Actually, this is not a blog about the use of antibiotics and hormones in poultry. It is about the pharmaceutical industry’s risk averse approach to developing antibiotics. In the interests of balance, I think we have to look critically at the industry as well as regulatory agencies.
Vancomycin has been a real workhorse antibiotic for the treatment of MRSA infections in our hospitals. But we now have three new antibiotics for the treatment of these infections, linezolid, daptomycin and, in 2009, telavancin. At the same time, there have been a number of scientific and clinical studies to suggest that vancomycin isn’t such a great antibiotic for the treatment of MRSA infections. Both linezolid and daptomycin were compared, in their late stage clinical trials, to vancomycin and both were shown to be “non-inferior.” Thus, they both were no worse than vancomycin within a reasonable statistical margin of error. Because antibiotics work so well in a normal clinical trial, it is usually impossible to actually show superiority of one antibiotic over another. In a few, more specialized trials, there is some evidence that linezolid might be superior to vancomycin, but these data were never approved by the FDA. Had the FDA actually accepted these data and approved a label suggesting that linezolid was superior to vancomycin, Pfizer would have been allowed to make that claim in their marketing efforts. At the time that daptomycin and linezolid were studied, there was no antibiotic other than vancomycin for them to use as a comparator. But for telavancin, which was just approved in 2009, both linezolid and daptomycin had been approved and on the market for several years before the pivotal telavancin trials were started. Cerexa/Forest is developing a cephalosporin antibiotic active against MRSA. For their recently completed Ph. III trials, they also chose to use vancomycin as their comparator.
So why did Theravance - Astellas and Cerexa/Forest choose vancomycin as the comparator? I can think of a number of reasons why they should not have done so. First, vancomycin sells at a lower price. In Europe, the price of your comparator comes into consideration when you get into the ultimate price negotiations that you have to go through with each individual country to market a new drug. So using a higher priced comparator would have made the argument that you too can charge a higher price more palatable to the national authorities in Europe. In addition, some influential clinicians believe strongly that vancomycin is an inferior drug compared to both linezolid and daptomycin. There is some evidence to support this view even though the data could not be used by regulatory authorities to approve such a claim. In that case, why would you not want to show non-inferiority compared to what might be an inferior antibiotic? It is of interest that Cerexa/Forest are running a Phase II trial comparing ceftaroline to linezolid in the treatment of skin infections. This suggests that they are aware that some clinicians consider linezolid a superior drug but made an active decision not to pursue linezolid as a comparator in their first pivotal trials.
I think the answer to this question goes back to risk. Companies are risk averse and they worry that they might be wrong and that they might not succeed against the newer antibiotics even though the risk, in my view, is a small one given everything we know about all these drugs. I’m sure other considerations come into the discussion as well. Both daptomycin and linezolid are expensive. The companies, in this example Theravance-Astellas and Cerexa/Forest, would have to pay the going rate for the comparator drug for hundreds of patients. This would significantly increase the cost of the trials. Also, they might have considered that because vancomycin had been used in so many trials as a comparator, it was much better characterized and provided a more reliable comparator. Finally, they might not have wanted to provide additional data for their future competitors, Cubist (daptomycin) and Pfizer (linezolid). Perhaps they were all dissuaded by Arpida who carried out two Ph. III trials of their antibiotic, iclaprim, compared to linezolid and failed to show non-inferiority.
Theravance-Astellas or Cerexa/Forest might argue that, based on volume of use, vancomycin is still the most widely used antibiotic for the treatment of serious Gram positive infections in hospitals where MRSA is common. That vancomycin is the most widely used of the anti-MRSA drugs remains true partly for cost reasons, where vancomycin is considerably less expensive than linezolid and daptomycin. The fact that there are no data approved by a regulatory authority recognizing the superiority of either daptomycin or linezolid over vancomycin in the treatment of MRSA infections probably also contributes to this situation.
I believe that companies should be providing the best data for physicians and patients. This should be a prime consideration in the choice of a comparator for pivotal clinical trials. The comparator should be the gold standard. The gold standard is not always the same as the so-called standard of care.
Friday, February 12, 2010
Monday, February 1, 2010
Generic Antibiotics: Effective and Safe?
