the prevalence of obesity in the US and Europe has reached an epidemic level that pushed for the initiation of the development of new weight loss drugs.

   Tesofensine for Obesity

   Tesofensine, a novel obesity treatment, is under the development of a Danish pharmaceutical company. This inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin was first developed to treat Parkinson’s disease (PD) and Alzheimer’s disease (AD). After performing PD trials, tesofensine failed to show its efficacy in treating the disease. However, significant weight loss was found to be associated with the administration of the drug to the patients. This led the company to switch the purpose of the drug from treating PD to obesity. The performed trials showed strong evidence of the efficacy of tesofensine in inducing weight loss.

   In several Phase 2 trials, tesofensine produced effective results. In a TIPO-1 study with 203 patients, the subjects were instructed to follow an energy-restricted diet. Then, they were randomized to treatment with 0.25 mg, 0.5 mg, or 1.0 mg tesofensine, or placebo once a day for 24 weeks

   Patients who were treated with 0.5 mg tesofensine achieved a total mean weight loss of 13-14kg at 24 weeks. At the end of 24 weeks, changes in weight were measured in all participants. Data showed that tesofensine 0.25 mg, 0.5 mg, and 1.0 mg induced a mean weight loss of 4.5%, 9.2%, and 10.6% respectively. The weight loss induced by diet and placebo only achieved a 2.0% mean weight reduction.

   In the TIPO-4 trial, a 48-week open-label extension of the TIPO-1 trial, the weight loss induced by tesofensine was shown to be sustained. After an initial eight-week washout period, patients who continued with 0.5 mg tesofensine experienced a total mean weight loss of 13–14 kg at 24 weeks.

   In the TIPO-2 with 32 obese patients, tesofensine induced a significant reduction in their desire to eat and increased their level of satisfaction.

9. Retrieved from https://professional.diabetes.org/abstract/effect-tesofensine-weight-loss-appetite-physical-activity-and-qol-obese-subjects-results-24.
   View Summary +

   Obesity is the condition in which a person has too much body fat. The most common way to determine if a person is overweight or obese is to calculate his/her body mass index (BMI), which is an estimate of body fat that compares a person’s weight to his/her height. Evidence suggests that tesofensine can help reduce BMI by acting on brain chemicals responsible for the regulation of food intake.

   Tesofensine in Obesity

   Tesofensine, an inhibitor of the pre-synaptic uptake of the neurotransmitters (brain chemicals) norepinephrine, dopamine, and serotonin, was shown to be safe and effective in animal models and humans.

   A phase II trial assessed the efficacy and safety of tesofensine in the treatment of obesity in a 24-week randomized, double-blind, placebo-controlled, multi-center trial at 5 Danish obesity centers. After a 2-week run-in phase, 203 obese patients were prescribed an energy-restricted diet and randomized for the treatment of tesofensine 0.25 mg, 0.5 mg, or 1.0 mg, or placebo once daily for the span of 24 weeks. The primary outcome was the percentage change in body weight. One hundred sixty-one (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 2.0%. Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo.

   Adverse events were generally mild and transient including dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia. Tesofensine exerted a dose-dependent increase in blood pressure and heart rate. After 24 weeks, tesofensine 0.5 mg showed no statistically significant increases in systolic or diastolic BP compared to placebo, whereas heart rate increased by 7.4 beats per minute.

   The physical activity questionnaire showed that tesofensine increased the time patients spent walking and being active, and reduced the time spent watching TV compared to placebo. The 2 highest doses of tesofensine significantly affected appetite measures compared with placebo, with a 3- to 4-fold reduction in hunger, and a reduction in expected next meal size. Desires for sweet, fatty, or salty foods were reduced in the 2 highest dose groups. In terms of quality of life, consistent beneficial effects of tesofensine were found compared to placebo. Significant improvements were seen in the “Overall Score” and domains of “Physical Function” and “Self-Esteem”, with modest improvements in “Sexual Life”, “Public Distress” and “Work”.

   The study showed that tesofensine treatment resulted in statistically significant and clinically relevant weight loss, and may affect energy balance by affecting appetite and physical activity. Tesofensine also significantly improved the quality of life in areas that are highly relevant for obese patients.

