Is The Blockbuster Era Over for Big Pharma?

It's been quite a ride, at least for the drug companies fortunate enough to have discovered one. The blockbuster drugs are the ones that transform companies with a flood of revenue, changing them forever in just a few short years while the patent is in force. There's a list of famous names in this category, going back to Valium from Hoffman LaRoche, through Zantac with Glaxo, and leading to the biggest of them all (so far): Lipitor (Warner-Lambert and then Pfizer).

Companies have set up their entire research structures to increase their chances of finding drugs like these. But the time for them may be ending. Many researchers (and you can count me in this group) worry that the "low-hanging fruit" has been picked by now. Drugs (and drug targets) like the ACE inhibitors for high blood pressure or the statins for cholesterol are very thin on the ground. Those were wonderful opportunities: clear biochemical choke points, right in the middle of disease processes that affected millions upon millions of potential patients, with chemical matter that could be found, assayed, and perfected. Those, I have to say, were definitely the days.

But now that we've run through all of these kinds of targets that we know about, we're left with a much harder list. (The genomics frenzy in the industry about ten years ago was set off by the thought that there might be some lay-up targets out there that no one knew about  yet). There are still plenty of diseases, of course, whose successful treatment would lead to a blockbuster drug - Alzheimer's is a good example. A general cancer therapy would be an incredible discovery. A safe drug that raises HDL cholesterol (instead of just lowering LDL) would be a winner. And everyone knows that an obesity therapy that really worked would be a massive success, too. But the problem is, we don't know how to find these things, and there's significant doubt about whether some of them can even exist.

Take cancer: there really isn't a single disease by that name, as far as we can see. There are hundreds (perhaps thousands) of diseases where cells divide uncontrollably and refuse to die off they way that they should. We've given then all the name "cancer", but that's a bit like coming up with a disease called "fever". The biochemical pathways involved can be quite different from case to case, and it's those pathways that our drugs have to deal with. So far, it looks as if we can achieve spectacular successes in narrow fields, where the tumor cells happen to depend on specific factors that we can shut down. But most cancers have multiple weapons firing, and most cancers are (so far) too tough for us. The odds of one drug being able to do the trick are vanishingly long.

The same goes for obesity. Human feeding behavior is complex, and boy, is it well backed up. There are multiple redundant feeding pathways with exta backup redundancy backups, because every species whose members could lose their appetites easily is now dead. Finding a single drug that could thoroughly alter food intake - well, one that does it without making people violently ill, that is - is nontrivial at best, and completely impossible at worst. Considering the number of promising anti-obesity drugs that have crashed terribly, the second possibility is a pretty good bet.

Alzheimer's, though, is perhaps a better one. There may well be a single pathway for the disease, although we're not quite sure what that is. I used to work in this field in the early 1990s, and if you'd told me that we'd still be arguing about the cause of Alzheimer's in 2009, I'm not sure what I would have done. (It would have been reckless.) But if we do figure it out, and it turns out to be something a drug can alter, and we manage to do that - well, that would indeed be a big one. But it's not happening any time soon, unfortunately.

It's a frustrating business, being able to see all these opportunities but not being able to do much about them. The hope has been that research will find a way out, that we'll come up with some great new insights into these conditions which will lead us to therapies that we can't even picture now. Speed the day. It may happen. But it may not, and it may take a long time, no matter what.