Today I am going back to the FDA’s Advisory Committee (AIDAC) meeting on a new antibiotic, telithromycin (Ketek), in December, 2006. Telithromycin is an antibiotic distantly related to erythromycin and azithromycin (Zithromax, Z-Packs) that is active against strains resistant to the older antibiotics. During this meeting, the committee recommended that its marketing approval be withdrawn for the indications of sinusitis and bacterial exacerbations of chronic bronchitis. Telithromycin was contentious from the start. Bob Moellering and I wrote a Perspective on the entire process for Lancet Infectious Diseases in 2008 if you are interested in a summary of telethromycin’s history. But the argument at the AIDAC in 2006 essentially boiled down to the following logic:
1. The FDA has decided that superiority or placebo controlled trials would be required to show efficacy for self-limited infections like otitis media, sinusitis and bacterial exacerbations of chronic bronchitis.
2. Telithromycin is associated with rare but serious liver toxicity, aggravation of myasthenia gravis (a rare neurologic condition) and more common visual disturbances that are generally not very serious.
3. Because telithromycin was not subjected to superiority or placebo controlled trials to prove efficacy in sinusitis and bronchitis, the FDA asked, what is its benefit:risk ratio?
Predictably, the committee found that, since efficacy had not been proven, and telithromycin was associated with some toxicity, the benefit:risk ratio was poor (some might say 0). A few of us at the meeting, including the FDA itself, pointed out that generic antibiotics, like augmentin and others, had never been subjected to placebo controlled or superiority trials in the same indications and that they too had toxicities not unlike those associated with telithromycin. We asked what the FDA would do about that situation. The response from Dr. Jenkins of the FDA is quoted below from the meeting transcript:
DR. JENKINS: We definitely hear your concern about a fair level playing field for all the antimicrobials that have the indication and we will take that back and put on our thinking caps about what approaches there might be to get the level of evidence that we would like to have today for all of those products. But I can assure you it will be a very complex endeavor and maybe similar to me trying to climb Dinali.
Clearly, if one is to buy the arguments as posed by the FDA and its Advisory Committee in 2006, since in terms of numbers of prescriptions those for generic antibiotics far outweigh those for brand antibiotics, the potential risk for Americans is that much greater for generics. So, either the FDA does not really think that these drugs have no proven efficacy, or they do not believe their own data on the toxicity of generic antibiotics or they just have not yet been able to figure out what to do with their homemade conundrum.
To me, the solution is simpler. To require placebo-controlled trials dooms us to never having another new antibiotic for otitis, sinusitis or bronchitis. This is another example of the FDA requiring infeasible trials for approval. The FDA needs to put on their thinking caps about new trial designs that are feasible. Then, they need to ask whether the generics have come to an acceptable level of proof based on a more feasible approach. If the answer is “yes” then we’re done. If not, then marketing approval for the generics for these indications must be denied until they achieve the same level of proof the FDA is requiring for new antibiotics.
I have been trying to follow-up with the FDA since it has now been three years since they started their attempt on “Dinali.” So far, no one seems to be home.
1. The FDA has decided that superiority or placebo controlled trials would be required to show efficacy for self-limited infections like otitis media, sinusitis and bacterial exacerbations of chronic bronchitis.
2. Telithromycin is associated with rare but serious liver toxicity, aggravation of myasthenia gravis (a rare neurologic condition) and more common visual disturbances that are generally not very serious.
3. Because telithromycin was not subjected to superiority or placebo controlled trials to prove efficacy in sinusitis and bronchitis, the FDA asked, what is its benefit:risk ratio?
Predictably, the committee found that, since efficacy had not been proven, and telithromycin was associated with some toxicity, the benefit:risk ratio was poor (some might say 0). A few of us at the meeting, including the FDA itself, pointed out that generic antibiotics, like augmentin and others, had never been subjected to placebo controlled or superiority trials in the same indications and that they too had toxicities not unlike those associated with telithromycin. We asked what the FDA would do about that situation. The response from Dr. Jenkins of the FDA is quoted below from the meeting transcript:
DR. JENKINS: We definitely hear your concern about a fair level playing field for all the antimicrobials that have the indication and we will take that back and put on our thinking caps about what approaches there might be to get the level of evidence that we would like to have today for all of those products. But I can assure you it will be a very complex endeavor and maybe similar to me trying to climb Dinali.
