And now we turn to “Why you can’t say a thing about whether a drug is any good until it’s been through all the clinical trials”, part nine hundred and seventy-five thousand, two hundred and ten. Today’s example is evofosfamide, TH-302 from Threshold Pharmaceuticals. The idea behind it seems perfectly reasonable on paper: it’s a prodrug of a nitrogen mustard compound, a classic (and classically nasty) variety of chemotherapy. In this case, though, the reactive species doesn’t get released until the drug gets into a low-oxygen environment. It has a nitroimidazole group on it, a class of compounds known to be activated under those conditions, and in this case, when there’s not enough oxygen around to intercept the pathway, the compound will fall apart to reveal the nitrogen mustard end.
A prodrug of this sort that’s activated by hypoxia would seem to be useful in a number of solid tumors, whose cellular environments are notoriously oxygen-poor. There are a number of programs underway to exploit this exact idea, with Threshold being one of the most advanced. They signed a deal with Merck KGaA (Merck-Darmstadt) to develop the compound, and earlier this year (after the drug won fast-track status from the FDA for advanced pancreatic cancer) you could read articles that would tell you about how Threshold could turn into a big deal once their trial results came in.
Or not. To be fair, one of the analysts quoted in that last link did say that the company was in for an “eventful next twelve months”, which is a bit like J. P. Morgan’s prediction that the market would fluctuate. Threshold now has the Phase III data, and it’s a wreck. The compound completely missed, which crosses out Merck KGgA’s top oncology candidate and has sent Threshold’s stock down into delisting territory. It traded at $6 to $8 dollars back when they signed the development deal, and at $4 to $6 since then, but as I write, it’s at sixty-three cents, and the survival of the company is very much in doubt.
Which is a pity. We certainly need something that will affect advanced pancreatic cancer, a diagnosis which is pretty much a death sentence under current medical knowledge. And Threshold’s idea was not a bad one at all. It just didn’t work, for reasons that are not clear. A lot of clinical results are not clear – even the good results aren’t always good for the reasons that people were expecting. Next time you feel like putting some money down on a small company that’s in Phase II with an oncology deal, consider Threshold, who were once as handsome and tall as any of them. . .