Wednesday, September 21, 2016

Superbugs Meet OMEGA

There is a lot of attention being paid to the emerging global health crisis of antibiotic resistant infections these days.  Today was the special session of the United Nations General Assembly that patched together a relatively bland (draft) statement looking forward to more studies to report back in two years. As my brother-in-law always says – keep your expectations low. But on the positive side, the international attention to this looming crisis can only be good. We can only hope that Europe, especially the UK, keeps moving forward with concrete plans backed up with real resources (read money) to address this problem today rather than tomorrow. What we need are the kinds of pull incentives that DRIVE AB has been discussing and that are being considered most seriously in Europe.  Of course, BARDA has not stopped in its tracks either in terms of providing push incentives as was evidenced by today’s announcement of a portfolio grant of up to $132 million the Medicines Company.

One of the problems that remains unresolved and is not addressed well anywhere is the lack of new antibiotics in the pipeline.  What I mean is that we have a science deficit that will not be overcome anytime soon given the paltry number of researchers now working in the area. The reasons behind this are multiple (read my book or follow my blog).  But a recent report from the Pew Charitable Trust outlines the problem very well and focuses on the key scientific problem facing us. Specifically, we are talking about the problem of Gram-negative superbugs with their double membrane and their extensive system of efflux pumps that either prevent antibiotics from getting into the bacteria altogether or pump the antibiotics  back out before they can kill the bacterial cells.

This brings me to the OMEGA project (Outer Membrane Efflux Gram-negative Assault).  The origin of this was a phone call I received last year from Jonathan Thomas, the chairman of the board of the California Institute for Regenerative Medicine (CIRM). CIRM is a research funding agency of the State of California focused on stem cell research.  It has a very large budget (~$3 billion).  So JT (as he is known) is familiar with research around new therapies. He is passionate about doing something concrete about the antibiotic resistance problem before it kills us all. I put him in touch with Kim Lewis and the OMEGA project was born.

The OMEGA project has as its major goal the discovery of new antibiotic candidates that can be placed into clinical development.  After our first meeting with a small group of highly skilled experts, we have developed a two-pronged approach.  The first is to develop a much better understanding of the permeation of antibiotics into Gram-negative pathogens. Others have tried this, but not with the focus we plan to apply here. We believe that small molecules (antibiotics) will fall into a few well defined categories depending on how they penetrate the bacterial cell.  Each category (or bin) will have a different set of chemical rules that must be followed to allow the compound to penetrate the bacteria more efficiently (See Lynn Silver's paper).  We believe that the tools to decipher the complex process of permeation are now available. The rules that we discover will serve to help the chemists optimize compounds to make better antibiotics. Our job is to understand these rules insofar as possible.

The second prong of our approach is to undertake the discovery of novel, natural product antibiotics using several, modern, and only recently validated methods. The two prongs come together when we have to optimize any natural product antibiotics that we discover using these methods.

So far, the OMEGA project remains a twinkle in the eyes of its originators – JT, Kim Lewis and myself.  To make the project a reality will take funding.  Raising these funds is our next step. But I am confident, based on our first meeting with true experts in these areas, that the OMEGA project will succeed where others have failed.

If we don’t provide new lead compounds, we will never have a robust pipeline of new antibiotics for the future.  And that is what OMEGA is all about.

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?