Antibiotics - The Perfect Storm - The BOOK - NOW AVAILABLE

Monday, November 24, 2014

Will FDA Strike Again?

On December 4 and 5, the FDA is gong to hold back-to-back advisory committee meetings.  On Dec 4, the meeting will discuss clinical development approaches for antibiotics designed for patients with unmet medical need – in other words, those with serious infections caused by highly resistant bacterial pathogens.  On Dec 5, the committee will consider the submission by Cerexa/Forest/Actavis for ceftazidime-avibactam in the treatment of intra-abdominal, urinary tract and other infections where resistance is problematic.  These meetings could be of historical importance.  I won’t have the space to deal with the Dec 5 meeting preview here –the FDA has not yet released the background materials for that meeting – more later.

The FDA has already released background material for the December 4 meeting on the development of antibiotics for unmet needs. I have read this document and find myself, once again, disappointed. About half of the document is a historical review justifying the FDA approach to non-inferiority trials over the last several decades. They now say they are very satisfied with the outcome of their labors and are ready to move on to the next thing.  Unfortunately, while they may be satisfied with themselves, I think it is too early to pop the champagne. I can only conclude that this part of the backgrounder is more for FDA’s political watchdogs in congress than for anyone truly interested in bringing new antibiotics to the patients and physicians who need them. While I agree that the FDA has made significant progress in at least allowing the conduct of clinical trials that are actually feasible in the real world, the endpoints they have chosen for these trials still leave much to be desired. I won’t even begin to talk about the requirement for placebo-controlled trials for sinusitis and bronchitis – that NO ONE has undertaken since the edict came out around 2003. For skin infections, the endpoint remains a decrease in the size of the skin lesion at day 2-3 – not cure. For community-acquired pneumonia it remains symptomatic relief on day 4 or so – not cure. For hospital-acquired pneumonia it remains mortality even though about half of the mortality in this disease is completely unrelated to the infection being treated.  It should be cure of the infection. The situation is still much better and, in my view, more rational in Europe where cure of the infection remains the relevant endpoint for all these infections.

But the most worrisome section of the backgrounder is that dealing with the development of new agents targeting resistant pathogens – the unmet needs population. A few highlights (lowlights) that caught my attention are noted below.

1.     A superiority trial nested within a non-inferiority trial. Actually – this may be a highlight – I’m not sure.  We’ll have to hear the discussion.  But the last time I was involved (indirectly) with the agency on just such a design, we had designated a subgroup of the overall population, those with resistant infections, as an analysis population. Here we were going to look at failure rates for the control antibiotic and the new drug.  We carefully provided for patient safety by excluding patients with the most serious infections from study entry and by allowing a rapid switch either to the alternate regime (blinded) or exit from the study to receive another standard of care antibiotic. The FDA balked at the design because they didn’t like the subgroup analysis portion.  But the backgrounder now indicates that they would accept such an analysis.  Which FDA is which?
2.     For superiority trials, they still seem to be laboring under the illusion that head to head trials are feasible.  They’re not.  See my blog on superiority trials.
3.     As I noted in that blog on superiority designs, externally controlled trials would be the most feasible. But the FDA seems at a loss as to how to actually design such trials. They are harkening back to mortality rates as a preferred endpoint in externally controlled superiority trials – again – for the most part – completely infeasible especially in the circumstance they are discussing – multiple body site infection trials. The FDA seems to recognize the infeasibility of this approach, but they go on to flounder around about other possible approaches.  I’m worried that they don’t know what the endpoints should be at the different body sites.  (Hint – Cure)!!
a.     They suggest the possibility of an externally controlled non-inferiority design where you could actually show superiority.  This at the very least will increase trial numbers and expense at a time when we want to do the opposite and at worst is simply infeasible.
b.     They note that there may be disparate outcomes in different body sites and they give the examples of tigecycline and doripenem in ventilator-associated pneumonia as examples. Clearly they are correct – but good human PK/PD work prior to an efficacy trial should be able to deal with this.  Also, as the FDA suggests, some stratification may be necessary – but this would have to be done in a way that trial size remains small.
4.     They also discuss single pathogen trials. Here they seem to rely on rapid diagnostic approaches that (1) do not really exist and (2) when they are “available” are not sufficiently rapid. (See my blog on rapid diagnostics). Clearly, the FDA is still lost here.
5.     Finally, I will note that in several areas they mention the fatal words “further work.” The last time they said that, related to trials in skin infections, the antibiotic pipeline was set back at least 5 years.

I look forward to listening in on this meeting.  I can only hope that the AIDAC will see some of the same issues that I see and that they will help sort this out – but my expectations are low.

