Antibiotics - The Perfect Storm - The BOOK - NOW AVAILABLE

Wednesday, December 10, 2014

Antibiotics go Wild and Crazy!

This week Merck announced that it will acquire Cubist for $9.5 billion at a 35% premium over the stock price. Cubist is a mid-size pharmaceutical company with a recently diversified portfolio of products all acquired through acquisition. They currently market Cubicin and Dificid for Gram positive infections and C. difficile respectively.  Cubicin is already a $1 billion seller. They will soon market tedizolid and ceftolozane-tazobactam through their acquisitions of Trius and Calixa. Merck is clearly targeting the specialty hospital marketplace with this acquisition and may hope to complement the Cubist products with their own imipenem-cilastatin-MK-7655.  7655 is currently in Phase II trials for urinary tract infections where it has been for two years now.

This announcement is bittersweet for me. This clearly continues a string of good news for antibiotics and antibiotic R&D.  It is further proof that large pharmaceutical companies now agree that antibiotics can provide a return on investment and that they are willing to put there money where there mouths are. The acquisition of Cubist will also bolster the appetite of investors beyond the excitement provided by Cubists own acquisitions of Optimer and Trius last year.

On the negative side, there are always the “synergies” that go along with these mergers.  The Merck investment in their antibiotic R&D portfolio has been exceedingly modest over the last decade or so.  Will this change or will Merck now go about ridding itself of the Cubist R&D organization to achieve its promised cost-savings?  On the risk side, essentially all of Cubist’s late stage antibiotics have come from external sources.  Their own discovery organization has contributed little to the late stage pipeline.  Merck’s own discovery organization has provided only MK-7655 – a knock off or avibactam – and little else for many years.  How Merck will deal with the two discovery groups is a matter of concern and remains a complete unknown at least to me.

Speaking about the commercial side, Merck is selling ertapenem, launched in 2002 where it is doing reasonably well. Cubist has done a yeoman’s job with Cubicin bringing in $1 billion in revenues almost exclusively from the US since its launch in 2003. Cubist has never had a real European marketing organization and has depended on unreliable partners like Novartis for their meager European sales. Will Merck be able to do better? One would hope so.

Recently, Cubist lost the first round in a battle over their more recent patents for Cubicin.  The patents that were denied by the court included methods for purification of Cubicin and for the current dosing regime that was discovered in preclinical and later in clinical studies to reduce muscle toxicity and at the same time maintain antibiotic efficacy. While these patents are subject to appeal, it is not clear the Cubist will prevail.  That said, Merck has clearly determined that the future revenues to be gained by Cubist’s new products, tedizolid and ceftolozane-tazobactam are worth the price they have offered even without the additional 4-5 years of exclusivity for Cubicin that may be wiped off the map by the courts.


 With the re-entry or expansion of large pharma’s efforts in antibiotics, the deep pockets of pharma have opened once again.  That means that venture capital and perhaps even private equity will now also loosen their purse strings to support new antibiotic research and development.  A new golden age for antibiotics is knocking at our door.  Lets be sure to welcome it with our ongoing efforts to improve the regulatory and financial climate for new antibiotics.

Friday, December 5, 2014

FDA Beats Europe!




Today the FDA beat Europe on the antibiotics front for the first time in a long time.

There was another advisory committee for anti-infectives at FDA today.  This one focused n the presentation of ceftazidime-avibactam for approval for use in patients with urinary tract infection, intra-abdominal infection bacteremia and nosocomial pneumonia in patients with limited or no other treatment options. As you may know from previous blogs, avibactam is a novel beta-lactamase inhibitor (where beta-lactamase is the major mechanism of resistance to beta-lactam antibiotics like the penicillins, cephalosporins and carbapenems) that provides activity against key resistant pathogens including carbapenem-resistant Enterobacteriacea (CRE) that kills almost 2000 Americans every year according to the CDC. Ceftazidime was developed initially by Novexel, which, in turn, was purchased by Astra-Zeneca in 2009 but where Forest-Cerexa (now Actavis) retained the US rights to the compound.

Incredibly, the phase II data, completed in 2010 by Novexel, comprised the main data used for approval.  The PK/PD data were also mainly, but not entirely, based on data from Novexel also available in 2010. The complete microbiology surveillance dated from 2012 – but could have obviously been done sooner.  What accounts for the delay?  The evolution of FDA thinking on providing rapid availability of new antibiotics active against key resistant pathogens for patients who need them accounts for this delay. 

Today’s meeting shows that in spite of all the arguments of yesterday (see that blog), the FDA is moving forward to carry out their mission of providing tools and options for American physicians and patients when needs arise and perhaps even ahead of time. Perhaps FDA is dumb like a fox.  Yesterday’s disappointing meeting clearly prepared the advisory committee up for today’s approval of ceftazidime-avibactam for use in patients with unmet needs based on limited data.

Questions posed to the committee and their votes –

1.     Has the applicant demonstrated substantial evidence of safety and efficacy of ceftazidime/avibactam for the proposed indication of complicated intra-abdominal infections, when limited or no alternative treatments are available?  
Yes = 11, No = 1.

2.     Has the applicant demonstrated substantial evidence of safety and efficacy of ceftazidime/avibactam for the proposed indication of complicated urinary tract infections, including pyelonephritis, when limited or no alternative treatments are available?
Yes = 9, No = 3.

