David's New Book

Wednesday, October 4, 2017

Antibiotic Approvals - Is the Glass Half Full?

Since the reboot of antibiotic development that the US Food and Drug Administration undertook in mid-2012, there has been a clear acceleration in the rate of approvals of new antibiotics.  The graph below shows FDA approvals of New Molecular Entities of antibiotics over time – and it speaks for itself. Clearly, even after the reboot, we are not reaching the rates of approval we saw during the 80s and 90s – the heyday of antibiotic discovery and development. But there seems to be a clear improvement.



A close look at those approvals shows that two of the antibiotics approved in 2014 (dalbavancin and oritavancin) were holdovers discovered in the 90s that had previously been discontinued from development related to changing FDA regulations, to market considerations and to technical issues. Both are administered intravenously and target only Gram-positive pathogens. Nevertheless, the post-2012 approval rate remains encouraging. Will this continue?

I “borrowed” the analysis below from a public presentation by John Rex describing the DRIVE-AB recommendations for pull incentives. Here he analyzes the current pipeline focusing on resistant pathogens in terms of WHO priorities and the likelihood of approval of products currently in clinical trials. It looks like it is conceivable that today’s rate will continue over the next five years but that new antibiotics active against resistant strains of the gonococcus, Acinetobacter and Pseudomonas will remain rare for the foreseeable future. The forecast is much more favorable for antibiotics active against Enterobacteriaceae including those possessing extended spectrum B-lactamases and those active against Gram-positive pathogens.


The WHO has concluded that this pipeline is insufficient to meet our needs over the next decade and it is difficult to argue with that.  Clearly, we need to stimulate additional research – hence the need for both push and pull incentives.

Tuesday, September 26, 2017

Pull Incentives for Antibiotics - Update

There have been at least two recent developments on proposals for pull incentives.  One comes from the DRIVE-AB meeting this month and the other from the Office of Health Economics in the UK.  Both recommend “partial de-linkage” models. As I have said consistently, de-linkage is a non-starter and I think the prevailing opinion is now in agreement with that view.  De-linkage means that there would be no “marketing” spend by companies in the sense that they would not need any “sales” to support income.  Revenues would come entirely through a market entry reward of some sort. But this approach divorces the company from needed physician educational efforts and provides no incentives for generics to enter the market after the expiration of exclusivity for the product.

The recommendation from DRIVE-AB is illustrated below. It shows a market entry reward starting payments at the time of drug approval and continuing for five years. At the same time, the company is allowed to charge some price for the drug that is sold during those years.  The company can earn sales revenue both during the five years of the reward payments and thereafter. The reward remains contingent on various milestones that the company must meet including manufacturing, physician education, microbiological surveillance and other activities essential to introducing a new antibiotic to the market. DRIVE-AB predicts that this approach would stimulate antibiotic R&D to the extent that antibiotic approvals would quadruple over the next thirty years.  Personally, I think that probably does not take into account sufficiently the scientific risk inherent in antibiotic discovery and therefore that this is an optimistic prediction based on historic rates of approval. Nevertheless, I agree that this would clearly stimulate antibiotic R&D and would motivate investors and companies to continue in antibiotic R&D or to get back in that business.

The new publication from the Office of Health Economics promotes an insurance model as a market entry reward. In this model, with the approval of a new, needed antibiotic, company would receive sufficient reimbursement to provide for a net present value (NPV) of $100 million. This would cost the health system something like $262 million per year over ten years or $2.6 billion.  The question for me is, is $100 million in NPV enough? The answer from the marketing folks at Wyeth in the year 2000 was “no!”

Both of these models and a number of others, including and especially the exclusivity voucher model, could work. The insurance model is a better fit in Europe where most countries provide some sort of national health insurance already.  It is probably not a good fit in the US. I guess I don’t see anything wrong with different countries using different approaches as long as there is a clear and predictable return on investment for the companies such that they are motivated to continue or to re-enter the antibiotic research field.

I see a number of questions that are still extant. First -  how much do we really dislike and distrust the pharmaceutical industry that will be the source (in all likelihood) of these new products? During a recent lecture one of the audience members posed an interesting question. “If we are going to have to spend this amount of money, why wouldn’t we spend it on research in a government antibiotic R&D effort that would not require profits?” I’m sure this question comes, in part from a basic distrust of and anger towards a pharmaceutical industry that many see as consistently gouging consumers. And who can argue with that?  My answer was that the expertise exists today within industry.  But I suppose that could change, even though I remain extremely skeptical.