Now, it just remains for me to wish all of you in the US a most happy Thanksgiving holiday.  I’ll probably come back to you after the AIDAC meetings with summaries.

Tuesday, November 4, 2014

Viehbacher, Sanofi and Antibiotics

Sanofi CEO Chris Viehbacher was just fired by the Sanofi Board.  Viebacher was previously head of the US business for GSK.  When Andrew Witty was appointed as CEO at GSK, Viebacher jumped ship for Sanofi.  But he apparently brought with him Witty’s and GSK’s passion for antibiotic R&D.

The story of antibiotics at Sanofi is a very mixed one.  At the time of the Sanofi merger with Aventis, Aventis was in the midst of spinning off its entire antibiotic research unit in Paris.  Sanofi, then under the direction of Jean-Francois Dehecq, and after much debate, completed the spin-off to form Novexel in December, 2004.  Novexel was purchased by AstraZeneca in 2009 in a complicated deal with support from and obligations to Forest (now Actavis). Hence, all those Sanofi assets, some after considerable development at Novexel, went to AstraZeneca and Forest.   One of those assets was the compound now called avibactam, which has just completed its phase III trials in intra-abdominal infection and should be approved next year.

Enter Viehbacher 2008.  He quickly decides that exiting antibiotic R&D was a big mistake and he tries to restart the group at Sanofi’s research site in Toulouse, France.  Under his new R&D head, Elias Zerhouni, (an academic researcher who headed the NIH in the US for a number of years under George W. Bush) they hire a new head of anti-infectives research.

Around the same time, with pressure from patent losses, Viehbacher and Sanofi developed a grand plan to reduce costs and increase research productivity by closing research sites in France and moving more research to their new Boston site at their newly acquired Genzyme affiliate. But this led to protests from everyone in France from the government on down to Sanofi employees threatened with job losses.  As a result of this political pressure, their plan went from something like 2500 jobs cut to 800 and counting. Having worked as an executive in France (but based in the US) – I can only empathize with Sanofi management.  France is not a very business-friendly place and necessary strategic restructuring is challenging in the best of times. Part of this plan involved closing their research site at Toulouse where the nascent anti-infectives research group is located.  Within less than two years their new head of anti-infectives resigned. The group was left in better shape in terms of their understanding of anti-infective R&D but worrying about their future either in Toulouse or possibly in Lyon.  The departure of Viehbacher can only add to their anxiety.

Since 2008, anti-infectives research in Toulouse has produced no projects in late stage development. While this is not surprising given that they had to restart essentially from nothing and given the turmoil of the last six years, it remains disappointing.  Perhaps their most important foray in external collaborations was their agreement with Rib-X (now Melinta) in 2011 for novel antibiotics targeting the ribosomes of Gram-negative superbugs. But this apparently led nowhere and the collaboration was dissolved in 2013.

With the departure of Viehbacher, the Sanofi board has apparently already approached Pascal Soriot, the current CEO of AstraZeneca – who wants out of the antibiotic R&D business.  Luckily (as far as I am concerned), he was not interested in Sanofi.  And there, who can blame him given the travails of running a business in France? My big question is – what will happen to antibiotic R&D in the next version of Sanofi?  Will they regroup and make progress or will they join the legions of other companies abandoning the area?  As always, we await further developments.

Wednesday, October 29, 2014

Actavis-Forest - Are They Serious? - And - AZ Follow-up

It looks like the answer might be “yes.”  Actavis-Forest recently purchased Durata to acquire the recently approved long-acting, intravenous, glycopeptide antibiotic, dalbavancin, for $675 million or so.  I guess they were convinced that dalbavancin will be a big seller.  This is the second time dalbavancin has been sold.  The first was the sale of Vicuron with dalbavancin and anidulafungin (an antifungal) for $1.9 billion to Pfizer.  Dalbavancin failed to win approval at the FDA and Pfizer abandoned its further development.  Durata obtained dalbavancin from Pfizer.  The crazy part of the story is that George Horner was instrumental in the sale of dalbavancin to Pfizer when he was CEO of Vicuron and was also instrumental in leading the formation of Durata and its acquisition of dalbavancin back from Pfizer.  What goes around comes around!

Actavis-Forest – or at least Forest - thought that ceftaroline was going to be a billion dollar drug as well.  But it looks like ceftaroline sales are growing exceedingly slowly and if it earns $120 million in sales for 2014, four years following its approval in the US, it will be doing well. At the same time, Forest decided not to exercise their option to purchase Nabriva’s lefamulin, a novel pleuromutilin antibiotic available in both IV and oral formulations, that could have been in phase 3 trials for a year already. 

