I wanted to provide an update of sorts to a piece from a few years back. This was the lawsuit brought by Mark Charest against Harvard et al. over royalties relating to Tetraphase, the antibiotics company founded by Andy Myers of their chemistry department out of his group’s synthetic work in the area. Charest believed that he had been shortchanged on potential royalties, as that earlier blog post details, but he and Harvard eventually reached an out-of-court settlement.
It would be interesting to know if that was a cash transaction, or if Charest just got the royalty rates he was seeking. That’s because the company’s lead antibiotic, eravacycline, has been having a rough time of it. The compound failed a clinical trial in 2015, and a few days ago, news came that it had missed endpoints in another, both of them in complicated urinary tract infections. Eravacycline was well tolerated, but the trial was trying to show non-inferiority to another antibiotic entirely (Merck’s carbepenem compound ertapenem), and it did not. It also missed another primary endpoint in response rate data. (The previous urinary infection trial was aimed at non-inferiority to levofloxacin).
Eravacycline is a fluorinated tetracycline, of a sort that would be probably very difficult to come by other than through total synthesis. It has demonstrated non-inferiority (versus meropenem) in complicated intra-abdominal infections, and the company has submitted an NDA for that indication. But overall, it has not been easy for Tetraphase, as the stock price demonstrates: back just before the 2015 failure, TTPH hit $50/share, and it’s currently just over $2. This in a biopharma bull market.
This history illustrates several things about antibiotic development. You may, for example, be wondering about all this non-inferiority stuff. That’s a route to approval because of drug resistance – it’s expected, naturally enough, that antibiotics of different compound/mechanistic classes will be able to pick up the slack for each other as resistant organisms develop, so if you can show that a new agent is at least not inferior to an existing one of another class, then the drug is presumed to have value – soon enough, anyway.
There’s a perception, among people who don’t actually know what they’re talking about, that antibiotic development must not be all that bad. After all, you have direct assays to kill the exact organisms that cause infections (and their variants), and you can see just how potent various compounds are in the most direct way possible. The animal models aren’t bad, either – if you can clear infection in a small mammal, your chances of doing so in a larger one are pretty decent. The connection with human disease is (in many cases) admirably close. The problem is finding compounds that will actually do anything useful in these assays. Having tried some of that myself, I can testify that it is quite painful (and believe me, I didn’t get to experience all the field has to offer in that line).
Good bacterial targets are not all that easy to come by, and when you do find them, screening them against (even very large) compound collections often yields nothing actionable. And if your assay is against the protein target alone, you may well just be fooling yourself, because actually finding active compounds that will get into whole living bacterial cells in useful amounts is extraordinarily frustrating. Bacteria, after all these years of fighting it out, have evolved layer after layer of defense mechanisms to keep that very thing from happening, and they’re capable little creatures. Even if you do take them unawares, it won’t be for long – their rapid generation times (and their annoying tendency to actually speed up their mutation rates under stress) mean that they’ll probably find a way out of your trap pretty soon.
So I wish Tetraphase well. We most definitely need new antibiotics, and as an organic chemist I’m glad to see total synthesis potentially riding to the rescue. But it’s a hard business!