Clearly, if one is to buy the arguments as posed by the FDA and its Advisory Committee in 2006, since in terms of numbers of prescriptions those for generic antibiotics far outweigh those for brand antibiotics, the potential risk for Americans is that much greater for generics. So, either the FDA does not really think that these drugs have no proven efficacy, or they do not believe their own data on the toxicity of generic antibiotics or they just have not yet been able to figure out what to do with their homemade conundrum.
To me, the solution is simpler. To require placebo-controlled trials dooms us to never having another new antibiotic for otitis, sinusitis or bronchitis. This is another example of the FDA requiring infeasible trials for approval. The FDA needs to put on their thinking caps about new trial designs that are feasible. Then, they need to ask whether the generics have come to an acceptable level of proof based on a more feasible approach. If the answer is “yes” then we’re done. If not, then marketing approval for the generics for these indications must be denied until they achieve the same level of proof the FDA is requiring for new antibiotics.
I have been trying to follow-up with the FDA since it has now been three years since they started their attempt on “Dinali.” So far, no one seems to be home.
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.
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.
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.
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.
Thursday, December 31, 2009
Hope and skepticism for 2010.
I have been reviewing recent efforts in Europe to deal with the antibiotic conundrum. I am astonished that Europe is so far ahead of the US in their thinking and that the European effort is being led by Sweden, which has some of the lowest antibiotic resistance rates in the world. Having lived there several years, I find Europe amazing. because it is such a huge bureaucracy of such disparate cultures, languages and even alphabets. It is hard for me to imagine that such an organization can function.
It is clear that Europe recognizes that there is an ongoing need for new antibiotics active against key resistant pathogens. They estimated that 25,000 European patients died from an infection caused by such organisms and that these infections led to 2.5 million additional hospital days and additional in hospital costs of 900 million Euro ($13.5 million) per year. Overall, the additional costs to society of these infections was estimated at 1.5 billion Euro ($2.25 billion) per year. In their report, it was clearly stated that these figures almost certainly represent an underestimate since all costs, such as those attributed to intensive care for example, could not be taken into account in their model.
The various reports also examined the numbers of antibiotics in various stages of development. Suffice it so say that there are precious few, especially when looking at those active against resistant gram negative pathogens.
In proposing various solutions, the European reports examined the approach of the EMEA to antibiotics. Here, there could have been a great deal more detailed analysis and thinking in proposing ways forward. The EMEA is currently considering new guidance on developing antibiotics, and from my view, it is more of the same.
But perhaps the most important contribution to European (and global) thinking came from Policies and incentives for promoting innovation in antibiotic research, commissioned by the Swedish Government and written by Professor Elias Mossialos and his co-workers at the London School of Economics and Political Science. Their basic suggestion is to use a combined “push-pull” mechanism. In one embodiment of such an incentive, Europe would essentially take on some proportion of the development costs for a compound thus reducing or eliminating the risk for the company depending on the amount provided. This, in their model, is equivalent to purchasing an option to buy quantities of the antibiotic should it be approved by an appropriate regulatory body and should it meet preset criteria such as activity against resistant pathogens (which would in turn require more precise definition). This would be the “push” part of the mechanism. If the antibiotic were to be approved, Europe would then be obligated to purchase a set amount, I presume in terms of courses of therapy, at some set price. This would be the “pull” portion. The attractiveness of this model to industry would largely depend on the size of the “pull.”
Many companies use a calculation of the presumed Net Present Value (NPV) of a product to decide whether or not it is worth pursuing. It is because of this calculation that many companies have abandoned antibiotics since the ultimate sales do not provide much value above and beyond the costs of development. In the calculation of NPV for a product, upfront expenses like those for late stage clinical development and the early marketing expense for launching the product count heavily. At the same time, later earnings are discounted for inflation. So companies are always looking for products that provide for high, early sales – “a steep revenue curve.” The European approach is attractive when viewed this way. The “option” on the product will relieve a portion (hopefully a large portion) of the upfront expenses for late stage clinical development. The “pull” would bolster the early portion of the sales curve. Thus the push-pull approach, if both components were large enough, would have a substantial effect on the overall NPV for the product.
The European Council has now recommended that the European Commission implement these or similar proposals to ensure a pipeline of new antibiotics. They gave them a time frame of two years(!!). I am both skeptical and hopeful at the same time.
