The Regulators

According to an interview by the Wall Street Journal with Thomas Lonngren, the outgoing Executive Director of EMEA, pharmaceutical companies must innovate and regulatory agencies have to get together.  From my prismatic view of the world through the kaleidoscope of antibiotics, this seems easier said than done – especially given the state of affairs at the FDA. 

Innovation in antibiotics has been difficult to say the least. But I see hopeful signs on the horizon.  New classes (at least for human therapy) are being studied by a number of companies, large and small, with a few having reached late stage development.  BC-3781, a pleuromutilin from Nabriva and NXL-104, a non-beta-lactam beta-lactamase inhibitor from Astra-Zeneca-Forest are examples of such compounds in phase II or later.  The siderophore monobactam from Basilea and the siderophore monocarbam from Pfizer are examples of new classes entering early clinical development.  Of course, we are all still waiting for the genomics revolution to hit antibiotics either in terms of antibiotic discovery, choice of patient populations for study or even for non-clinical safety studies.

Although the regulators frequently call for more innovation, it turns out that in many cases it is the regulators themselves that stifle it.  A good example is the conundrum antibiotics developers now face in designing trials in community acquired bacterial pneumonia.  The patient population for analysis must be those who have a documented bacterial infection.  But even in the best of trials, no more than 30% or so of patients enrolled will fit this definition for lack of a bacterial diagnosis at baseline.  The trials remain infeasible just based on the size of the enrollment population at this rate of diagnosis.  The diagnosis rate must be at least 50% for trials to be feasible.  To get there, given the paucity of FDA approved diagnostics available for pneumonia-causing pathogens in human specimens, experimental methods would have to be used.  This would require (1) a diagnostics company to see a potential market in such a diagnostic such that they would develop one (so far no one does) or (2) trail-blazing and risk-taking on the part of the pharmaceutical company sponsor.  I don’t object to this as long as the sponsor has $30 million or more per trial to put at risk.  Here, regulators could help by providing such a pathway and/or sponsoring research that would lead to a path forward.  But to hold companies hostage awaiting a way forward will only lead to more defections from antibiotic discovery and development. 

One wonders if the regulators are following Mr. Lonngren’s advice and speaking to each other about coming together on a feasible path forward for the development of antibiotics for community-acquired pneumonia.  The same could be said for hospital-acquired pneumonia, ventilator associated pneumonia, and skin and skin structure infections where guidelines from the FDA require either infeasible trials or trials that are feasible but insensitive or clinically irrelevant.  These guidelines differ markedly from anything coming from EMEA. 

My hope would be that EMEA would reject the FDA guidelines and simultaneously try and bring the FDA to a more rational stance. After all, EMEA has stated publicly on numerous occasions that the development of new antibiotics for resistant infections is their highest priority.  This laudable stance seems the polar opposite to that of the FDA. 

So – will EMEA follow Mr. Lonngren’s direction and both stand up to the FDA and try and bring the FDA along on some more reasonable (read feasible) path or not?  We all await the results of the scientific advisory group that they will convene sometime soon. 

And by the way - Happy New Year to all of you out in antibiotic land. 

Related articles

• Drug Regulator Urges Innovation (online.wsj.com)

Timeout!

At this time of year, my thoughts turn to others – one in particular.  No – its not cholera in Haiti. 

Many years ago, when infectious diseases physicians could still perform and read their own Gram’s stains, examine their patients’ cultures and susceptibility tests, I was training with Manny Wolinsky of non-tuberculous mycobacteria fame.  At my side, was Michael Lederman.  For reasons I could never understand, Michael decided that he would go into immunology and ended up being on the front lines of the HIV epidemic.  I finally realized that he did this because he was smarter and more prescient than me.  After all – how many companies who started in antibiotics are still carrying out research in the area?  For HIV – most companies who started out there are still in the fight. 

