Thursday, May 29, 2014

Pfizer Blinks!

This week, Pfizer announced that it was renouncing its pursuit of Astrazeneca after its last and “final” offer of $120 billion was rebuffed.  Personally, as far as I am concerned, and for the good of new antibiotics and pharmaceutical research, this can only be a good thing.  Besides, it couldn’t have happened to a nicer company! A combination of these two giants would have had a drastic effect on pharmaceutical research – probably mostly here in the US. Astrazeneca is already trying to shed its antibiotic research centered in Waltham, MA.  Pfizer, of course, discarded theirs several years ago.

The consequence of this will be that either Pfizer will go trawling after other large fish (but I can’t imagine who the next victim might be) or they will continue their breakup and split into a pharmaceutical company and a generics company. There are precious few other companies that offer a tax break (being headquartered in the UK), and that have an attractive pipeline. 

In my opinion, the shining jewel of the Astrazeneca pipeline is their series of antibiotics containing the Beta-lactamase inhibitor, avibactam. Pfizer would not recognize the gold in this rock anyway.  Other companies may have a problem with this jewel since it is tarnished by the deal with Forest (now Actavis) who has the US rights to the compound and who is responsible for US regulatory efforts. Forest has shown itself to be anything but stellar in terms of marketing antibiotics and recently, even in terms of developing them.  Forest took on development of ceftaroline-avibactam, for example – and that seems stuck in place.  Astrazeneca recently showed that ceftaroline (already marketed) is superior to ceftriaxone in the treatment of community-acquired pneumonia.  Superior!  Who says you can’t show that antibiotics are superior? But these data did not come from Forest (really).  So any company wanting to buy Astrazeneca’s antibiotic pipeline will either have to buy out Forest as well or deal with Forest as a partner.  I am sure that this is dissuasive.

I know that several people, including me, have offered to assemble a group of investors to buy out Astrazeneca’s antibiotic franchise, but all have been rebuffed.  I think AZ is looking for a company to buy out the products to be sure that they will be marketed appropriately.  They don’t trust private investors to do that, I suppose. Or – perhaps they just want more money.

In any case, physicians and patients in desperate need of antibiotics like those being developed by AZ-Forest are waiting by the sidelines while Nero fiddles.  So – Roche – in spite of its warts, I think the AZ antibiotics franchise is a good fit for you.  What are you waiting for?


Sunday, May 11, 2014

FDA and Pneumonia - More Irony

The FDA released its long-awaited new Draft Guidance on hospital-acquired pneumonia this week. Their guidance has not changed since I wrote a blog about my last meeting with the FDA antibacterial drug development task force back in September of last year. To reiterate what I stated back then . .  .
The FDA position is that they are unable to identify prior data on the clinical response to inadequate therapy or no therapy of HAP or VAP in the literature or in previous antibiotic trials.  Therefore, they cannot assign a treatment effect to antibiotics and therefore they have no justification of a non-inferiority margin using clinical response endpoints. Many thought leaders actually agree with this position and further claim that clinical response is vague and ill defined. So the FDA examined the literature using both observational studies and previous trials comparing inadequate to adequate therapy of these infections.  They identified a treatment effect of 42%. Then, of course, they did their discounting thing to get to an effect of 20% and a proposed margin of 10%. 

And, in fact, as the FDA pointed out during their advisory committee meeting, if you use a different method to calculate the 10% NI margin – the relative risk method, trial numbers actually go down as mortality decreases.  In their calculation, at a 15% mortality, which is more typical of modern trials in HAP/VAP, only 268 patients would be required in each arm given other reasonable assumptions. This is feasible.  But, if the FDA, statisticians and thought leaders agree on this -  should we care?

My belief, in addition to the problem of feasibility using mortality as an endpoint, is that it is confounded.  That is, many of the deaths seen in such trials are due to comorbidities and not infection.  How many of the deaths we see in such trials are we talking about?  One good study would suggest that there is about 13% overall mortality attributable to underlying disease and not infection.  I have discussed this with Brad Spellberg – he thinks this is high and he assumes that the real number is closer to 10% or about 50-67% of the total mortality (15-20% overall) seen in current trials of HAP/VAP. Statisticians argue that for non-inferiority this is not “confounding” in their world.  In my world, it means that those deaths – at least half of them, are unrelated to infection, are irrelevant, and drive the non-inferiority trial conclusion to the null hypothesis – non-inferiority.  I have never heard a statistician say that this is a good thing (at least until recently).  Brad notes that the trial is feasible assuming you use the ITT population and not just those with a bacterial pathogen identified at baseline.  I agree.  I also think (and Brad may agree)– “who cares?”

