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This year a trio of obesity drugs has stormed onto the stage and they will soon face their respective FDA decisions. The trio consists of Vivus’ (NASDAQ:VVUS) Qnexa, which was already voted down by an FDA panel, Arena’s (NASDAQ:ARNA) Lorcaserin, and Orexigen’s (NASDAQ:OREX) Contrave. Following Qnexa’s jilting by FDA panel, many investors piled into Arena as lorcaserin’s side effect profile appeared the most benign of the three. Lorcaserin faces its own FDA panel on September 16. While I’m guessing that multiple issues will be discussed – including potential off-label use with fentermine – one of the issues likely to be addressed is the potential of valvulopathy in long-term use of lorcaserin. There is very good reason to believe, however, that these concerns will be little more than a distraction on the way to lorcaserin’s approval.

What is Lorcaserin?

Lorcaserin is a 5HT2C receptor agonist. 5HT, aka 5-hydroxytrptamine and serotonin, is responsible for regulating a number of biochemical pathways in the body. While we know of the existence of as many as 13 5HT receptors throughout the body, the 5HT2C receptor is located in the brain and is thought to control things like mood, addiction, and appetite. Lorcaserin appears to be reasonably selective for the 5HT2C receptor in particular. Think of the receptor as a lock, and Lorcaserin its key. When the key fits into the lock, a biochemical cascade usually ensues resulting in the drug’s desired effects. Agonism of this particular receptor leads people to feel more satiated - preventing the patient from over-eating – and may play a role in the prevention of impulsive eating. This strategy is not necessarily unique as the drug combination Fen-Phen utilized a similar 5HT receptor agonism to assist in weight loss.

Fen-Phen and Heart Disease

Fenfluramine, the infamous ‘fen’ of the weight loss combination fen-phen, was pulled from the market in 1997 for its role in heart valve abnormalities associated with users of the drug. Fenfluramine was unfortunately less selective for the 5HT2C receptors. Furthermore, its metabolite, nor-fenfluramine (the body removes the two carbon chain from nitrogen as part of the metabolism process), was especially promiscuous with the other 5HT receptors. Both molecules provided a significant agonism of the 5HT2B receptor – located within the heart. When the 5HT2B receptor interacts with a molecule that fits into it (think the lock and key again) white growths start to occur on the surface of cardiac valves. It was this interaction that was later linked to cardiac fibrosis and eventually valvular heart disease in patients taking the Fen-Phen drug combination.

Shouldn’t Lorcaserin also be an agonist for the receptor?

Yes and no. Both Lorcaserin and fenfluramine derive their activity from their structural similarity to serotonin. Lorcaserin, therefore, should show some activity for the bad 5HT2B receptor – and it turns out it does. However, Lorcaserin’s EC50 (its half maximal effective concentration) for the receptor is 804 nM, compared to as low as 23 nM for the more active nor-fenfluramine, depending on the enantiomer of the molecule (both are present during metabolism). Basically, that means the concentration of Lorcaserin in the body must be 35 times more than that of nor-fenfluramine to elicit a similar response. Furthermore, EC50 curves are sigmoidal – not linear – meaning a relatively large change in activity occurs over a relatively small concentration change making the activity nearly non-existent at therapeutic doses.

What else did Arena do to address this issue?

Because of the chance (albeit a small one due to the EC50 data), that Lorcaserin could exhibit effects similar to that of fenfluramine, a number of further steps was taken in the clinic by Arena. First, echocardiograms were taken of patients in the BLOSSOM, BLOOM, and BLOOM-DM phase III clinical trials. They were even reviewed by an independent safety board, the Echocardiographic Data Safety Monitoring Board, up to one year of treatment. In addition, to preempt the FDA concerns over longer term usage, Arena is reporting safety data along with echocardiograph data out to two years, whereas Orexigen and Vivus are only reporting data out one year. In all the echocardigraphic data and relative rates of valvulopathy out to two years, Lorcaserin showed no statistically significant increase in rates of abnormalities. Not even close to being statistically significant in all dose ranges and all time periods.


I think it’s likely that the valvulopathy issue will come up during the FDA panel as the panelists wrestle with the likely outcome data for patients taking the drug up to two years and beyond. There is, however, no data presented in any of the trials that looks in any way troubling in terms of valvulopathy. Furthermore, the potential off-label use of Lorcaserin with phentermine (the safer part of Fen-Phen) is also a concern, but only as far as its potential to produce the same valvulopathy occurrences. Expect the FDA panel to pass Lorcaserin with flying colors with respect to cardiac safety. I also think there’s a good chance that co-dosing with phentermine will be more or less given the green light – although I also think there’s a good chance they’ll expect some sort of data to be collected on the effects of the two together post market launch. I rarely hold through panel dates but I may gamble on this one if the stock price looks attractive on the night before the panel. I’m speculating that Lorcaserin will be an easy panel pass.

Disclosure: No positions.

Source: Arena's Obesity Drug Likely to Pass FDA Panel With Flying Colors