Michael is known as Leachem to his friends.  He likes to speak and write backwards.  They say that most brilliant people are quirky!  He experienced a life-threatening type-I aortic dissection this past week.  I understand that he is recovering well.  But I wonder how his interaction with the hospital bureaucracy went given his penchant for speaking and writing backwards.  I’m sure that the main reason he survived is that he made his own diagnosis within milliseconds of experiencing symptoms and was able to prod the surgeons into taking him seriously. Leachem is a spectacular clinician and diagnostician and I am sure that even his own illness would not have interfered with his ability to discern his own diagnosis immediately and correctly. 

Leachem, being an acute ID physician, is more than aware of the dangers of being in the hospital.  When told that the only people washing their hands were the infectious diseases colleagues visiting him, while still on the ventilator, he wrote “____heads!”  on a pad of paper.

I understand Leachem is back at home recovering at this point.  Home is a much safer place than the hospital.   So, I wish him an his family all the best.

Superbugs and NXL-104

Image via Wikipedia

You know there is trouble brewing when the latest superbug hits the New England Journal of Medicine.  That’s just what happened this week with the publication of a perspective on the latest superbug – or super resistance gene – NDM-1 – by Bob Moellering.  NDM-1 stands for New Delhi Metallo-Beta-lactamase.  It is actually a gene encoding an enzyme (beta-lactamase) that chews up our most advanced antibiotics.  Having a metal ion in its active site and not a serine, it is resistant to our usual Beta-lactamase inhibitors including the latest addition to our pipeline for the treatment of serious Gram-negative infections, NXL-104.  Luckily, NDM-1 does not attack one of our antibiotics, aztreonam.  Most of the pathogens that carry NDM-1 also carry other B-lactamases that do hydrolyze aztreonam.  They also carry a host of other resistance genes.  This may be related to the fact that this gene and the plasmid that carries it evolved in India and is widespread on the Indian subcontinent.  In India, there is widespread use of antibiotics without prescription and frequently in low dosage or for only a few days resulting in inadequate therapy perfect for selecting resistant bacteria.

Dr. Moellering cites the Centers for Disease Control as stating that NDM-1 bearing bacteria should respond to the usual infection control measures.  While that may be true, our experience with other new Beta-lactamases, with MRSA and with all the other superbugs has been that once they start to spread, with the exception of a few especially diligent centers, the cat is out of the bag.  NDM-1 has already found its way to the UK and even over here to the US.  It is probably just a matter of time before it becomes even more widespread.

Once again, we will need new antibiotics to fight this infection.

NXL-104 is an inhibitor of Beta-lactamase with serine at their active sites – so not NDM-1.  But it does hit some of the most difficult of these enzymes like those that hydrolyze our most valuable antibiotics like imipenem.  NXL-104 was originally discovered at Aventis (now Sanofi-Aventis) but was spun off into Novexel at the end of 2004.  Novexel took the compound through Phase II trials in combination with ceftazidime, another antibiotic plagued with resistance – but which is susceptible to hydrolysis by NDM-1. Forest is developing NXL-104 in combination with their recently approved antibiotic, ceftaroline. 

Last year at the ICAAC meeting, David Livermore pleaded with industry to combine NXL-104 with aztreonam.  With aztreonam being resistant to NDM-1 and with 104 inhibiting the enzymes that might otherwise hydrolyze aztreonam – NXL-104-aztreonam could clearly be a winner for this particular superbug.  Is there enough of a medical need?  Will there be enough of a medical need in the next five years (when NXL-104 might be launched)?  I don’t know.  But I am sure that these are exactly the questions Astra-Zeneca and Forest are asking themselves.

Astra-Zeneca and Forest acquired Novexel in a complicated deal at the end of 2009 – almost exactly one year ago.  In their annual report from 2009, Astra-Zeneca stated that ceftazidime-104 should enter phase III trials at the end of 2010.  So far (to my knowledge), that has not happened.  So I wonder what happened to NXL-104 and whether the powers that be are seriously considering David Livermore’s suggestion . . . .

