Wait The New Anti-Obesity Drug; Will This Have Significant Impact On Weight Loss? – By Dr. Warsame Dhere

warsame 029Obesity is accepted globally as a rising health hazard in developed and developing world.  Gaining energy and storing as fats in the adipose tissue (fat tissues) without burning the energy till it causes adverse effects on health is referred to us as obesity. This causes the accumulation of fats which increases the volume distribution of the body which can cause metabolic disorder. This leads the rise of risk factors associated with this condition including diabetes, cardiovascular problems, dyslipidemia, cholesterol and other risk factors. Physical activities with control of calories intake remain the most useful strategies of battling with obesity.

Since the obesity was seen as a major health hazard there was anti-obesity drugs introduced into the market. Despite these drugs worked on reducing body weight they showed serious side effects such as pulmonary hypertension and regurgitant cardiac valvular disease.  These serious side effects caused their withdrawal from the market.

Pharmaceutical companies never stop working hard on finding very effective anti-obesity drug that can significantly reduce body weight without causing serious side effects. Arena pharmaceuticals are now conducting phase III clinical trial of hopeful anti-obesity drug candidate called Lorcaserine.

Chemical name of Lorcaserine is (IR)-8-chloro-2, 3, 4, 5-tetrahydro-1-methyl-1H-3-Benzazepine. Lorcaserine was derived from arylethylamine motif. This compound was formerly found in number of non selective serotonin agents. It was later modified to bicylic compound to restrict the number of conformations available within the compound. The new compound 3-Benzazepine showed high affinity and specifity for serotonin 2c receptor compared to other serotonin sub-receptors. Serotonin 2c receptor act as mediator of the appetite pathways of the brain and central nervous system and thus stimulating this particular receptor causes the suppression of appetite which further reduces food intake. This leads to significant reduction in the amount of fats synthesised because of less energy intake and stored, thus reducing body weight.

Serotonin 2A and 2B receptors mediate the pharmacology of the risk factors associated with the former non selective serotonin agents and to avoid activating these two receptors were important.

This particular drug showed full selectivity for serotonin 2c with 15 fold and 100 fold more selective compared respectively to serotonin 2A and Serotonin 2B receptors. This selectivity increased the efficacy of the drug and reduced the unwanted side effects which were major issues for anti-obesity drug.

Preclinical studies show that Lorcaserine undergoes rapid absorption and reaches maximum plasma concentration within 2 hr after oral administration. It has volume distribution of approximately 252 L in adult of 92.5kg. Lorcaserine is mainly excreted through urine and the major urinary metabolite is N-carbamoyl glucoronide and there is circulating sulfamate metabolite in the plasma.

This new drug will be used for obesity and over-weight patients in combination with calorie control and regular physical activity. This drug was effective in dropping weight and it showed improvements in risk factors associated with obesity such as cardiovascular disorders. This drug was effective to cause weight loss in obese and over-weight patients which has at least one risk factor associated with obesity such factors are hypertension, cardiovascular disorder or dyslipidemia.

The drug passed three clinical trials which were randomized, double blinded, placebo-control. More than 3000 obese and overweight patients participated in phase II and III to assess the efficacy and safety of the drug. Phase II trial assessed 469 obese patients in the range of 18-65 years of age. In this phase patients which got chronic diseases or diabetes were excluded.  All patients took part the trial obtained lifestyle modification such as maintaining exercise pattern with reduced calorie diet. These patients were treated with either the placebo or Lorcaserine at 10 mg q.d, 15 mg q.d and 10mg twice daily for 12 weeks. Changes in body weight were constantly measured to check any weight loss. More than 50% of patient lost 5% or more of their body weight while 2.3% of the patients treated with placebo lost at least 5% of their body weight.  Reduction was also observed in waist circumference and cholesterol level.

In phase III trial the efficacy of the long term use of the drug was evaluated. The patients were treated with the drug for 2 years. More than 3000 obese patients with BMI 40-45 and over-weight patients with 27-29.9 were recruited with or without at least one associated risk factor. Diabetic patients and patients detected with valvulopahty are excluded.  Patients were either treated with Lorcaserine or placebo 10mg twice daily while undertaking exercise with calorie control. 47% of those patients treated with Lorcaserine achieved at least 5% reduction in body weight in first year.

In second year patients treated with lorcarserine were either moved to or remained in the intervention group in 2:1 ratio but patients with placebo remained in the control group. The aim of this study was to check how quick those treated with lorcaserine can regain weight. Those patients that were switched to placebo regain body weight compared to those remained taking lorcaserine.

Another phase III trial was conducted which focused on patients with type 2 diabetes. Large proportion of patients treated with lorcaserine 10 mg twice daily achieved more than 10% weight loss compared to other placebo group.

The recommended dose of lorcaserine is 10 mg twice daily administered orally and it can be taken with or without food.  It is recommended that if the patient does not achieve the target which is 5% weight loss than the drug should be discontinued as they are more likely not to benefit therapeutically from the drug. The most common side effects that non-diabetic patients experienced were upper respiratory infection, headache, dizziness and nausea. In addition to these diabetic patients experienced hypoglycaemia. Those patients stopped proceedings because of adverse events where 7.1% and 6.7% in lorcarserine and placebo groups. Most drugs that interact with lorcaserine are those agents that affect the serotonergic neurotransmitter system, such as Triptans, monamine oxidaze inhibitors (MAOI), Selective serotonin reuptake inhibitors (SSRI), Selective serotonin-nor epinephrine reuptake inhibitors (SNRI), and Tricylic antidepressants (TCAs).

Reference list

Smith. et al. (2008). Discovery of Lorcaserine. Journal of Medicinal Chemistry. Vol 51: 305-313. (This article discusses the discovery of lorcaserine and its related chemistry and how 3 benzazepine are derived and the biological evaluation)

Wang B. Bai. (2010). The use of Lorcaserine in the management of obesity. Dove Press Journal: Drug design, development and Therapy. Vol 5: 1-7. (This article discusses the use of Lorcaserine in the management of obesity taking into account the clinical trials and the outcome. The successful achievement based on the clinical trial and how this drug will be useful for the management of obesity)

Thomsen et al. (2008).  Lorcaserine a novel selective human 5-HT2c  agonist: in vitro and vivo pharmacological characterization. Journal of Pharmacology and experimental therapeutics, 325: 577-587. (This article discusses the pharmacology aspects of lorcaserine including in vivo and vitro results of the drug. Pharmacodynamics and pharmacokinetics of the drug as well

Dr. Warsame M Muuse
Keele University