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Arena's (NASDAQ:ARNA) Lorcaserin (Belviq) is likely to become a blockbuster drug, and a lot of investors are looking forward to its launch. The molecule, as we know now, acts by stimulating the serotonin (5-HT2C) receptor in the brain to regulate appetite and mood. It is also expected to produce an average of 3.0-3.7% weight loss in one year.

However, we need to be very cautious about what exactly we are expecting from the drug. This is warranted caution, especially after the hoopla around the launch of Vivus's (NASDAQ:VVUS) Qsymia which ultimately led to an anticlimax. The anticlimax centering on Vivus resulted from over-expectation and under-delivery. The stock went up above $30 riding on those high expectations, and is currently crawling around $10 levels in its anticlimactic stage. Let not the same thing happen to Belviq.

I remember, during school tests, some of the better students would keep going back to their books for a last minute check. In this article, I am going to do some of my own last minute checking on Belviq, and from a completely different angle. The angle is the broad mechanism of the Lorcaserin molecule, which I will classify below into a certain type, and see how effective that type itself has generally been.

Let me begin, then, by highlighting several biomedical mechanisms that have been used over the years to target obesity. This will not only help us classify Lorcaserin, but also see whether it - and the mechanism, in general - exclusively targets obesity or is just a supplementary medication technique, or even a combination therapy to reduce fat or hunger in obese patients.

3 Biomedical mechanisms for treating obesity

1: Altering the neural signal in the brain to regulate appetite

1a: Appetite is regulated by Serotonin. Overproduction of Serotonin causes cardiac valve disorders. However, it is the primary target for anti-obesity R&D because it creates a feeling of well-being and satiety. So, increase in Serotonin causes you to eat less; at the same time, increased levels of serotonin causes fatal side effects, especially in the heart.

The mechanism for increasing serotonin levels is to instigate 5HT transporters in the body. This is what molecule like fenfluramine and others do. However, these molecules and associated drugs are known to cause heart problems.

Lorcaserin works in ways similar to fenfluramine. It activates the 5HT2C receptor in the brain and increases serotonin level to reduce food intake and satiety. It is believed that selective 5HT2C agonists have lower risk of cardiac valve enlargement compared to fenfluramine due to their specific structure. But, non-selective activation of 2C receptor has multiple side effects similar to 2A and 2B receptors despite successfully reducing hunger.

We must remember that the body has no natural or induced mechanism to control serotonin levels, and it has no flushing mechanism to remove extra serotonin. Lorcaserin only increases serotonin, it does not control it. Therefore, there is possibility of cardiac side effects with increasing doses of Lorcaserin. This is the precise reason the FDA also wants six more post marketing study to evaluate long-term cardiac risks.

In contrast, there are a few molecules such as the Glucagon-like peptide-1 that alter the neural signal by understanding the peptide expression pattern in the brain with better efficiency in weight loss.

1b: Glucagon-like peptide-1 (GLP-1) is one such molecule that can be used as supplementary medication for weight loss (it is mostly used for type-2 diabetes). GLP-1 is a GI tract hormone, secreted from the intestine in response to food intake. This enhances the secretion of insulin and inhibits glucagon secretion and also suppresses food intake and appetite. Victoza (liraglutide) from Novo Nordisk (NYSE:NVO) and Byetta / Bydureon (Exenatide) from Eli Lilly (NYSE:LLY) are two successful GLP-1 receptor agonists primarily used for the treatment of diabetes by lowering glucose levels.

A Meta analysis clinical study was conducted over a large population with 3,395 participants with GLP-1R and 3,061 control group received placebo, oral anti-diabetic drugs or insulin to determine weight loss in obese patients with or without type 2 diabetes. The result proved that GLP-1R agonist groups have higher weight loss compared to controlled group. This will perhaps be a route to developing another anti-obesity agent with attractive weight lowering effects. The good thing is that this mechanism does not influence serotonin levels.

In addition, there are a few other mechanisms available for anti-obesity medicines that can either dissolve fat storage or alter nutrients adsorption within the gastrointestinal (GI) tract.

2: Targeting adipose tissue to alter fat storage and promote fat oxidation

Drugs have shown their potential in preclinical studies that target metabolic tissues, such as adipocytes (fat cells) in liver and skeletal muscles. But, they are unsuccessful due to severe side effects. This is evident from the two FDA approved drugs targeting adipose tissue as mechanism:

a) Sibutramine or Meridia from Abbott (NYSE:ABT), since withdrawn, a neurotransmitter reuptake inhibitor that suppresses appetite while acting in the brain; and

b) Tetrahydrolipstatin (originally marketed by Roche as Orlistat or Xenical), a pancreatic lipase inhibitor that limits fatty acid formation and inhibits their adsorption in the GI tract.

Neither of them is effective medication for weight loss due to severe side effects.

In addition, another product Rimonabant (Acomplia) from Sanofi-Aventis (NYSE:SNY), a cannabinoid receptor 1 antagonist, is an appetite suppressant, and acts directly on adipose tissue. However, this product is considered to have mood altering effects, and was withdrawn from the market. Furthermore, the blood-brain barrier remains an obstacle for therapies, which is controlled by the central nervous system.

Therefore, mechanisms other than inhibition of lipases are unlikely to be effective in decreasing intestinal or cellular fatty acid adsorption. However, no drug using this mechanism has yet reached clinical development because they were unsuccessful in their targets or have severe side effects.

Lastly, we have the therapy used to change absorption mechanism within the GI tract either by preventive measures or surgical procedures.

3: Alter nutrient adsorption within the GI tract

Surgical process is one of the effective methods for long-term weight loss in severely obese patients that can happen by altering nutrient adsorption within the GI tract.

This is possible when we are unsuccessful in all preventive measures (non-surgical process) that involve combined therapy of dietary supplement and physical exercises. Normally, surgical procedures include two processes: a Restrictive procedure that works by reducing the amount of food consumed at one time; and by altering the entire digestion process through Malabsorptive procedure. But, risks are always associated with weight loss procedures like with all surgeries.

There are several drugs and drug candidates that act on above mechanisms either as single or combined therapies to target obesity; some of them are unsuccessful in the market while others are in development stages; however, almost all have severe side effects.

Table1:

(click to enlarge)

Source: Anti-obesity pipeline

Conclusion:

I have highlighted several biomedical mechanisms that have been used over the years to target obesity, directly or incidentally. Conventionally, monotherapies like Belviq seem like successful potential candidates for weight loss.

However, the picture we have painted here shows Belviq in its proper background against all other biomedical developments in obesity. This backdrop shows us the elements of uniqueness in Lorcaserin - there aren't many - and indicates to us just what the future might prove for the drug. While it has some unique properties, like being a selective agonist for 5HT2C, we are yet to fully understand how effectively this mechanism will use serotonin to control appetite while controlling its side effects on the heart.

Source: A Study Of Arena's Lorcaserin Against The Backdrop Of Several Anti-Obesity Mechanisms