Even at 268 evaluable patients per arm, given the disappearing nature of the disease, enrollment might still be challenging.  It will certainly remain a very expensive trial.

I argued that we could easily justify a non-inferiority margin for clinical response using pharmacometrics to define the treatment response. The main problem here is that the data set used for the calculations right now rests on a single trial of tigecycline in ventilator-associated pneumonia.  Based on these data, though, in a separate blog written long ago, I pointed out that the margin under these circumstances (before a lot of FDA discounting) could easily be 17.5%. But I admit that we need more robust data.  We can obtain the needed data from contemporary trials of doripenem and levofloxacin in hospital-acquired and ventilator associated pneumonia.  The FDA could have access to these data easily.  My insistence on this is maybe why they are no longer speaking to me – who knows?

An interesting example, speaking of irony, is the Astrazeneca trial of ceftazidime-avibacatam in hospital-acquired pneumonia.  In their trial, they have used clinical response as their primary endpoint and not mortality. They are clearly betting that their submission will be approved anyway given the importance of this product to American patients and physicians. I fervently hope that they can get their act together enough to finish the trial and get the data submitted – but as you know – it is hard to say what will happen to AZ’s antibiotics programs right now.

The FDA’s guidance comes out around the same time as the WHO report on resistance. The editorial in the New York Times today notes that we need to provide incentives to get companies back into the antibiotic R&D game to continue to have antibiotics active against resistant pathogens. We also need realistic regulatory pathways. While the FDA’s new pathway for hospital acquired pneumonia may be feasible, it remains, in my view, less than ideal and remains without harmonization with Europe.  Europe is still ahead in this game as far as I am concerned.


Sunday, May 4, 2014

A Week of Irony

It has been a big week on the antibiotics front. First, some detail on what Astrazeneca thinks they are doing on antibiotics.  I have no idea.  In a teleconference with analysts, their CEO stated that their goal for the infectious disease unit is “partnership” not sale. But other news statements seem to indicate that they are selling the business including meropenem, a generic antibiotic that still sells well. I’m not sure if they are talking about two separate deals, one for meropenem (sale) and one for their pipeline (partnership) or what.  Maybe someone from AZ can sort this out for me and my readers. As I mentioned last week, partnership will be complicated by the recent merger between Forest and Actavis.  The future of this pipeline, in my view, is essential to being able to treat at least some of the highly resistant infections that we encounter with increasing frequency.

On top of this, Pfizer, a company that abandoned antibiotics just a few years ago, continues to pursue AZ (who seems to want to give up on antibiotics) and may now proceed to a hostile takeover bid. History teaches us that when Pfizer wants something, in this case protection from US corporate tax rates and an attractive AZ oncology pipeline, nothing stops them from getting it – just ask Warner-Lambert. This is not going to be good for research in general and it may devastate antibiotics research at a time when we most need new antibiotics.

Along those lines, the WHO released their report on antimicrobial resistance this week.  Their report emphasizes a number of things including resistance in TB, HIV, malaria, influenza, and last but not least, ordinary bacterial pathogens. The WHO notes especially the rising incidence of resistance in various world regions.  They caution that the pipeline for dealing with resistant infections, especially those caused by Gram negative pathogens, is relatively dry.  A brief excerpt from the report is shown below (click to enlarge).

So, here we are. We have a company with a promising pipeline for the treatment of resistant Gram negative infections, an impending public health calamity – especially in certain regions of the world (including various areas of the US) caused by resistant infections, and the company will either be taken over by one hostile to antibiotics or the company itself may abandon some or all of its pipeline.

I’m waiting for a white knight – Roche – are you still there? – to come along and pull us all out of this mess.  Apparently it is unlikely to be either AZ or Pfizer!