David's New Book

Wednesday, January 14, 2015

Roche Does it Again!



Yesterday, Roche, Meiji and Fedora pharmaceuticals announced a deal that could be worth up to $750 million to develop OPO595, Fedora’s phase 1 DABCO B-lactamase inhibitor. Roche will develop the drug throughout the world with the exception of Japan where Meiji will obtain commercialization rights.  I was unable to find the details of the deal – but this is the broad outline according to a Fedora press release.

There are a number of fascinating aspects to this.  The President and CEO of Fedora is Christopher G. Micetich, the son of Ron Micetich.  Ron was the discoverer of tazobactam, one of the early inhibitors of B-lactamase and marketed by Wyeth as piperacillin-tazobactam – a billion dollar plus product. I was involved in the early days of tazobactam showing that piperacillin would be a good partner for the inhibitor.  Later, I helped develop the drug in the clinic and even later was involved with the marketing strategy for piperacillin-tzobactam for Wyeth. The world is so small . . .

Once again, this deal clearly shows that Roche is serious about getting into antibiotics.  This will be their second major clinical stage deal after their deal with Polyphor late in 2013. It also leads me once again to question exactly what they are doing.

As far as I can tell from published data from ICAAC in 2013, OPO595 is a DABCO type non-beta-lactam beta-lactamase inhibitor – that is – it is similar to both avibactam and Merck’s MK-7655. Avibactam (partnered with ceftazidime) has completed one phase 3 trial and will complete another soon.  The FDA’s advisory committee has already voted to approve avibactam (combined with ceftazidime) mainly based on its phase 2 data.  Merck’s MK-7655 is partnered with imipenem and is still in phase 2 trials as far as I can tell. But both of these DABCO inhibitors are years ahead of OPO595 which is only in phase 1. Why would Roche leap into a third DABCO inhibitor.  Perhaps they are thinking about its “enhanced” anti-bacterial activity beyond its ability to inhibit beta-lactamases.  But my experience (and I have a lot of it) with this class is that some antibacterial activity is typical.  Avibactam can have activity against E. coli at as low as 4 ug/ml.  Novexel had a DABCO compound, NXL-105, with activity against Pseudomonas aeruginosa that was thought to be partly related to its ability to bind PBPs of Pseudomonas.  In fact, the entire DABCO series started at Roussel-Uclaf  targeting antibacterial activity through PBP binding and was only later discovered to have potent B-lactamase inhibition activity. So I’m not convinced that OPO595 will have much of an advantage over the other DABCOs based on data published so far.

One potential strategy for Roche/Meiji would be to try and quickly develop a combination with a monobactam similar to the aztreonam-avibactam combo that is in phase 1 trails at AstraZeneca. This combo has the advantage of being active not only against Gram negatives bearing extended spectrum beta-lactmases, but also against those harboring metallo-beta-lactamase like the NDM-1 superbugs.  Many of us have been screaming at AZ to develop their version of this quickly for years – but so far – no dice. Here Roche/Meiji might try and beat their competition to market with this combination targeting NDM-1 like superbugs - and go on from there. But will this pay off? We await further developments . . .