David's New Book

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?

Wednesday, August 24, 2016

Pfizer and Astrazeneca

What goes around comes around.

Today Astrazeneca and Pfizer announced that they had entered into an agreement where AZ would license their marketed antibiotics (Merem, Zinforo and Zavicefta) and those in development to Pfizer.  Pfizer will pay AZ $550 million upfront and $190 million in January (total $740 million). There are also a number of milestone payments envisioned that could bring the total cash payments close to $2 billion.  In addition, AZ will reap double-digit royalties on sales. Medimmune and Entasis were both excluded from the deal.

To put this deal in perspective, AZ paid $350 million upfront for Novexel and what is now Zavicefta (plus other assets none of which have yet made it to market). 

Back in 2013 Astrazeneca announced that it would focus on areas outside of infectious diseases. They stated that they wanted to “partner” their anti-infectives efforts going forward. Since then, the infectious diseases franchise at AZ has been up for sale to the highest bidder.  What’s been going on for the last three years? No one was bidding high enough for AZ (or at least that’s what I deduce based on my discussions with those trying to make a deal with AZ). There were apparently two problems.  First, we are talking about ex-North American rights. Second, AZ had a rather inflated idea of the value of their products (according to my contacts). During this time, AZ spun out their antibiotic discovery group to form Entasis. And they formed a fully-fledged business unit out of their antibiotic development group. 

In 2011, Pfizer abandoned antibiotic research entirely. They fired all (or almost all) of their anti-infectives researchers and developers.  They also downsized their entire research effort globally by almost 25%. This occurred in a company with a rich history in antibiotic discovery and development.  Pfizer was one of the first companies to join the antibiotic revolution with penicillin. Then came the first, good, oral tetracycline, doxycycline in the 1960s. Later came the beta-lactamase inhibitor, sulbactam. Diflucan or fluconazole was invented at Pfizer’s facility in Sandwich, UK in the 1990s. They acquired Zyvox through their purchase of Pharmacia. With their acquisition of Wyeth, they had piperacillin-tazobactam and tigecycline. How could a company with this history abandon antibiotics research in the way that it did?

What’s now left at Pfizer? Apparently there is still a small core of antibiotic developers there.   A few of the researchers involved in antibiotics moved over to Pfizer Vaccines (previously Wyeth Vaccines). Some moved to other therapeutic areas within Pfizer.  But the vast majority are long gone.  Many went to AZ and are now either working elsewhere or at Entasis or are unemployed. But – I understand that there will be a significant transition period where the AZ developers will be able to support Pfizer’s efforts and even provide experience and guidance going forward. They may even get a shot at a job in Pfizer. So this might work better than if, say, Pfizer were just to jump back in the way the Roche did.

On the one hand, I want to be excited that Pfizer is getting back into the antibiotics business. Companies that have lost their expertise in antibiotics can struggle for years to regain their footing. My contacts suggest that the transition from AZ to Pfizer is structured such that this will be a smooth process and will avoid this struggle. I take their word for it, but I’ll be watching.

In terms of big pharma companies still doing antibiotics R&D – the numbers haven’t changed.  We’ve just replaced AZ with Pfizer.  It’s a shell game.

I still find it depressing that those who worked so hard to bring exciting, new antibiotics like ceftazidime-avibactam to market at AZ, now, once again, face an uncertain future.

Thursday, August 11, 2016

Confounding Aminoglycosides?

I’m still stuck on the recent FDA meetings where pathways to regulatory approval for pathogen-specific antibiotics were discussed. The example chosen to illustrate the challenges in identifying a pathway was a fictional drug called X-1 that was entirely specific for Pseudomonas aeruginosa. I suggested a superiority design trial where patients with a high risk for Pseudomonas infection would be enrolled and treated with a combination of a carbapenem, X-1 and, if desired, an aminoglycoside. Controls would include those treated with only the carbapenem plus (or not) aminoglycoside. As I noted, the centers would have to be those where there was a rate of carbapenem-resistance among Pseudomonas but not at such a high level that physicians would feel uncomfortable with empiric carbapenem therapy.  (Globally, the rate for carbapenem resistance in this organism is in the range of 15-20% range.  In this range, most patients are still treated empirically with a carbapenem, usually in combination with an aminoglycoside).   In my design, I suggested that the evaluable population for analysis of superiority would, in fact, be those with carbapenem-resistant infections.

