David's New Book

Friday, October 21, 2016

Low Expectations

I don’t know about you, but for me, this is the season of low expectations.  My brother-in-law constantly reminds me to keep my expectations low and my standards high. In this US campaign season, I find that it is increasingly hard to avoid feeling blue by continually lowering those expectations.

A good example is the result of the UN General Assembly.  The opportunity to actually do something concrete about the emerging crisis of antibiotic resistance in the absence of a robust pipeline of new antibiotics was an exciting one. But as often happens when multiple players with competing interests get together to try and accomplish something, we now play a waiting game. Although what to expect at the end of the wait is not really clear.  Recently, Allan Coukell of the Pew Charitable Trust wrote a summary of the UNGA statement. 193 countries signed a political statement that is extremely vague and does not include any commitment for financial resources to spur innovation. 13 pharmaceutical companies signed a separate statement where exploring new ways for the public and private sector to collaborate to spur innovation was a goal. The divide between industry and government seems clear.  The UNGA expects to revisit the issue in two years.
What we need now is some way to assure antibiotic developers that they will achieve a return on their investment. There are a number of ways this could be funded.  First, the savings on health care provided by having the means to treat infections will be enormous – it just requires a capital investment in our future.  Second, if more immediate funding is required, we could charge a very small tax on current pharmaceutical sales that would be dedicated to an antibiotic market fund. This tax would be applied to all pharmaceuticals without exception – but would need to be pennies or less on the dollar.

A nagging worry for me is whether, at this point in time, even if we identify a financial mechanism to assure a return on investment, pharmaceutical companies will be interested enough to return to antibiotic research. I have been asking the folks at DRIVE AB to investigate this – but have heard nothing as yet. I recently heard that Merck was skeptical of the market entry rewards that we have been discussing.  They may be more interested in pricing and reimbursement as the preferred market mechanism.  That will likely remain the way forward in the US in any case.

We need to train our antibiotic hunters of the future before we lose all our expertise to the ravages of time and the current lack of funding for antibiotic research.

And we need to continue working on new regulatory pathways for antibiotic development – especially for pathogen-specific products.

We need to raise the prices of key generic antibiotics like penicillin to avoid drug shortages.

Beyond all this, we need to improve our surveillance globally, control the use of antibiotics in agriculture, and improve our stewardship of antibiotic use in humans. But even with these steps, we will have a constant need for new, effective antibiotics and for that we need to correct our current problem of the market failure for antibiotic discovery.

I find that I am unable to lower my expectations sufficiently to avoid this current state of depression around the state of progress in global antibiotic policies that is afflicting me. A sure cure would be the commitment of at least a few national authorities to the market entry rewards that Astra-Zeneca was negotiating before their antibiotics business was sold to Pfizer. But, alas, I fear that all this is now on hold.

Tuesday, October 4, 2016

Holding our Breath

The crisis of antibiotic resistance and our failure to produce a robust pipeline of new antibiotics to combat the problem is not going away. And we’re not doing what we need to do.  We are all just holding our breaths, sticking our heads in the sand and pretending the problem will go away before we have to go to the hospital and face the crisis in a very personal way.

The CDC just published a report in JAMA looking at antibiotic use in US hospitals. The study only looks at the years 2006-2012. They found that about 55% of all hospitalized patients received at least one dose of an antibiotic during their stay.  If my memory serves, when I was in practice in the 1980s and 90s, 75-80% of patients were treated with antibiotics – so at least things have improved since then.  But the 55% number has been stable during the years of this current study.  But what changed over time was the use of certain antibiotics.   Carbapenems, B-lactam-B-lactamase inhibitor combinations, and tetracyclines (I presume tigecycline) saw increased use by 30-40% during the years of study.  Certain other classes, like the fluoroquinolones for example, saw a decrease in use over the years of study. This suggests that physicians are increasingly worried about resistance and are treating their patients as if resistance was already a problem in their hospitals – and they may well be correct. 

On the bright side, we had a historic first this year with a statement from the UN General Assembly on the threat of antibiotic resistance to global health and the global economy.  But on the downside, the statement contained no serious targets and no funding.

The US just saw its first debate between the major party candidates.  We heard about Miss Universe, taxes, ripoffs and many other important topics but not a single word on antibiotic resistance.  This total disregard has been the story of the US presidential campaign so far.

The US congress just passed a funding bill that included $1 billion for efforts to fight the Zika virus – probably too little too late.  But on the problem of antibiotic resistance, perhaps the greatest emerging health crisis we have ever faced, we got bupkus.

In Europe we look to the United Kingdom for leadership in dealing with the antibiotic resistance crisis. Dame Sally Davies, David Cameron, George Osborne, Jim O'Neill, the Wellcome Trust have all been key leaders in the fight to actually get something done before we end up in an era where simple surgery and modern cancer chemotherapy could be life-threatening because of complicating antibiotic resistant infections. What happened there?  Brexit – that’s what happened. Cameron and Osborne are gone. Dame Sally and the Wellcome are still there – but where?

The most frustrating part of this is that fixing the problem is not rocket science.  Its not like sending humans to Mars. OK – the science of discovering new antibiotics is not easy.  But, as I have stated in many previous blogs (1, 2, 3) and as the O’Neill Commission has repeatedly pointed out, we can do this.  We have already come a long way in fixing our broken regulatory system (mainly a US problem). We need to invest (yes, as in money!!!) in antibiotics to shore up our failing free market system.  We need to invest in training our antibiotic hunters of the future. We need to get smarter in our scientific approaches.

What is missing?  What is holding us back? There is clearly an absence of public awareness of the seriousness of the emerging problem. We may not see a surge in public concern until the crisis is already upon us in full force. Those in positions of public responsibility must act responsibly and with foresight.  If they don’t, our children, our grandchildren and we ourselves will pay a price too terrible to contemplate.

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.