On the plus side, it is now clear that Actavis will file an NDA with the FDA using the data on ceftazidime-avibactam coming primarily from the recently completed trials in intra-abdominal infection plus data from in vitro, in vivo animal studies and from human pharmacodynamics. The urinary tract infection data will be submitted later as an sNDA according to the Actavis press release.

I am sure that there are many factors that Actavis-Forest have been considering in thinking about their commitment to the antibiotics space.  One factor may be that Actavis is headquartered in Europe.  Forest was an entirely US-based company with little in the way of ex-North American sales.  In their agreement with AstraZeneca for avibactam combinations, Forest was responsible for the US and AZ for everything else.  I believe that the relationship between the two companies was never a comfortable one on either side. Now that Actavis-Forest is based in Europe, the agreement with AZ becomes a little more bizarre. Wouldn’t it be an interesting turn-around in Actavis now purchases the entire avibactam franchise from AZ . . .

I, probably more than anyone, applaud the fact that Actavis-Forest remains committed to antibiotics.  But I have to say that I am a little confused by their strategy and their choices.  Their lack of an antibiotics discovery group remains a disadvantage for them. I also question their competence in the antibiotic marketplace. Yet here we are with Actavis having three potentially big selling antibiotics in their portfolio,  ceftaroline, dalbavancin and now ceftazidime-avibactam.  They have ceftaroline-avibactam (for which they have primary responsibility) lingering in phase II development as well as the rest of the avibactam portfolio including aztreonam-avibactam. I fervently hope that they can get it together enough to make a success of their endeavor in the antibiotics space.

In a follow-up to my previous blog on AstraZeneca and their seemingly imminent departure from antibiotics research, I can now add a few details. First, I have confirmed that researchers had been advised, at least informally, to find jobs elsewhere with two people having intimate knowledge of AZ research. Secondly, I am informed that as of about one month ago, there was not even a budget for the research group as of January 2015. AZ’s statements to the Wall Street Journal note that they have important drugs in development and they allude to their positive results from the ceftazidime-avibactam intra-abdominal infection trial.  At the same time they reiterate what they have been saying since March of 2013 – that anti-infectives will not be an area of focus for them and that they would be opportunistic in the anti-infective space.  That means, a far as I can tell, that they will try and partner, sell, spin-off or exit entirely.  So – in sum – I stand by my blog from last week.  I only hope that all of this leads to the continued development of their portfolio and that their researchers can continue to hunt for new antibiotics somewhere.

Tuesday, October 21, 2014

AstraZeneca is Cutting and Running!

For the past two years I have been warning that AstraZeneca would be giving up on antibiotic research and development.  Well, that day is arriving.  It looks like they will continue with their submission for market approval of ceftazidime-avibactam – but what comes after that is still unclear.  I have been able to confirm that AZ has told its antibiotics researchers that they should make efforts to find other jobs in the near future. Even though there has been no official announcement yet that the antibiotics research group will be disbanded, their scientists are starting to head for the hills.  As far as antibiotic discovery and development goes, this has to be the most disappointing news of the entire antibiotic era.  AZ has the strongest antibiotic pipeline in the industry and has an active and successful discovery effort. To jettison all this in spite of everything that has occurred in terms of regulatory reform and everything that is occurring and will occur in terms of improving the antibiotic marketplace, to me, is just the worst kind of hubris no matter what their other financial difficulties might be.

President Barak Obama has just issued a set of executive orders – OK - mostly without any sort of teeth and lacking any new funding – to improve both the regulatory and financial climate for new antibiotics.  David Cameron has ordered the establishment of an advisory panel on the economics of antibiotic development and marketing led by a renowned economist. If nothing else, this should show that the sun is rising on the antibiotic marketplace. But M. Soriot, the CEO of AZ, is not listening and

if he is, he apparently believes that all this will be too little too late for his antibiotic pipeline. To give him credit (not much), he did try and “partner” or sell or spin off his antibiotics unit over the last two years – apparently without success.  My guess is that he wanted more out of such a deal than anyone was willing to offer. So he, like Pfizer, Wyeth, Lilly, BMS, and many others before him, has decided that the solution to AZ’s ills is to jettison their antibiotic research altogether rather than accept something less than what he wanted. 

Given the importance of antibiotic research to society, one must ask where the heads of government are in all this. Did President Obama approach M. Soriot?  Did Prime Minister Cameron speak to Soriot?  I have it on good authority that the answer for the latter question is “no.” Should these government leaders share in the responsibility for the loss of AZ’s antibiotic research unit?  Absolutely!

