F. Scott Fitzgerald was a very good writer, but one of his most famous lines is about as wrong as it can be. It’s actually a cliché to point out the complete wrongheadedness of “There are no second acts in American lives”, such are the huge number of counterexamples. And that goes for biopharma, too.
I’ve written about Zafgen several times on the blog, but most recently to survey the wreckage left after the failure of their interesting epoxide-laden drug candidate, beloranib. The company originally set out to target methionine aminopeptidase 2 (MetAp2), but as they developed beloranib for Prader-Willi syndrome it turned out to be working through other mechanisms. They’ve clearly never lost sight of that original story, though, because (to the surprise of some observers) they’re back with another related compound (ZGN-1061) for the same target, this time in diabetic patients. It’s described as being in the fumagillin class, so it’s surely another epoxide-based compound (which is the mechanism by which it inhibits its target).
Here’s a piece by Adam Feuerstein detailing their comeback try. The company has spent a good amount of time and effort working out what went wrong with beloranib (safety problem due to fatal blood clots), and trying to make sure that ZGN-1061 doesn’t have that same profile. I have to give them a lot of credit for that, and a lot of credit for having been able to keep and round up enough resources to be able to do it at all. A wipeout like beloranib would have sunk many small companies, but here they are heading back into the clinic.
This clinical effort, though, is going to be more expensive than the last one. The benefits of going after an unusual population like Prader-Willi patients is that they are easy to identify and there is no medical treatment available. You will be the first to ever help them, and demonstrating that benefit should be a pretty straightforward proposition, clinically. Diabetes, on the other hand, is trickier. A MetAp2 inhibitor should lower circulating glucose levels (beloranib did), and there’s no doubt that that is of benefit in diabetic patients. But the tricky part is safety. FDA criteria in this area are quite stringent, and you have to do a lot of work to show that you’ve cleared the bar. What’s more, there’s a lot of competition – a whole list of drugs and a whole list of different mechanisms. It’s a crowded field with plenty of options, and making one’s way in it is going to be a lot harder (and a lot more costly) than it is in a rare disease.
I feel sure that the way it was supposed to work was that beloranib was going to demonstrate its use in the Prader-Willi population, where it wouldn’t be so hard to demonstrate benefit and approval had much better chances. Then it (or a followup) could go for the larger diabetes market, using the rare disease revenue stream. This is a common strategy: get a foothold in the smaller, underserved patient population and then try to expand. But now Zafgen is going to have to do that the hard way, and I wish them the best of luck.