The response I received was a horrified, “But the aminoglycoside is an active drug.  It will confound your results.  You will never know what to attribute to X-1 vs. the aminoglycoside!” Some insisted this would be true even if the aminoglycoside were only administered for the first few days of therapy. I beg to differ (at least for serious infections outside the urinary tract).

There are a number of studies examining the effect of aminoglycosides on Pseudomonas aeruginosa infections. One, from Leibovici et. al. in Israel.  In their prospective observational study, they were unable to demonstrate an advantage of adding an aminoglycoside to B-lactam therapy outside of those patients who were neutropenic and those with bacteremia. But more interesting was that for patients where the aminoglycoside was the only “appropriate” drug based on susceptibility testing, patients had a 40-100% higher mortality compared to appropriate beta-lactam monotherapy.

Another study looked at bacteremia caused by Pseudomonas aeruginosa. In this study from Spain, it appeared as though a higher mortality among those treated “appropriately” was mostly due to those who received an aminoglycoside as the only active drug.

Several other studies confirm the lack of an advantage for combination therapy of beta-lactam plus aminoglycoside compared to beta-lactam alone in treating these infections. Several, like the two I noted here, suggest that there is a treatment disadvantage when, in fact, an aminoglycoside is the only active drug in the regimen.  These studies suggest to me that a few days of an aminoglycoside in the design I suggested would be anything but confounding.

Friday, July 29, 2016

Money for New Antibiotics - What Could be Wrong with That?

I was beaming with pride in those who worked to bring the public-private effort to fund a major new effort in the discovery and development of antibiotics as was announced yesterday. CARB-X will establish a sort of incubator for academic groups and small or even mid-size companies, potential spin-offs and others working on early to mid-stage antibiotic development. The entity is a partnership between Boston University Law School (I’ll try and explain below), the Department of Health and Human Services (BARDA) in the US, the Wellcome Trust in the UK and the new AMR Centre also in the UK.  The National Institutes of Health will provide “in kind” support like access to their preclinical services.

The really good thing about this is the clear recognition by people with money that we need to develop new antibiotics to address the emerging problems of antibiotic resistance today and those that will surely be here tomorrow. Another potentially important aspect of this is the coalition that brought this forward. But why Boston University Law School? Maybe because that is where Kevin Outterson is.  BU will be the center of the advisory board for the effort and will include a mix of scientists and clinical developers with experience in antibiotics. There will obviously be legal issues around the formation of new companies, patents, intellectual property and other topics that will require legal advice. Having a legal team available to help will be important going forward.

I consider this a very important step forward.  But at the same time, I have a few thoughts for us to consider (and I’m not the only one). According to Kim Lewis, who spoke with Asher Mullard for Nature (quoted here in Scientific American), “If more money is going into the general area of antibiotics, that’s a good thing. But I’m really surprised that we are getting another influx of funds into development rather than into discovery.” The main problem, says Lewis, is the lack of compounds that can punch through the outer membranes of ‘gram-negative’ super-microbes such as Escherichia coli and Klebsiella pneumoniae. Researchers need to work out how to systematically make or find compounds that can slip through bacterial protective barriers, he says. And Kim is right. As Kim points out, we need new compounds to develop.  We absolutely need more money for fundamental antibiotic discovery research.  The NIH has been woefully behind in their efforts in this important area (although they have just had a new influx of funds).  Their “in kind” support mechanisms are helpful, but extremely slow and bureaucratically cumbersome to use.  Sure – if you have no choice these services are a lifesaver for academics or even small companies. But this could be done much more efficiently.

The other problem I have been harping on (to no avail) for the last 12 years is the lack of training for our antibiotic researchers and developers.  Perhaps the CARB-X  will provide this training as well, but it seems to me that those who are untrained are simply not likely to be funded or “placed” in the incubator.

Erik Gordon, professor at the University of Michigan's Ross School of Business, speaking to CIDRAP News, was even more skeptical. "Antibiotic development needs the backing of non-profit organizations to make the economics work," he said. He added, however, "I'm not sure funneling that much money into an accelerator system based at a law school, where few antibiotics have ever been developed, with so many cooks, is the best use of the money or the best way to develop the new antibiotics we need."

Another looming problem to be addressed has nothing to do with money.  At least some, if not most, of the antibacterial compounds that will come out of CARB-X will be adjunctive therapies or perhaps pathogen-specific therapies.  We need a clear and feasible regulatory pathway for the development of these compounds.

And this brings me, finally, to post-market or “pull” incentives.  That’s where the rubber hits the road, folks.  Very simply, if we don’t make the economics work for antibiotics, we won’t have any.