David's New Book

Thursday, January 21, 2010

Consolidation, de-consolidation and antibiotics.

Over the last 30 years there has been tremendous consolidation within the pharmaceutical industry. In 2003, Karen Bush of Johnson and Johnson looked at the histories of six of the large pharmaceutical companies over the preceding 20 years. Karen found that these six companies derived from mergers and acquisitions of 70 precedent companies. If extrapolated to large pharmaceutical companies in general, this would indicate a 91% consolidation over 20 years. Since then, we should add the merger of Aventis with Sanofi to form Sanofi-Aventis, and the recent purchases of Schering-Plough by Merck and of Wyeth by Pfizer. I cannot begin to imagine how many jobs were destroyed by this process. This also means that there are simply fewer and fewer companies around who might be doing antibiotic research even if they were so motivated. In fact, we are now down to only 4-5 large companies still active in antibiotic discovery research.
The industry, in my view, cannot continue to survive in its current large company, blockbuster-dependent configuration. There are simply not enough multi-billion dollar drugs being discovered to support all those companies that need them for survival. Take Pfizer-Wyeth for example. This will be a $60 billion company needing to generate anywhere from $3 to 6 billion in additional revenues (or cost savings) every year. There will be cost savings after the merger, but eventually Pfizer will have to come up with one or more very big products to survive. And this is not just true of Pfizer, but applies to all of the current giants with 10s of billions of dollars in revenue coming in each year. I do not believe that this is feasible. The giants will have to break themselves up into more bite-size pieces.
In terms of antibiotics, Pfizer-Wyeth will have; piperacillin-tazobactam, a billion dollar product that is just starting to feel major effects from loss of its patent position; tigecycline, launched in 2005 and now selling around $250 million; and linezolid which is selling over $1 billion but which is threatened with loss of its patent exclusivity in 2015. For a start-up company, this would be a very strong beginning. It would allow a rapid entry into the public markets for additional investors. The new company could then go about its business of both trying to discover and develop its own new antibiotics and to bring in products from outside, perhaps from biotech, to fill out its pipeline. In my view, the new company would be much smaller than its current configuration within the larger company in the sense that it would have a small number of key internal folks who would manage programs through, mainly, outside contractors, much as is done in biotech. The marketing organization could be more streamlined and could incorporate collaborations with external parties. This would allow the new company to break away from old outdated marketing policies of the larger parent (if they exist). This solution also has the advantage of avoiding the enormous large pharma bureaucracy, allowing the new company to react more quickly to changing situations and to make decisions more efficiently. When will large pharma realize this and how long will it take the smaller entities that will emerge to start cranking on antibiotics again? I just hope I am around to see it and that some of the folks who have been displaced by the ongoing mergers and acquisitions will land back in the antibiotics game.

Thursday, January 14, 2010

Connecting the dots . . . not.

For this blog, I was inspired by the events following the failed underwear bombing of a US bound airliner on Christmas day and research I did for my last blog on KPC carbapenemase. I contacted the CDC to see if they had any updated active (as opposed to passive) US surveillance data on these highly resistant pathogens. I was a little shocked by the response I received – don’t hold your breath.

In 1999, the department of Health and Human Services formed the Interagency Task Force on Antimicrobial Resistance. The basic premise was to get various government agencies form a common plan of attack for the problem, to communicate with each other and to develop cross-agency plans and projects. Aside from those agencies like the CDC, NIH and FDA, the Task Force ultimately included the Agency for Healthcare Research and Quality (AHRQ), Centers for Medicare Medicaid Services (CMS), the Health Resources and Services Administration (HRSA), the Department of Agriculture (USDA), the Department of Defense (DoD), the Department of Veterans Affairs (VA), and the Environmental Protection Agency (EPA). In this way, all aspects of the problem of resistance, antibiotic overuse, infection control, surveillance for resistance, antibiotic use in animals and crops, environmental contamination with antibiotics and our suffering antibiotic pipeline could be addressed in a coordinated way. Great idea! But what makes any of us think that the rest of government is better able to connect the dots than our various intelligence agencies?

The plan is available online through the CDC website (www.cdc.gov). Some agencies, especially the CDC, have done a good job in educational outreach of antibiotic resistance and have carried out some important surveillance under the auspices of the Task Force. The NIH, in 2006, established the Drug Discovery and Mechanisms of Antimicrobial Resistance (DDR) to provide appropriate expertise to review research grants on resistance. (Of course it took them 20 years to put this in place since it was first recommended by another task force back in 1986). Even though this year only 1 in 17 grants will be funded, NIH has succeeded in reversing a trend going back to the 1950s of not funding antibiotic research. The Centers for Medicare and Medicaid Services, as part of their quality initiative for hospital reimbursement has identified certain hospital acquired infections for which it will no longer pay. This one initiative may have considerable impact even though it is a controversial one. The FDA, as far as I can tell, has slid backwards in their goals of stimulating antibiotic discovery and development. Large pharmaceutical companies have continued to leave the field in the last decade and essentially none of those who halted antibiotic research have come back to it.

