Thursday, October 21, 2010

Why a Lorcaserin Phentermine Drug Interaction Study is Needed Now



Tomorrow is the PDUFA date for Lorcaserin and everyone expects a Complete Response Letter from the FDA.  The big question will be what is required to gain approval the next go around.  Regardless of the outcome, I think it is important that Arena begin plans for a Phase IIIb study to look at Drug Interaction effects of taking Lorcaserin in combination with Phentermine.
Locaserin has excellent efficacy on its own and unfortunately, the short-sighted FDA (and Wall Street) has focused only on mean, placebo-adjusted weight loss figures, which in Lorcaserin’s case is about 3%.  On the surface, that sounds terrible; however, when you look at the meaningful numbers, it is deceptive and doesn’t give a fair analysis of the real-world efficacy.  I’ve said before that weight loss medications are ‘self-regulating.’  Only patients who experience results are likely to continue to take the drug, it is just common sense.  I’m sure many of you have had a 10-day prescription for an antibiotic.  You are supposed to take the whole bottle.  Well after 6 or 7 days, when you are back to feeling great, most stop taking it.  Same is true with weight loss drugs.  If after a few weeks, you aren’t losing weight, you stop taking it. 
This is why Completer analysis is so very important in looking at weight loss drug efficacy.  Of course in the FDA’s review of Lorcaserin, at least as it pertained to the Advisory Committee, they focused mainly on the mean weight loss statistics.  There was no discussion whatsoever about the excellent placebo-results on Lorcaserin either.  More patients lost weight in Lorcaserin’s Placebo-arm than in any other weight loss trial.  That is an indicator that the trial was very well-run and patients stuck to the diet and exercise plan.  Arena could have easily have been less diligent in the trials regarding counseling and the placebo results would have been more in line with those of Qnexa’s trials. 
I could practically guarantee that not ONE of the panel members could tell you what Arena’s categorical efficacy was without digging through Arena’s Briefing Documents.  They could probably all tell you that the mean, placebo-adjusted weight loss was only 3%.
Here are the facts for Lorcaserin’s Completer weight loss analysis (patients who stayed in the trial for a full year):
-          Average Weight Loss for Completers was 8%
-          One-third of patients lost at least 10%
-          The Top Quartile lost an average of 35lbs
-          Patients were TWICE as likely to lose more than 5% of their body weight on Lorcaserin
-          Patients were THREE TIMES more likely to lose more than 10% of their body weight on Lorcaserin
Those statistics are not ‘modest,’ they are impressive.  Yet the FDA and Advisory Committee focused only on placebo-adjusted mean weight loss for the Risk vs. Benefit discussion.  We already have proven that the Risk part of the equation was overblown due to the FDA’s errors in calculating Neoplasm risk, which they continue to ignore.  Had the FDA used common sense in spending some time discussing Completer analysis and without the neoplasm risk fabrication, the results of the panel would have been much different and we’d be awaiting an approval and not a CRL.
So if Lorcaserin’s efficacy is so good for over half the people who take the drug, then why bother doing a drug interaction with Phentermine?  One of the obvious reasons is that it is highly likely some physicians and weight loss clinics will regularly prescribe the two in combination.  Phentermine is still the only approved weight loss therapy on the market that meets the FDA’s 5% weight loss guideline and is the most widely prescribed drug for weight loss.  Unfortunately, you can only take it for 13 weeks at a time because it is a Class IV controlled substance and when patients stop taking it, they quickly gain it back.
I find it interesting that the FDA has spent little time following their own guidelines when it comes to evaluating combination weight loss therapies in the case of their view of VVUS’ Qnexa.  The FDA states that a combination drug should “exhibit a potentially meaningful improvement in the safety profile compared to the individual components.”  Not only does Qnexa fail to do that, but it demonstrably compounds the worst safety risks commonly associated with its constituent drugs!  Qnexa is only 3% more effective than Phentermine used alone.  VVUS is basically taking the most effective generic, combining it with a small amount of Topiramate (which increases the side effects and risk) and saying, take these two together for long term weight loss.  Qnexa is a retread of generics ‘packaged’ to show great efficacy, when in reality, it isn’t much more effective than Phentermine as a mono-therapy.
Phentermine is a powerful drug for weight loss but should still be limited to 13 weeks of use.  It is outlawed in a number of countries.  However, it could be a powerful tool combined with Lorcaserin to speed up early weight loss and introduced later in the treatment cycle when the patient hits a weight loss wall.  I suspect you would see Fen-Phen type results of 30lb average weight loss, with a far better safety profile.
I’d propose a 26 week trial to compare the following:
1)      Phentermine + Placebo for 13 weeks followed by Placebo for 13 weeks.
2)      Phentermine + Lorcaserin for 13 weeks followed by Lorcaserin for 13 weeks.
You’d want to look at Adverse Events during the first 13 weeks, weight loss at 13 weeks and then at 26 weeks.  I’d also consider echos at baseline, 13 weeks and 26 weeks.  I would bet you’d average 10% weight loss at 26 weeks with more people keeping the weight off in the Lorcaserin group than Phentermine + Placebo group at the end of 26 weeks. 
We already know the combination works well in animal studies as evidenced by this graph found in one of Arena’s patents for Lorcaserin.  (Compound C is Lorcaserin)

This trial would demonstrate that the efficacy and safety of a Lorcaserin + Phentermine therapy is excellent.  For most patients, Lorcaserin as a mono-therapy would be enough but for others, using in combination with Phentermine and then going to just Lorcaserin for maintenance would work even better.  It would add to the body of evidence that Lorcaserin is a powerful and much needed tool for physicians.  This combination would be just as effective and far safer than Qnexa for long term use.
We are spending close to $170B a year treating Obesity in this country yet the FDA continues to evaluate weight loss drugs as a vanity drug instead of an invaluable tool to improve the health of our nation.  The average completer weight loss with Lorcaserin would reduce a person’s chance of becoming a Type II diabetic by 58%.  A diabetic reduces their average life span by a decade.  Not only can Lorcaserin improve patient’s quality of life, it could save our country Billions of dollars a year in healthcare costs.  It is sad the FDA can’t see the forest through the trees but what else is new? 

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