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The founding members of Chimera Research Group have over 50 years of combined experience in the biotech and pharmaceutical sector. Their experience includes work at Investment Banks, Hedge Funds, Pharmaceutical Companies, top-tier Universities, and the U.S. Food and Drug Administration (FDA).... More
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  • Why Arena’s Lorcaserin Will Not Be Used In Combination With Phentermine 6 comments
    Jul 7, 2010 7:55 PM | about stocks: 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:
    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.


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Comments (6)
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  • John Tucker
    , contributor
    Comments (390) | Send Message
     
    Jason, I ran across an interesting article (Obesity (2009) 17, 1730–1735) that would seem to suggest that there are a lot of weight loss doctors out there who don't follow the FDA's safety recommendations very closely. The authors did an anonymous survey of weight loss clinics and found that phentermine, which is recommended for short term use only, was being used chronically by most clinics as their mainstay drug, and at an average dose that was 1.5x the maximum dose recommended on the label.

     

    So I've always wondered if this Lo-Phen issue was a barrier to approval. If lorcaserin turns out to be a billion dollar drug, with 10% of patients on lo-phen, that's 100,000 patients or so on an untested combo. But I'm not aware of any precedent that would clarify how the FDA might handle this situation.
    8 Jul 2010, 08:16 AM Reply Like
  • John Tucker
    , contributor
    Comments (390) | Send Message
     
    Interesting Bloomberg article: www.bloomberg.com/news...
    8 Jul 2010, 08:47 AM Reply Like
  • Chimera Research Group
    , contributor
    Comments (388) | Send Message
     
    Author’s reply » Hi John,
    Thanks for your comments. I do realize, and the FDA has noted obesity docs are quite aggressive in prescribing meds.
    The bloomberg article was quite interesting, suggesting the FDA will not look at historical Fen-Phen data- though I doubt it. Why else would Lorcaserin have been tested on 7000 subjects? And if a blockbuster in waiting, why such a low market cap? People know there may be speed bumps. Eisa has backended all the payments post approval. Lief has suggested if FDA requests more trials, they'll be ready.
    On the other hand, Vivus is expecting bigger upfront and higher profit sharing:
    www.bioworld.com/servl...
    8 Jul 2010, 01:40 PM Reply Like
  • Joseph Krueger
    , contributor
    Comments (283) | Send Message
     
    The partnership was a good deal for Esai and suggested that they had very little faith in lorcaserin. Basically, they threw ARNA a $50 million bone to cover some development expenses, dangled another $150 million carrot, and said "we will manufacture and market it for you for a large cut of the sales" . If they had their own preclincal/clinical development program for a drug like lorcaserin they would have spent close to a billion dollars (like ARNA did) to get this far. So they got an 80% discount, from that perspective...
    19 Sep 2010, 10:28 AM Reply Like
  • Joseph Krueger
    , contributor
    Comments (283) | Send Message
     
    "Until there is evidence to the contrary, there is likely to be a warning against the use of Lorcaserin in combination with phentermine."
    I think this is one major factor in the panel's hesitation about lorcaserin. It is an obvious off label use.....you can't let Lorquess on the market until you know more about this combo, even if just preclinically. Personally, I think the panel was looking for reasons to reject lorcaserin based on this fear, and found plenty of basis in weak clinical efficacy and preclinical rat studies.....plus the day before they seemed to feel it would be OK to leave Meridia on the market....why let another weakly effective diet drug with known risks on the market when Meridia is there already?
    19 Sep 2010, 10:24 AM Reply Like
  • Chimera Research Group
    , contributor
    Comments (388) | Send Message
     
    Author’s reply » You could hear the crazies on the boards raving about a Lor-Phen combo. $15 billion dollar drug! What crap.

     

    Actually, I think FDA should let all three on the market- with REMS. FDA has greater power in that area now. I believe Meridia sales fell to something like $50M now over its troubles.
    Let the market decide- start with Vivus drug, can't take the SEs? switch. Probable multibillion dollar market, majority goes to Vivus, the other two split the rest. Don't know about Orex, but at least subgroup of Arena have good benefit.
    19 Sep 2010, 11:59 AM Reply Like
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