David's New Book

Monday, September 5, 2016

Superbugs vs. Pfizer and Avibactam

Over the last week or two, I’ve been trying to speak to contacts at Astrazeneca and Pfizer about the marketed compounds and the one important pipeline compound that Pfizer has now acquired.  For the most part, no one is talking because the regulatory authorities have not yet approved this deal (or so they say). There has, however, been a good deal of speculation in the press and in response to my last blog about Pifzer’s motivations here. The consensus of opinion is that this is a move to bolster the products being sold by their hospital sales force. If this is true, what does it say about aztreonam-avibactam which is still lingering in early clinical development at AZ?

I have written previously about the sad (some would say deplorable) situation of aztreonam-avibactam at AZ. I was told in no uncertain terms that I should lay off. The drug will never make a return on investment and is only being developed at the insistence of John Rex and a few others in AZ, they said.  It will be developed when its developed. So, I dutifully shut up. I now feel free to speak out once again since this important product is about to be in new hands. “What are the plans?”, I asked Pfizer. They’re not talking.

Aztreonam-avibactam is an antibiotic that combines a Beta-lactam (aztreonam) that is resistant to hydrolysis by the uncommon but fearsome metallo-beta-lactamases like NDM-1. Avibactam cannot inhibit these enzymes, but it does inhibit the serine beta-lactamases that are frequently found in the superbugs that also carry NDM-1-like enzymes and that could attack aztreonam. The fact that these superbugs are still uncommon is the basis for AZ’s fear that their return on investment will never be recovered.

But the story is not simple (as usual).  AZ’s current product, ceftazidime-avibactam, could be combined with aztreonam to treat NDM-1 like superbug infections. Physicians could do this themselves now. They don’t have to wait for aztreonam-avibactam to hit the market.  The problem with this approach, that is apparently already being undertaken by some physicians, is that the dosage that they use is probably not correct. They may well be under-treating these infections.  This under-treatment leads to potential downstream problems.  It could encourage the emergence of higher levels of resistance. And it might provide a less expensive (but less active) competitor for the better drug, aztreonam-avibactam given in the correct dose. With the emergence of the plasmid-mediated colistin resistance, mcr-1 (that is now occurring here in the US), aztreonam-avibactam becomes an even more important product.

For these reasons, I have always favored a much more rapid development of aztreonam-avibactam – but my entreaties have fallen on deaf ears at AZ. Will Pfizer be just as hard of hearing?