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Zafgen’s Second Act

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.

11 comments on “Zafgen’s Second Act”

  1. Morten G says:

    Very jealous of insects and their hemolymph trehalose. Seems like a much better solution than blood glucose.

  2. Wavefunction says:

    The Better than the Beatles problem.

  3. steve says:

    Weird choice. It’s going to be difficult for an injectable to compete with the large number of orally active anti-diabetes drugs out there. As an anti-angiogenic compound it might have been an easier road to go after an oncology indication. Diabetes meds face huge hurdles in safety after the Steve Nissen fiasco, where he claimed PPARgamma drugs (rosiglitazone and pioglitazone) had cardiovascular safety issues that later proved not to be the case. Now all diabetes drugs need very large and expensive cardiovascular outcome trials for approval. It will be a very high bar for Zafgen to meet; simply showing that the drug doesn’t cause blood clots won’t be enough. Oncology is much more straightforward as the patients are dying and safety is not as much of a paramount concern as diabetes, where patients will need to take the drug for years or even decades.

    1. Jane says:

      They might be able to get a foot in the door by focusing on refractory patients. Of course that adds to the efficacy hurdle. Refractory patients are refractory for a reason.

  4. KN says:

    Beloranib, not belonarib.

    1. Derek Lowe says:

      How true – just fixed it. Thanks!

    2. Mark Thorson says:

      I sometimes wonder if pharma companies create obfuscated generic names to promote their branded name. Look forward to Soothall [Thorson Pharmaceuticals brand, xyzqwxib].

      1. Hap says:

        But in the alien pain relief market, xyqwxib is a blockbuster. Win-win!

        1. Pennpenn says:

          Yeah, if you buy into Zarkon & Yipslarg’s hype machine…

      2. Diver Dude says:

        If you wonder about this, you’ve clearly never been in a product branding strategy meeting. Snake oil salesmen are saints in comparison ☺

  5. Adam Hallett says:

    There weren’t any patient deaths in the clinical trials for obesity. They made a big mistake choosing Prader-Willi for their big push.

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