10. Doggrell SA. Tesofensine–a novel potent weight loss medicine. Evaluation of: Astrup A, Breum L, Jensen TJ, Kroustrup JP, Larsen TM. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1906-13. Expert opinion on investigational drugs. 2009; 18(7):1043-6. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19548858.
    View Summary +

    Obesity is a complex condition involving an excessive amount of body fat. Obesity isn’t just an aesthetic concern. It is a serious medical problem that increases the risk of life-threatening diseases and complications. Some of these are considered the leading causes of death worldwide. Obese people are prone to heart diseases, stroke, diabetes, high blood pressure, arthritis, some types of cancer, gallbladder and gallstone diseases, and breathing problems such as sleep apnea and asthma.</p

    Common Causes of Obesity

    The following factors can lead to obesity:

    Physical inactivity: The lack of physical activity causes extra energy to be stored in your body as fat.
    Eating a high-calorie diet: Too much calories will be stored in your body as fat.
    Overeating: Eating too much without burning calories through physical activity makes you store more energy in your body which is then converted into fat.
    Genetics: In some cases, obesity occurs in families due to the inheritance pattern caused by changes in genes.
    Medications: There are a number of medicines that may cause obesity such as anti-diabetics, antipsychotics, antidepressants, and blood pressure-reducing medicines.
    Psychological factors: Most people who are stressed often eat a lot to relieve their negative emotions.
    An underlying disease: Diseases such as hypothyroidism, insulin resistance, polycystic ovary syndrome, and Cushing’s syndrome are common causes of obesity.

    Tesofensine – A Novel Potent Weight Loss Medicine

    To assess the potency of tesofensine as a novel weight loss medicine, a Phase II clinical trial was conducted among obese subjects. During the study period, the subjects received tesofensine at a dose of 0.5 mg for 26 weeks. After the treatment period, tesofensine caused a significant and clinically relevant weight loss, suggesting that it can be a therapeutic option for obesity and that it produces more effective weight loss than other anti-obesity agents. However, tesofensine also induced an increase in blood pressure and heart rate that may increase the risk of psychiatric disorders.

    The results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings need more confirmation in phase III trials.

11. Gilbert JA, Gasteyger C, Raben A, Meier DH, Astrup A, Sjödin A. The effect of tesofensine on appetite sensations. Obesity (Silver Spring, Md.). 2012; 20(3):553-61. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21720440.
12. Bello NT, Zahner MR. Tesofensine, a monoamine reuptake inhibitor for the treatment of obesity. Current opinion in investigational drugs (London, England : 2000). 2009; 10(10):1105-16. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19777399.
13. Retrieved from https://nexs.ku.dk/forskning/borneernaering/publikationer/publikationer/?pure=da%2Fpublications%2Fthe-longterm-effect-of-tesofensine-on-weight-loss(c610afa0-1d6c-11df-8ed1-000ea68e967b).html.
14. Astrup A, Meier DH, Mikkelsen BO, Villumsen JS, Larsen TM. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity (Silver Spring, Md.). 2008; 16(6):1363-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/18356831.
15. Appel L, Bergström M, Buus Lassen J, Långström B. Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 2014; 24(2):251-61. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/24239329.
16. Hansen HH, Jensen MM, Overgaard A, Weikop P, Mikkelsen JD. Tesofensine induces appetite suppression and weight loss with reversal of low forebrain dopamine levels in the diet-induced obese rat. Pharmacology, biochemistry, and behavior. 2013; 110:265-71. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23932919.
17. Lehr T, Staab A, Tillmann C, et al. Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach. Br J Pharmacol. 2008;153(1):164–174. doi:10.1038/sj.bjp.0707539. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2199391/.
18. Axel AM, Mikkelsen JD, Hansen HH. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced obese rat. Neuropsychopharmacology. 2010;35(7):1464-76. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055463/.
19. Van de giessen E, De bruin K, La fleur SE, Van den brink W, Booij J. Triple monoamine inhibitor tesofensine decreases food intake, body weight, and striatal dopamine D2/D3 receptor availability in diet-induced obese rats. Eur Neuropsychopharmacol. 2012;22(4):290-9. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/21889317.
    View Summary +

    The novel triple monoamine inhibitor tesofensine is also considered a serotonin–noradrenaline–dopamine reuptake inhibitor. This means that it inhibits the reabsorption of the neurotransmitters or brain chemicals serotonin, norepinephrine, and dopamine. As a result, the concentrations of these neurotransmitters increase. The therapeutic benefits of tesofensine can be attributed to this effect because these neurotransmitters exert several vital functions at different regions of the brain.

    Obesity is linked to lower striatal dopamine D2 receptor availability or lower levels of dopamine receptors in the brain. Dopamine receptors are widely distributed within the brain where they play essential functions such as modulation of motivation, cognition, drive, and other important motor functions. Interestingly, obese people have fewer receptors for dopamine. [1] Hence, the dopamine deficiency in obese individuals may lead to binge eating or increased food intake as a
    mean to compensate for decreased activation of these circuits.

