BiDil's Bid for a Narrow Label

The FDA's Cardiovascular and Renal Drugs Advisory is meeting today to discuss BiDil, a treatment for congestive heart failure developed by NitroMed (Nasdaq: NTMD  ) . Even though the drug is a formulation of two easily available generic medications, I recently wrote about my high hopes for it. Now the moment of truth has arrived. Although things appear to be going NitroMed's way, there is a dark horse spoiler looming in the shadows that should keep investors on their toes today.

The African American Heart Failure Trial (A-HeFT) study that forms the backbone of NitroMed's application produced compelling evidence that BiDil reduces mortality in African Americans with heart failure. As I noted previously, the strength of the clinical package argues for approval, and options trading in NitroMed indicates that most investors feel the drug will get some form of market clearance.

The FDA is making it clear that that presumption is warranted. In a briefing document released yesterday, the agency said "the safety profile of BiDil in A-HeFT was not very different from that of placebo." The FDA concluded that "BiDil could be safe and effective in African American subjects suffering from heart failure."

Interestingly, the questions the FDA is posing to the panel today hint that BiDil might be given a broader label than NitroMed originally sought.

The panel will weigh several questions today, including:

A-HeFT enrolled only the subgroup in which BiDil appeared to work in V-HeFT I [Vasodilator-Heart Failure Trial, an earlier, all-races trial]. The strength of evidence is fairly strong that BiDil works in that subgroup [i.e., African Americans]. How strong is the evidence that BiDil does not work in the subgroup excluded from A-HeFT [i.e., other races]?

And:

Should BiDil be approved for the treatment of heart failure? If so. to what NYHA [New York Heart Association] Classes do these benefits apply?... [And] in whom should it be indicated?

While I still very much doubt that the panel or the FDA will approve the drug for use in anyone but African Americans, a surprise decision to extend the label to heart failure patients of all races would have a huge impact on NitroMed -- ironically, it would have a negative impact. The alternative is for the FDA to do something unprecedented -- approve a race-specific medicine. That's the road it will probably take, but it poses some difficulties. As the FDA briefing document notes:

What is problematic in relating the effect observed in A-HeFT to race and interpreting it at the pathophysiological or molecular level is the definition used, an old-fashioned way of determining race which relies one's perception of one's race.

In other words, definitions of race are slippery, and it would be nice to know why this drug works in some people and not in others at a molecular or genetic level. Race may turn out to be a simple but blunt tool for deciding who will benefit from the drug, one that stops the drug from going to non-blacks who might benefit and that pushes BiDil to some African Americans who will not.

While this problem will likely fall on the prescribing physician, it does point to some significant potential off-label use for BiDil in non-African-American patients -- namely, among anyone who does not respond well to ACE inhibitors. While most whites respond well to ACE inhibitors, many blacks do not, and one of the presumptions about how BiDil works is that it controls hypertension among African Americans who are not achieving adequate control otherwise.

But the distinction between who does and does not respond well to ACE inhibitors is not necessarily clearly cut along racial lines (which aren't clear cut to begin with). Some of the discussion today will likely explore why BiDil works in some people and not in others, and by exactly what mechanism.

The huge irony is that if BiDil is approved for African Americans only, the drug will have patent protection to 2020. That's because patents based on this demographic were filed after studies showed the drug was ineffective in a broader population. If the drug is approved for a general heart failure audience, older use patents will apply and the drug would appear to have exclusivity only to 2007. What would seem like a win for NitroMed would turn out to be a major liability.

It does, however, appear quite likely that BiDil will be approved for any African American with heart failure, not just those who are resistant to ACE inhibitors, as the proposed label had suggested. And doctors may conclude that it makes sense to try the drug on anyone else with heart failure who is resistant to ACE inhibitors -- an eventuality that could significantly expand the market for BiDil.

More likely than the distant possibility of an all-race approval is the possibility that the FDA will grant approval for NYHA Stage II (mild/moderate) heart failure. The strongest evidence of efficacy is in more advanced Stage III and IV patients, since these were the patients enrolled in the A-HeFT study, but the agency is considering the possibility of a broader label. There were significant numbers of Stage II patients studied in earlier trials, and there may be enough support to grant a wider approval -- which would be good news for the company.

So despite the fact that the FDA is signaling a likely approval of BiDil, there are still a couple of issues for investors to bite their nails over. Still, NitroMed is going into this meeting with a good chance of ending up with the best of all worlds: A broad indication in a population that gives them exclusivity for the next 15 years, and a bit of justification for off-label use in an even broader population.

Karl Thielis an analyst forMotley Fool Rule Breakers, which regularly covers the biotechnology industry. Karl does not own stock in NitroMed. The Motley Fool has adisclosure policy.


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