3.     Has the applicant demonstrated substantial evidence of safety and efficacy of ceftazidime/avibactam for the proposed indication of aerobic gram-negative infections (including hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia and bacteremia) when limited or no alternative treatments are available?
Yes = 0, No = 12

4.     Has the applicant demonstrated substantial evidence of safety and efficacy of ceftazidime/avibactam for the proposed indication of aerobic gram-negative infections (including hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia and bacteremia) when no alternative treatments are available?
Yes = 1, No =11

Of course, for the last question – the committee was basically voting on the use of ceftazidime in hospital-acquired pneumonia – an indication for which it has been approved for almost 30 years. Why were they so negative?  They wanted data in humans that were largely lacking in the NDA. One caveat – the FDA does not have to follow the advice of its advisors.  We await further developments here.
 
Today’s meeting also provides some optimism that Actavis is serious in their desire to enter the antibiotics arena.  Will they be commercially successful? That remains to be seen. 

AstraZeneca is responsible for submitting the ceftazidime-avibactam dossier to the European regulatory authorities.  This is planned for early 2015 and will be based on data that includes the phase III data according to their recent press release – accounting for the delay compared to Actavis and the FDA where the submission did not include recent phase III data. This means that the drug will be available in Europe about one year after its release in the US.  Was this a result of EMA’s guidance or the preferences of AstraZeneca or both? I don’t know the answer.  But it looks like we may be going back to the normal situation of 20 years ago where antibiotics are launched in the US well before they reach the market in Europe.


For now, today’s FDA advisory committee sets an important precedent for the future and puts the FDA well ahead of Europe in the speed with which it can move and in its willingness to approve new antibiotics based on a more limited data set. In spite of remaining issues with FDA guidance, required endpoints and other problems, today they positioned themselves well ahead of Europe and the rest of the world in responding to the needs of Americans.  I can only say – well done!  Its about time!

Thursday, December 4, 2014

FDA and Resistant Infections - the Advisory Committee



Well, today was a big day for the FDA, or not, depending on how you look at things.  The Advisory Committee met to discuss the FDA’s approach to the streamlined development of antibiotics for patients with unmet medical needs – i.e. – those with highly resistant infections where treatment options are limited.  Once again, the makeup of the committee leaves much to be desired.  There are precious few members with expertise in the development of antibacterial drugs in general and in industrial settings in particular.  There are clinicians, statisticians, experts on malaria and on microbiology and pharmacology – but not on the design and execution of clinical trials for antibacterials.  So, my expectations on what would come from the committee per se were low.

The FDA briefing materials also contributed to my low expectations for this meeting.  There was no consideration of the use of pharmacometrics to understand control levels of response in inadequate therapy against which superiority trials of new drugs could be tested. This is in spite of the obvious fact that the FDA is rapidly improving in its ability to understand and manipulate these kinds of data as indicated by the briefing materials for the Cerexa meeting on December 5.

The FDA seemed stuck on active control designs for superiority trials that, according to most industry speakers, will never be feasible.  There was also a good deal of discussion on the use of non-inferiority trials and then an extrapolation from those data plus a large in vitro and PK/PD data base to patients with more rare resistant infections.  This is all good – and we may be stuck with this if the FDA cannot find other ways forward – but what everyone wants is studies in patients with resistant infections.
 
In spite of my expectations, there were some moments where I could see light. There was a clear consensus (except the statisticians) that streamlined trial design is a good idea to allow for the rapid availability of antibiotics for resistant infections to patients and physicians that need them. Things fell apart later when trying to dissect out the details as to how one would do this in practice.

Richard Wunderink and Jeff Alder reminded us how difficult it is to carry out studies in ventilated patients with far less than one patient per center per year being enrolled. The superiority trial for linezolid vs. vancomycin for MRSA VAP took over five years to enroll. Clearly ways to streamline trials in these patients are desperately needed.  But can we get there? There were no clear answers here today. 

Paul Ambrose reminded us all that resistant bacteria are just bacteria.  They follow the same PK/PD rules as susceptible bacteria.  The implication is that with good PK data plus clinical data in susceptible infections – we can be assured that the antibiotics will work in resistant infections.  My only caveat- as noted by some panel members and speakers is that the patient comorbidities may play a confounding role here.

Several speakers emphasized the restrictions on prior antibiotics as being key in preventing trial feasibility because of the impossibility of patent enrollment. While stratifying for prior antibiotics may be good, and stratifying across body sites (pneumonia vs UTI for e.g.) could also be good – these multiple stratifications rapidly lead to increased trial numbers which remain out of reach. I took comfort in the fact that Ed Cox of the FDA in his first sentence (almost) mentioned feasibility before he mentioned scientific rigor.  Maybe there is room for hope here.
The approaches discussed for antibiotics that cover a broad spectrum of pathogens like non-inferiority trials with some extrapolation will not work, though, for those drugs only active against specific pathogens like Acinetobacter or Pseudomonas.  At the end of today’s meeting, I am concerned that there is no clear way forward at FDA for such specifically targeted drugs right now. It looks like the FDA wants to move forward – and if they do – it will be by the seat of their pants on a case by case basis as far as I can see.  But that is better than succumbing to paralysis and not moving at all.




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.