Another remaining question revolves around the numbers. How much NPV should society provide?  This, in turn, depends on how we value new antibiotics active against key resistant pathogens. It also depends on how we value the existence of a robust pipeline that is, in a way, our insurance against emerging resistance to the new agents that we are using sparingly hoping to avoid the rapid emergence of resistance.


No matter which model we prefer for pull incentives, and no matter whether we are angry at the pharmaceutical industry, we still need a robust pipeline of new antibiotics for the future.  And the only way we will get there is by assuring companies, at least for the foreseeable future, that they will have a sufficient enough return on their investment that they should, in fact, invest in antibiotic research and development.

Friday, September 15, 2017

Antibiotics and Climate Change

What do antibiotics and climate change have in common? We have our heads in sand for both.  If we can’t see it, it won’t hurt us. I was inspired by an article in the New York Times today on climate change contending that even some Republican congressmen and senators are reconsidering their hardline positions on climate change in the wake of hurricanes Harvey and Irma. I asked myself , “Is this what it takes? Do we have to suffer through death and destruction to recognize the accuracy of climate science?”  If the answers to these questions are “yes,” then I guess we also have to wait for the antibiotic apocalypse before we get a substantial change in policy.

On the antibiotic-resistance front, we seem to be able to insist on antibiotic stewardship.  Initiatives from the Centers for Disease Control with enforcement through the Center for Medicare and Medicaid Services assure that hospitals and now outpatient and even long term care facilities will establish antibiotic stewardship programs in the US. But these regulatory moves (mandated by the 21st Century Cures Act) don’t cost much in terms of real government funding and, ultimately, will probably save healthcare dollars. The same thing is true for regulatory moves that will establish feasible and rapid clinical development pathways for antibiotics that target very specific, small populations of patients such as those that are only active against a single species of bacterial pathogens (Limited Population Antimicrobial Development [LPAD] in the 21st Century Cures Act) (LPAD Guidance is expected soon from FDA).  All of this and more in the 21st Century Cures Act is good and we should all be thankful that Congress was able to get its act together and pass this important legislation.
 
But all of this, including the critically important regulatory innovations will be for naught if we don’t fix the broken antibiotics market. Without a clear path for a return on their research and development dollars, private industry will simply not invest.  Companies that are currently investing in the area may finally give up the ghost and, like many before them, abandon the area altogether.

In thinking about the climate change article in the Times, I am reminded of the global pandemic of methicillin-resistant staphylococcal (MRSA) infections that began in the early 1980s. By the 1990s, MRSA became part of common language.  I gave a lecture at a retirement community yesterday and everybody recognized the term, MRSA. These resistant isolates grew to 30-50% of all staphylococcal infections, and in emergency rooms, up to 70% by the turn of the century.  Until 1999 there was only a single reliable antibiotic to treat serious MRSA infections – vancomycin.  By 1989 vancomycin resistant enterococcal (VRE) infections had emerged and were causing havoc in US intensive care units.  In 1999 linezolid (Pfizer) was approved and in 2003 daptomycin (Cubist) was approved.  Both these drugs became over $1B per year sellers because they offered an alternative to the only other drug available for MRSA, and they offered possible therapy for enterococcal infections as well.  But look what we had to endure before these drugs came out.

Today, we are dealing with KPC, NDM-1, Acinetobacter and other highly resistant infections.  Yes, we have drugs available today that we didn’t have just a few years ago and we have more to come in our thin but existing pipeline. The question is, will we have to wait until emerging resistance in Gram-negatives becomes like the MRSA and VRE of this century. To be assured of a robust antibiotic pipeline, we must take this last step and provide an assured return on investment for those companies that deliver such needed new therapies. If we wait for the apocalypse, it will take us a decade or more to rebuild lost abilities to discover and develop antibiotics.

There have been a number of well-considered proposals on how to fix this broken market (stay tuned for more details). All involve spending real money.  I’m talking about a total of $2 billion per year for 10 years globally.  The US share would depend on which other countries would partner with us (I assume Europe would do so. China?). And here we run into the problem.  Just like climate change, we would have to spend real money.  Of course, compared to jet fighters, nuclear arsenal maintenance, and other priorities, $20 billion over ten years is peanuts. But to our administration and to congress, this seems to be an insurmountable obstacle.