If I had to give the Interagency Task Force a grade after a decade of work it would be D. Why are they doing so poorly? There are two major reasons and you can guess what they are. Money is number one. These agencies all compete for funding within the federal budget. Those within HHS compete for HHS monies. The goals of the Task Force require funding which has never been forthcoming in any kind of systematic or dedicated way. Yet we lose more Americans every year to antibiotic resistance than to terrorism, automobile accidents, and war. We lost 58,236 Americans in the entire Vietnam War, but we lost 63,000 per year to antibiotic resistance just in our hospitals alone! That translates to over 630,000 Americans lost to resistance since the inauguration of the Task Force. Where are our funding priorities?

The other issue is that these agencies do not communicate well. The actions already undertaken by the various agencies were the result of efforts within each of them individually. Where is the coordinated attack? Where are the cross-agency goals and projects? This is related to the first problem – they compete for funding. They are all large bureaucracies that do not change their behavior quickly.

In my view, we need a centralized and independent authority with expertise in multiple facets of resistance and a reasonable budget. This budget can come in part from all the agencies already part of the Task Force. Let the agencies have some of their budget monies dangled in front of them that they would only be able to access with practical, important and coordinated plans to deal with multiple facets of the resistance problem. Let them compete for grant monies for a change.

FYI – We have just agreed to establish the EU/US Transatlantic Taskforce on Antibiotic Resistance, focused on appropriate use of antibiotics and strategies for improving the pipeline of new antibiotics. Lets hope it works better than the Interagency Task Force that has been in place for the last 10 years.

Saturday, January 9, 2010

And then there was none.

I was contacted recently by a journalist about antibiotics in development for Gram negative infections. The subject of carbapenem resistance in Klebsiella and other Enterobacteriaeceae like E. coli, came up and started me thinking about my next blog.
What am I talking about? These bacteria can cause everything from minor infections of the urinary tract and surgical wounds to serious, life-threatening pneumonia. Most of the time, they occur in hospitalized patients, but they also cause serious infections in those in chronic care facilities and even within our communities. In years past, we had a wide choice of antibiotics active against these bacteria. The sulfa drugs and tetracycline worked. Ampicillin or the combination of amoxicillin (similar to ampicillin) plus an inhibitor of the enzyme that destroys ampicillin, B-lactamase, worked (Augmentin). Most of the cephalosporins (similar to ampicillin but with activity against a wider array of bacteria) were also effective. Hospitals had the luxury of deciding which of the many effective drugs they would put on their formularies. In many parts of the world, including the US, those days are long gone.
In many hospitals and chronic care facilities today, resistance has gotten to the point where only one (essentially) class of antibiotics is left for physicians and patients, the carbapenems. For these physicians and patients, our antibiotic of last resort has become our drug of first choice. Given the “you use it you lose it” rule of antibiotics, you can guess what is happening now. These Gram negative pathogens, especially Klebsiella have acquired a gene for a new enzyme (B-lactamase) that can destroy the carbapenems. Its called KPC for Klebsiella pneumoniae carbapenemase. The first one of these was isolated from a patient in North Carolina in 1996. The new enzyme destroys the penicillins like ampicillin, even our most modern cephalosporins, and our last line drugs, the carbapenems. KPC is not inhbited by currently marketed B-lactamase inhibitors – so those combinations like Augmentin and others are not effective. In addition to KPC, these bacteria are frequently resistant to multiple other antibiotics, even the quinolones like ciprofloxacin or levofloxacin. To treat infections by these pan-resistant strains, physicians are going back to a really old antibiotic, colisitin. Colistin was discovered in 1947. Given the time when it was approved for use, we don’t really know how well it works nor do we know how toxic it really is. My own personal experience treating patients with colistin was not encouraging on either front.
KPC Klebsiella are now spread throughout the world. We don’t have good survey data for many geographic locales. (I can’t understand why this is so). In New York City, about 30% of hospital Klebseilla carry KPC. The strains are also widespread in urban hospitals of Pennsylvania and New Jersey. Israel, Greece and China also have significant epidemics of infection with these strains.
Do we have antibiotics effective against KPC bearing bacteria coming through the pipeline? We have a new B-lactamase inhibitor from Novexel, lovingly called NXL-104, which is highly active against the KPC enzymes. NXL-104 is being developed in combination with cephalosporins (ceftazidime and ceftaroline) by Novexel, soon to be Astra-Zeneca and Forest. NXL-104 containing combinations are extremely effective against the KPC bearing bacteria. To my knowledge, there is nothing else in the later stages of development for these bacterial pathogens.
There is hope, but one new B-lactamase inhibitor is not much of a global strategy when our last line antibiotic has already become our drug of first choice.