David's New Book

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.