    Obesity is also associated with reductions in motor output, which is commonly known as physical inactivity. Interestingly, a study found that impairments in striatal dopamine contribute to physical inactivity, which in turn leads to obesity. [2] Since dopamine is important for proper control of movement, a deficiency or impairment in the production of this neurotransmitter can affect motor movements. This in turn increases the risk of obesity.

    Van de Giessen and colleagues studied the effects of chronic tesofensine treatment on food intake and body weight in association with changes in brain dopamine levels of diet-induced obese (DIO) rats. [3] In this study, four groups of 15 DIO rats were randomized to receive one of the following treatments for 28 days:

    1. Tesofensine at a dose of 2.0 mg/kg
    2. Vehicle (control treatment)
    3. Vehicle plus restricted diet isocaloric to the caloric intake of group 1
    4. Tesofensine at a dose of 2.0 mg/kg plus a treatment-free period of 28 days.

    Researchers observed that the caloric intake and weight gain decreased significantly more in the tesofensine-treated rats compared to vehicle-treated rats. These results confirm previous findings that tesofensine has weight loss properties. After discontinuation of the treatment, it was observed that the caloric intake and body weight gain gradually increased again. Specifically, the rats treated with tesofensine exhibited significantly lower dopamine D2 receptor availability in brain regions such as the nucleus accumbens and dorsal striatum than both vehicle-treated rats and vehicle-treated rats on a restricted isocaloric diet. In addition, the researchers did not observe any correlation between food intake or body weight and dopamine D2 receptor availability.

    In conclusion, chronic tesofensine treatment leads to decreased food intake and weight loss

20. Nielsen AL, Larsen TM, Madsbad S, et al. [The effect of tesofensine on body weight and body composition in obese subjects–secondary publication]. Ugeskr Laeg. 2009;171(41):2974-7. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/19824222.
    View Summary +

    The novel triple monoamine inhibitor tesofensine is also considered a serotonin–noradrenaline–dopamine reuptake inhibitor. This means that it inhibits the reabsorption of the neurotransmitters or brain chemicals serotonin, norepinephrine, and dopamine. As a result, the concentrations of these neurotransmitters increase. The therapeutic benefits of tesofensine can be attributed to this effect because these neurotransmitters exert several vital functions in different regions of the brain.

    Obesity is linked to lower striatal dopamine D2 receptor availability or lower levels of dopamine receptors in the brain. Dopamine receptors are widely distributed within the brain where they play essential functions such as modulation of motivation, cognition, drive, and other important motor functions. Interestingly, obese people have fewer receptors for dopamine. Hence, the dopamine deficiency in obese individuals may lead to binge eating or increased food intake as a means to compensate for decreased activation of these circuits.

    Obesity is also associated with reductions in motor output, which is commonly known as physical inactivity. Interestingly, impairments in striatal dopamine contribute to physical inactivity, which in turn leads to obesity. Since dopamine is important for proper control of movement, a deficiency or impairment in the production of this neurotransmitter can affect motor movements. This in turn increases the risk of obesity.

    Results from a phase II trial with tesofensine for the treatment of obesity are presented in one study. In total, 203 subjects who are obese were included and they received tesofensine at different doses (0.25 mg, 0.5 mg, or 1.0 mg). Results showed that tesofensine treatment resulted in a mean weight reduction of 4.5, 9.2, and 10.6% higher than that of placebo. This weight loss effect was observed in obese subjects who received 0.25, 0.5, and 1.0 mg of tesofensine. It was therefore concluded that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved anti-obesity drugs. However, phase III clinical trials are needed to confirm the safety and efficacy of 0.5 mg tesofensine

21. Available at https://www.globenewswire.com/news-release/2018/12/17/1667781/0/en/Saniona-s-tesofensine-meets-primary-and-secondary-endpoints-in-Phase-3-obesity-registration-trial.html.
22. Nielsen, A. L., Larsen, T. M., Madsbad, S., Breum, L., Jensen, T. J., Kroustrup, J. P., & Astrup, A. (2009). Effekt af tesofensine på kropsvaegt og kropssammensaetning hos svaert overvaegtige–sekundaerpublikation [The effect of tesofensine on body weight and body composition in obese subjects–secondary publication]. Ugeskrift for laeger, 171(41), 2974–2977.
23. Available at https://link.springer.com/article/10.1007/s13679-020-00422-w.
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