A perfect example of regulatory risk…

I’m confident that most of the readers of this blog are familiar with Zafgen Inc. and their new obesity candidate ZGN-433.  The company is hot right now and for good reason: in a Phase 1b study, ZGN-433 produced a median weight loss of 1 kg (2.2 lbs) per week and follow-up cardiovascular data showed “rapid and significant” improvement in LDL, cholesterol, triglyceride and C-reactive protein levels.  To give you an idea of how impressive this level of weight loss is, FDA guidance requires obesity drugs to produce at least a 5% decrease in body weight (over and above that seen in the placebo group) over a period of one year.  ZGN-433 produced a median weight loss of 3.1%, compared to the placebo, in 26 days.

You might be thinking, if these results hold for the phase II and phase III trials, Zafgen has a slam-dunk here!  According to the CDC, 34% of adult Americans are obese and another 34% are overweight.  What a market potential!  Blockbuster?  Of course!  We’re talking mega-blockbuster here!

Not so fast!

In the past year, three different obesity drugs have been rejected by the FDA: Qnexa (Vivus), Contrave (Orexigen Therapeutics) and Lorquess (Arena Pharmaceuticals).  They were all rejected for rare, yet serious safety concerns ranging from birth defects (Qnexa) to cardiovascular issues (Contrave) to tumors in a rat model (Lorquess).  What is really surprising is that two of the drugs (Qnexa and Contrave) are combinations of previously approved drugs.  The rejection of Contrave, a combination of naltrexone (an opioid antagonist) and bupropion (an anti-depressant/smoking cessation aid), was particularly surprising since both of the drugs in the combination are known for their high level of tolerability and safety.  Of course, drug combinations can produce side effects that aren’t seen when either drug is used alone, but to reject Contrave despite the panel’s 13-7 vote to approve?  What’s going on here?

Well, the FDA is doing its best to predict the future and it doesn’t like what it sees.  For the same reason that obesity is such a lucrative market (the huge patient population), it is also wrought with safety issues.  The FDA is concerned that if an effective obesity drug were approved, it wouldn’t be just obese people taking it.  Sure, in the beginning doctors would reserve the drug for the truly needy, those who have tried to lose weight but have failed and are experiencing serious health consequences as a result.  But the FDA knows better.  Soon enough, people who are 10 or 15 lbs overweight would be taking it.  Then, people who want to lose those stubborn last 5 lbs would somehow get their hands on it (probably through an online pharmacy).  After that?  Well, if it works so well, why not just take it all the time, even if you’re not overweight?  Or, if you want to make a weight class for wrestling, it can’t hurt right?  And so on and so on.  Soon enough, tens of millions of Americans will be taking the drug and likely a good percentage won’t be following the label or their doctor’s directions.  The risk of <insert terrible side effect> is only two in one million?  Well, pretty soon there will be enough patients crippled by the drug to form a line out of the back of the room during the congressional hearings.  I’m sure it’s scenarios like this that cause the head of the FDA to wake up in the middle of night, her heart racing and covered in sweat as she envisions her career going down the drain.

So where does that leave Zafgen?  In a tight spot, indeed, but they do seem to have a game plan.  In a Xconomy interview, Zafgen’s CEO, Thomas Hughes, says he’s already thinking about how to develop a REMS (Risk Evaluation and Mitigation Strategy) for ZGN-433.  The company plans to target only the severely obese patient population and could use the REMS to control which doctors can prescribe the drug, which patient can receive the drug and which pharmacies can fill the prescriptions.  It’s a great preemptive strategy for when it comes time to submit the NDA.  Another encouraging factor is that the drug can only be administered via injection; no pills here.  Normally if a drug can’t be taken orally it would be viewed as a negative, but in the eyes of the FDA, that will likely be seen as an additional barrier to widespread use.

It will be interesting to see how the ZGN-433 program works out; an effective treatment for obesity is desperately needed, not only for the patients affected, but also for the country as a whole as healthcare costs continue to increase, in large part due to diseases like diabetes and heart disease where obesity is a major risk factor.  I’ll keep an eye out for any news from Zafgen and be sure to post any relevant updates.

Comment: It’s interesting to note that Zafgen has only three full-time employees.  It’s a great example of the “virtual biotech” model that I touched upon in one of my earlier posts: Pitching to a biotech venture capital firm: what not to do.

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