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November 3, 2011
Medivation Comes Through With MDV3100
Remember Medivation? That's the small biotech that was trying to develop a Russian compound as an Alzheimer's drug, an effort which blew up completely in early 2010. The company did have one other compound in development, targeting prostate cancer, a ligand for the androgen receptor called MDV3100.
You'll note from that link that it's a rather odd-looking compound, a thiohydantoin, which is a heterocycle that you don't see very often. The discovery of the compound is detailed here, in a collaboration between Michael Jung's group at UCLA and Charles Sawyers' at Sloan-Kettering (here's an interview with him). It's been a long road. The starting point was another known ligand, RU 59063, which comes out of research in France in the early 1990s. The whole left-hand side of MDV3100 (including the thiohydantoin) comes from that scaffold, but it behaves differently on the androgen receptor. Taking advantage of the wild and often intractable complexity of nuclear receptor signaling, it binds in a different mode than other AR ligands, and in a way that the receptor loses its ability to further bind DNA in the nucleus.
Here's the J. Med. Chem. paper (in open-access form) on the development of the series. The compounds were pushed through relatively quickly in cellular assays and in an in vivo model in mice, which allowed MDV3100 and its close analogs to stand out not only for their superior activity on the androgen receptor (which many compounds in the series had), but for their pharmacokinetics. Interestingly, the lead compound for some time seems to have been a spiro-cyclobutyl analog (RD162), but the corresponding gem-dimethyl compound was just as active and a lot easier to make, so that one became the clinical candidate.
Medivation's Phase III trial of the compound came in with data yesterday, and it was startlingly good, so much so that the trial was stopped early and the placebo group switched to the drug. The company's stock is going through the top of the chart in pre-market trading as I write, which shows that the expectations weren't all that high. But MDV3100 certainly seems to have come through, and considering how much failure we live with in drug discovery, it's nice to see something actually outperform. Congratulations to the company, and to Jung and Sawyers as well - they've added another straight-out-of-academia drug to the list, and helped to considerably advance the standard of care in prostate cancer. Good news all around.
Oh, and by the way. . .you have to wonder if this guy stuck around for this result. It all depends on what price he was in at - after today's trading, Medivation's stock might even make it up past where it was back when everyone was hoping that they had an Alzheimer's drug. Expectations!
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