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Lorcaserin

Arena Pharmaceuticals has developed an anti-obesity drug called lorcaserin hydrochlroide (ADP-356). It works by activating a very specific receptor on brain cells. This in turn leads to decreased appetite. It has completed phase three clinical trials, and the company filed a new drug application with the FDA in December of 2009. Unfortunately, due to concerns about tumor development in rats, the FDA denied its approval in October 2010 and requested a review of the data and possibly further animal studies.

How It Works

There is a certain chemical called serotonin (5-HT) that is a widely used neurotransmitter in both the human body and other animals. It has various actions, one of which causes a sense of happiness. This can be demonstrated by the effects of some antidepressants, like Prozac, that are in a class of medicines called selective serotonin re-uptake inhibitors. These SSRIs cause serotonin levels to be increased at the sites of nerve stimulation.

Lorcaserin Chemical Structure
[1R]-8-chloro-2,3,4,5-tetrahydro-
1methyl-1H-3-benzazepine

Differences from Past Similar Medications

In the past, drugs like Fen-Phen and dexfenfluramine utilized serotonin receptor stimulation to curb appetite. However, these weight loss drugs led to heart valve disease and were subsequently withdrawn from the market. Additionally, the illicit drug ecstasy has effects on the serotonergic system, such as causing hallucinations. Ideally a weight loss drug would decrease appetite while avoiding negative side effects.

There are several subtypes of the serotonin receptor family. Specifically, 5-HT_2C is the subtype that, when activated, produces POMC and curbs appetite. This is done in part by the decreased production of neuropeptide Y which stimulates appetite. Lorcaserin can stimulate other 5-HT receptors but has the greatest effect on the 5-HT_2C receptor.

In the 12 week Phase II clinical trial, obese patients lost 0.7 lbs to 8 lbs depending on the dose of lorcaserin taken.

In contrast, dexfenfluramine is much less selective, which consequently was the likely cause of its side effects. The 5-HT_2A receptor is activated by LSD, psychedelic mushrooms, and other hallucinogens. 5-HT_2B receptors are found on heart valves and are thought to have been activated in the cases of heart valve problems in people who took Fen-Phen.

Lorcaserin binds to the 5-HT_2C receptor 18 times stronger than it does to 5-HT_2A and 104 times more than 5-HT_2B. Additionally, it is much more selective for 5-HT_2C than many other members of the serotonin receptor class. Studies in mice show that it causes none of the behaviors induced by drugs that stimulate 5-HT_2A. At least in mice, it also concentrated 13 times more in the brain than in blood. This could mean that its effects can be localized to the brain and spare the rest of the body.

Safety and Concerns

It has not been shown to adversely affect heart valves or cause pulmonary hypertension, another concern with previous medications. It also seems to improve some of adverse effects fat tissue has on the endocrine and immune systems. Other potential disease that could be treated by lorcaserin-like drugs are: seizures, obsessive-compulsive disorder (OCD), Parkinson's disease, schizophrenia, depression, anxiety, sleep disorders, and drug abuse.

In its Phase II trial, lorcaserin was well tolerated. The most frequently reported side effects were temporary headache, nausea, and dizziness. There are three Phase III clinical trials evaluating this drug: the BLOOM, BLOSSOM, and BLOOM-DM trials. According to Arena Pharmaceuticals' web site, these trials so far showed that there was no increased risk of heart valve disease and that the only significant side effect was temporary mild to moderate headache.

After 2 years, these Phase III clinical trials showed that average weight loss was 17 lbs to 18 lbs.

As mentioned above, lorcaserin has yet to be approved by the FDA due to concerns about tumor development in rats. Further analysis will need to be done to determine if a cause and effect relationship exists and if it is relevant to humans.

Return to the Home Page or Weight Loss Drugs.

It is important you discuss any weight loss or exercise plan with your doctor. Only you and your physician can decide what is best for you. Some people have certain conditions that prevent them from doing all exercises, and goal body weights may be different for different people. You need to discuss all these things with your physician before starting any weight loss or exercise program. In addition, the dosage of any medicine may be different if it is used for weight loss and not its FDA approved indication. You should also discuss this with your doctor.

This article was written by John Vickery, MD.

References
http://www.arenapharm.com/wt/page/lho.html (accessed on 1/07/10)
MMWR Morb Mortal Wkly Rep. 1997 Nov 14;46(45):1061-6
J Pharmacol Exp Ther. 2008 May;325(2):577-87
Expert Rev Cardiovasc Ther. 2009 Nov;7(11):1429-45.
The chemical structure graphic is in the public domain and was obtained from http://en.wikipedia.org/wiki/Lorcaserin (accessed on 1/07/10)
"No F.D.A. Approval for New Diet Pill" @ http://www.nytimes.com/2010/10/24/business/24obesity.html?_r=1 (accessed 2/17/11)

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Last updated: 02/17/2011