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Why Arena’s Lorcaserin Will Not Be Used In Combination With Phentermine

|Includes:Arena Pharmaceuticals, Inc. (ARNA), WYE
It is tempting to believe that once Lorcaserin has been approved, it will be used off-label in combination with phentermine to create a safe and efficacious version of Fen-Phen, the once popular diet drug. This is not to be the case.
Some history:
Fenfluramine, the “Fen” in Fen-Phen, a potent agonist of 5-HT2B receptors, a type of serotonin receptor found in the brain as well as in high quantities on heart valves. It was approved in 1973, its enantiomer, dexfenfluramine was approved by the FDA in 1996 to Wyeth. Neither fenfluramine nor dexfenfluramine were popular diet drugs due to their mediocre efficacy. It wasn’t until 1992 when an article was published showing fenfluramine combined with Phentermine led to 15% weight loss when the Fen-Phen diet craze began. While Fenfluramine and Phentermine each on their own led to similar weight losses of around 8%, the synergistic effect of the combination allowed for use of lower doses of both drugs, but resulted in a significantly better effect.
In 1997, the Mayo Clinic documented 24 cases of women with valvular heart defects who were taking Fen-Phen, playing large role in the recall of fenfluramine and dexfenfluramine from the market. Further testing by the Mayo Clinic found about 30% of patients on Fen-Phen who were asymtomatic for heart disease were found to had abnormal echocardiographic results.
To this day, scientists are still debating how exactly fenfluramine (fenfluramine will refer to both it and dexfenfluramine) causes the heart defects, but revolves around stimulation of the 5-HT2B receptors, leading to excess cell proliferation and vascular remodeling. 
Lorcaserin is designed as a potent agonist of 5-HT2C, with greater than 100 fold selectivity over 5-HT2B, the apparent culprit in Fen-Phen. It has been tested in thousands of patients and shows no signs of causing heart defects. Lorcaserin has been shown to have mild side-effects, however, its efficacy is similar to that of fenfluramine- modest. Would it not make perfect sense to boost its effects with a dose of phentermine? After all, phentermine was not taken off the market, in fact, it is currently the number one prescribed stimulant obesity drug in the US.
Not so simple. As previously mentioned, the exact mechanism of Fen-Phen induced heart valve defects has not been deduced. It is known that Fenfluramine by itself is a culprit; it is also known that Phentermine on its own is not. But the combination of the two may increase the risk of heart problems through multiple mechanisms. Though this is far from proven, Phentermine faces guilt by association- cases of heart defects were not noticed until the two drugs were used together. A large part of this is because relatively few people used fenfluramine before the study documenting the superior effects of its combined use with phentermine. Also, in a retrospective JAMA, 2000 study, researchers showed 4.1% of untreated patients had Aortic Regurgitation, compared to 8.9% of patients who took fenfluramine only, and 13.7% of patients on the Fen-Phen combo. (Note: this was a Wyeth sponsored paper.)
Arena, being smart, has not tested Lorcaserin in combination with phentermine. If it did, even preclinical, it would have to report the data to the FDA. There is just no way to predict exactly what will happen when you put two compounds together. Arena will not be able to promote Lorcaserin as a combination pill without the studies, it will depend entirely on doctors prescribing the combo off-label. Aggressive doctors may be tempted to do just that, but I believe the FDA, with its emphasis on safety, already has that in mind. Until there is evidence to the contrary, there is likely to be a warning against the use of Lorcaserin in combination with phentermine. This warning would deter most doctors from prescribing a Lorcaserin-Phentermine combo.

Disclosure: No Positions
Stocks: ARNA, WYE