Please – lets not wait for the apocalypse. Lets do something now before we lose more companies and more expertise to denial of the inevitable.

Friday, September 8, 2017

Let's Kill Colistin/Polymyxin

COLISTIN

Today’s blog is inspired by recent grant proposals, discussions, publications and the promise of our antibacterial pipeline today. I see many proposals where the concept of a better polymyxin is envisioned or where the structure of polymyxin is used as a lead to generate a drug that will attack the bacterial membrane to allow penetration of other, more effective antibiotics. But my view is that we should relegate polymyxin and its relative, colistin, to the trash heap of unused drugs – the sooner the better.  And I believe that we are near the threshold of being able to do just that.

My strong feelings come from an experience I had during my training.  I’ve recounted this in both of the books I’ve written. I was working in a county hospital as an infectious diseases fellow.  The hospital was a trauma center and had a large burn unit. Burn patients were regular users of the infectious diseases service.  Even today about 70% of severely burned patients will experience a burn wound infection and these infections are a common cause of mortality in this group of patients. I was called to the burn unit to see such a patient with Pseudomonas aeruginosa bacteremia. I began treatment with carbencillin and gentamicin (you see how long ago this was). But the next day the lab reported that the isolate was resistant to all antibiotics tested except colistin.  And they told me that a second patient on the unit was now also growing Gram-negative rods in blood cultures. In all, we treated maybe six or seven patients for this infection with colistin.  All but one (as I remember it) died with continuing positive blood cultures in spite of adequate (above MIC) levels of colistin in plasma (measured by bioassay). All showed evidence of kidney damage during therapy. I was never forced to use colistin again because a robust antibiotic pipeline made that unnecessary for the most part.  For those rare patients where their infections seemed resistant to all available antibiotics except colistin, since they were all urinary tract infections, I was able to devise combination therapy to get those patients through their infection without having to resort to colistin. 
 
Today we now have ceftazidime-avibactam (caz-avi). A recent prospective observational study of caz-avi demonstrated a 9% mortality in the caz-avi group vs 32% in the colistin group – a 23% reduction in mortality when caz-avi was used as compared to colistin. Most infections treated were pneumonia or bloodstream infections. Renal failure was significantly more common the the colistin group and overall, there was a 64% chance that caz-avi treatment would lead to a better outcome compared to colistin.

We are also about to have plazomicin – a new aminoglycoside antibiotic. In their prospective randomized clinical trials they demonstrated an all cause 30 day mortality of 11.8% for plazo treated patients vs 40% for those treated with colistin. The difference in the subset of aptients with bloodstream infections was even more dramatic in favor of plazo.  11% of plazo treated patients and 29% of colistin treated patients suffered a serious adverse event related to decreased kidney function.

Vabormere (OK – it sounds like a body of water from the Tolkien novels), a combination of meropenem plus the broad spectrum beta-lactamase inhibitor vaborbactam, was just approved by the FDA based on data in the treatment of complicated urinary tract infections where it was non-inferior to piperacillin-tazobactam.  Vabormere seems to specifically target Gram-negative infections where the pathogen carries a carbapenem hydrolyzing enzyme of a particular type such as KPC that is widespread in the US. As a side note, it was approved based on a single trial and yet its label did not restrict its use to those patients without other alternatives. Would anyone like to guess whether vabormere will be superior to colistin in its ongoing trial of treatment of carbapenem-resistant infections?

Then there is cefiderocol – a novel cephalosporin antibiotic developed by Shionogi that uses a siderophore to get into Gram-negative bacteria. It has completed a trial in complicated urinary tract infections where it was non-inferior to imipenem, a carbapenem antibiotic.  In vitro, the compound is active against many carbapenem resistant strains including those not covered by caz-avi or vabormere. A competitor for cefiderocol would be aztreonam-avibactam that seems stuck in early clinical development. But both of these drugs should also be superior to colistin/polymyxin. 



For now, for most infections, even drug-resistant infections, there is no reason to use colistin/polymyxin.  Over the next year, we will be able to treat even more resistant infections without using these ineffective and toxic drugs. The only reason to continue their use is the cost of the new drug therapies.  But when compared to the cost of kidney failure and mortality, what are we talking about?