It is clear that Europe recognizes that there is an ongoing need for new antibiotics active against key resistant pathogens. They estimated that 25,000 European patients died from an infection caused by such organisms and that these infections led to 2.5 million additional hospital days and additional in hospital costs of 900 million Euro ($13.5 million) per year. Overall, the additional costs to society of these infections was estimated at 1.5 billion Euro ($2.25 billion) per year. In their report, it was clearly stated that these figures almost certainly represent an underestimate since all costs, such as those attributed to intensive care for example, could not be taken into account in their model.
The various reports also examined the numbers of antibiotics in various stages of development. Suffice it so say that there are precious few, especially when looking at those active against resistant gram negative pathogens.
In proposing various solutions, the European reports examined the approach of the EMEA to antibiotics. Here, there could have been a great deal more detailed analysis and thinking in proposing ways forward. The EMEA is currently considering new guidance on developing antibiotics, and from my view, it is more of the same.
But perhaps the most important contribution to European (and global) thinking came from Policies and incentives for promoting innovation in antibiotic research, commissioned by the Swedish Government and written by Professor Elias Mossialos and his co-workers at the London School of Economics and Political Science. Their basic suggestion is to use a combined “push-pull” mechanism. In one embodiment of such an incentive, Europe would essentially take on some proportion of the development costs for a compound thus reducing or eliminating the risk for the company depending on the amount provided. This, in their model, is equivalent to purchasing an option to buy quantities of the antibiotic should it be approved by an appropriate regulatory body and should it meet preset criteria such as activity against resistant pathogens (which would in turn require more precise definition). This would be the “push” part of the mechanism. If the antibiotic were to be approved, Europe would then be obligated to purchase a set amount, I presume in terms of courses of therapy, at some set price. This would be the “pull” portion. The attractiveness of this model to industry would largely depend on the size of the “pull.”
Many companies use a calculation of the presumed Net Present Value (NPV) of a product to decide whether or not it is worth pursuing. It is because of this calculation that many companies have abandoned antibiotics since the ultimate sales do not provide much value above and beyond the costs of development. In the calculation of NPV for a product, upfront expenses like those for late stage clinical development and the early marketing expense for launching the product count heavily. At the same time, later earnings are discounted for inflation. So companies are always looking for products that provide for high, early sales – “a steep revenue curve.” The European approach is attractive when viewed this way. The “option” on the product will relieve a portion (hopefully a large portion) of the upfront expenses for late stage clinical development. The “pull” would bolster the early portion of the sales curve. Thus the push-pull approach, if both components were large enough, would have a substantial effect on the overall NPV for the product.
The European Council has now recommended that the European Commission implement these or similar proposals to ensure a pipeline of new antibiotics. They gave them a time frame of two years(!!). I am both skeptical and hopeful at the same time.
Thursday, December 24, 2009
A Bittersweet End to 2009
Here it is, Christmas eve, and I'm blogging about antibiotics. What is wrong with me?
The end of this year is bittersweet for me. I have been an independent director on the board of a biotech company, Novexel, for the last several years. Yesterday, Novexel was purchased by Astra-Zeneca who, in turn, were supported by Forest Pharmaceuticals in the US. Novexel was a spin-out from Sanofi-Aventis and was able to take several of the compounds that were included in the spin-off all the way through Ph. II clinical development. I am very proud to have been part of that effort. Novexel built a strong scientific and management team - one of the best in biotech as far as antibiotics are concerned. This team was responsible for Novexel's success.
A trade sale has frequently been the best outcome for biotech investors and that has been even more true since the economic crisis of the last two years. In the case of Novexel, its products will now be developed through Phase III and will then be marketed by Astra-Zeneca and Forest. That is a great outcome for patients and physicians since new antibiotics active against resistant bacteria will be available to them as a result of this transaction. For the people of Novexel, things are less clear. Other biotech exits, like going to the public markets and licensing rights to products to support development and marketing have not been possible these last two years. But that strategy allows for the creation of new companies, like Cubist in the US and creates jobs as opposed to destroying them. This alternate strategy also engenders an ongoing innovation which may be lost with a trade sale.
So the end of 2009 is bittersweet. Good and valuable antibiotics will now be provided to patients who need them but a great biotech which brought these products forward from the lab bench to the late stages of clinical development will cease to exist.
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