Related articles

• "Super superbug" NDM-1 spreads in Europe (reuters.com)

Antibiotics and the FDA - Where are we?

Janeen Interlandi just published an interesting article in Newsweek where she explores the perfect storm we are facing over the future of antibiotics.  She concludes that we need a new way of thinking about antibiotics, but offers precious little in terms of direction. I guess she is just as confused as the rest of us.

I continue to believe that one way forward will be for the industry and the FDA together to devise FEASIBLE trial designs for antibiotics such that they can be developed and approved in the US.  The other option – I think of it as the nuclear option – is to declare the US antibiotic market irrelevant and inaccessible and to focus on Europe and, more importantly, the emerging markets like Brazil, Russia, China, India, Mexico and Turkey (BRCIMT).

But since the US is still a relevant, even important, market, lets examine what we have left in terms of a path forward for antibiotics and lets contrast that with where we need antibiotics the most.  The table below shows that those indications where the medical need, at least in the US, is the greatest for new antibiotics are either not so attractive markets or, in the case of hospital-acquired pneumonia and ventilator associated pneumonia, are indications where the FDA-required trials are simply infeasible.  The other message from this table is that there are precious few indications left in which new antibiotics will be marketed.

So, the choices we have are:

1.  A process that allows industry and FDA to actually come together and agree on FEASIBLE trial designs (the FNIH seems to be the same people saying the same things but in private).
2.  Incentives that will work (but we still need feasible trial designs for indications where there is clear medical need).
3.  Further loss of pharmaceutical companies from antibiotics research.
4. The nuclear option.

Under number 1 above, and in line with Ms. Interlandi’s article, I favor a new approach.  Lets take the current FDA team and all its consultants out of the room and replace them with FDA top management and their consultants.  Lets get an entirely different team of statisticians.  Lets get industry and IDSA to present their best and most innovative designs and strategies. Lets lock the room for about 3 months and make them come up with something FEASIBLE for antibiotic development.

If we can’t make this work, we’re left with the nuclear option.  Option 3 will probably occur anyway.

Related articles

• Are We Running Out of Antibiotics? (newsweek.com)

Paul Ambrose on the FDA's Skin Infection Guidance

This is a post submitted by Paul Ambrose (with a few comments by yours truly).

Ambrose et. al. suggested to the FDA an others that there was an alternative pharmacometric-based method to using historical data to estimate the magnitude of antibiotic treatment effect. The pharmacometric-based method overcomes the numerous limitations inherent in the interpretation of historical data and is based upon contemporary data and clinical endpoints.   Better yet, the methods would utilize authenticated clinical data that was part of recent NDAs.  The method relies upon the construct exposure-response or pharmacokinetic-pharmacodynamic relationships, which are typically evaluated as part of modern-day drug development.    
The upper and lower regions of exposure-response relationships for efficacy provide estimates of drug effect as exposure increases toward maximal-treatment effect or as exposure decreases toward no-treatment effect (Figure 1).  The difference between the patient response rates at the upper and lower asymptotes closely approximates the treatment effect (i.e., the maximal benefit of therapy in a given patient population).  Such an estimate provides the critical missing data needed to design non-inferiority studies with appropriate statistical power, which in turn obviates the need for superiority study designs.  Moreover, these data make it possible to estimate the no-treatment response rate without exposing patients to any risk (mortality or mortality) incurred by conducting superiority studies that are placebo-controlled or which utilize suboptimal dose ranges or comparator regimens).
 

Comments from Antibiotics – The Perfect Storm - For those of you not in the know – Paul is simply proposing to take the various drug exposures that might occur across a large clinical trial and extrapolate them to zero as a way of estimating the “no treatment”effect.  The treatment effect is then defined by the difference between that and, I suppose the mean or maximal drug exposure for the group of treated patients.

Paul and his collaborators have a number of other comments and critiques of the FDA’s stance. I refer you to their FDA Docket submission for more details.