At the same time and even more frustrating, is the fact that AZ is investing in a large research facility for Alzheimer’s disease and cancer in Cambridge, UK.  This facility will combine academic and industrial research like never before.  This is exactly the kind of endeavor that we need for antibiotic research but that no one is doing.  AZ could have incorporated antibiotic research in Boston into a Cambridge style arrangement – but they have chosen to jettison the whole thing instead.

Once again, we will have an exodus of competent researchers from the field.  I note that the head of the biology group at AZ’s antibiotics research center has already accepted a new job in the Boston area working on a company focusing on therapeutic bacteria of all things.  But he may be the exception.  Many of these folks will go on to other fields or they will retire and be lost to us as a resource for antibiotic discovery and development expertise.  This is a resource we cannot afford to lose. Sanofi, Roche – are you listening?  Hire these people!

Thursday, October 16, 2014

Frontline - The Trouble with Antibiotics

On October 14, PBS Frontline aired the second installment in its series of antibiotic resistance called, “The Trouble with Antibiotics.”  Although I was asked to preview the story for this blog – I found myself without internet access to be able to watch the show because of storms in our area.  It took five days to reacquire access – hence my tardy blog on the subject. 

The show is a fascinating look at the debate on antibiotic use on farms in the US and antibiotic resistance in American patients.  There is also a follow-up on the NIH outbreak of KPC Klebsiella.  But I concentrated on the issue of antibiotic use on farms and the inability of the FDA to regulate this use. There were many talking heads on the show saying that the connection between the use of antibiotics in animals and the appearance of resistant infections have never been clearly linked and that even in the cases where the evidence is strong – the numbers of patients affected are very small.  Wow! To me, this issue was settled back in the 1980s.  Here are some pieces of evidence that I find persuasive.

1.     First there was a study by Wolfgang Witte and his co-workers in the old East Germany.  Wolfgang worked at the East German CDC where all resistant organisms – coming from farms animals and from human infections – were collected from the entire country.  There were some advantages to a strict communist government I guess. These investigators identified resistance to an antibiotic called nourseothricin used in animals as a growth promotant.  The antibiotic was not used in humans – so there would be no particular reason for humans to be colonized or infected with nourseothricin-resistant bacteria unless they had been exposed to resistance coming from farm animals. In their studies, the researchers showed that this gene was carried on a genetic element that also carried another gene causing resistance to trimethoprim – an antibiotic used to treat urinary tract and intestinal infections in humans.  They clearly showed the link between the bacteria isolated from animals on farms and from humans both genetically and epidemiologically.  This remains one of the strongest studies ever done in this regard.  It was not cited in the Frontline report – because it wasn’t a US study?
2.     To me, the avoparcin story and its connection to the rise and spread of VRE is also very persuasive.  Avoparcin is an antibiotic related to vancomycin.  Vancomycin-resistant enterococci were first detected in Europe – specifically in France – in the late 1980s.  They rapidly spread throughout Europe and the US.  In America, they are now responsible for 20,000 infections in US hospitals and 1300 deaths every year according to the CDC.  In order to become resistant to vancomycin, a key antibiotic for treating these infections, enterococci have to acquire the ability to make an entirely different kind of cell wall – requiring a number of new genes. These genes come on a genetic element that is easily transferred – but how did this element end up in enterococci? Its origin – believe it or not – seems to be in the bacteria that produce vancomycin-like antibiotics since they themselves have to be resistant to the antibiotic’s effects in order to survive.  Bacteria in the guts of animals were selected, apparently through use of avoparcin as a growth promotant, and were then spread to humans through food in Europe.  Again – to me – this has been clearly demonstrated.  Further, when avoparcin was removed from the market as a growth promotant in a number of European countries, human colonization with VRE declined substantially.
3.     Highly resistant strains of Salmonella (DT104) have clearly been shown to colonize animals, to contaminate meat during slaughter and subsequently to cause disease in humans.  This organism has been the origin of a number of large recalls of hamburger in the US over the last several decades.

The Frontline show clearly described the FDA's attempt to regulate antibiotic use in animals in the 1970s and their utter failure to persuade congress to go along.  Apparently, four decades later, the FDA is still feeling the effects of their interaction with congress.  As I noted previously, we do not have a congress right now that is capable of acting in any sort of positive way - they only act by inaction. 

In their exhaustive and excellent review on this topic, Marshall and Levy state that the gaps in data do not justify our failure to restrict antibiotic use in animals in the US in ways similar to regulations implemented by European authorities.  To my mind, once gain, Europe is leading the way!  This is amazing to me since Europe in many ways is so much more dysfunctional than the US - but there it is.