Pfizer and Astrazeneca

What goes around comes around.

Today Astrazeneca and Pfizer announced that they had entered into an agreement where AZ would license their marketed antibiotics (Merem, Zinforo and Zavicefta) and those in development to Pfizer.  Pfizer will pay AZ $550 million upfront and $190 million in January (total $740 million). There are also a number of milestone payments envisioned that could bring the total cash payments close to $2 billion.  In addition, AZ will reap double-digit royalties on sales. Medimmune and Entasis were both excluded from the deal.

To put this deal in perspective, AZ paid $350 million upfront for Novexel and what is now Zavicefta (plus other assets none of which have yet made it to market). 

Back in 2013 Astrazeneca announced that it would focus on areas outside of infectious diseases. They stated that they wanted to “partner” their anti-infectives efforts going forward. Since then, the infectious diseases franchise at AZ has been up for sale to the highest bidder.  What’s been going on for the last three years? No one was bidding high enough for AZ (or at least that’s what I deduce based on my discussions with those trying to make a deal with AZ). There were apparently two problems.  First, we are talking about ex-North American rights. Second, AZ had a rather inflated idea of the value of their products (according to my contacts). During this time, AZ spun out their antibiotic discovery group to form Entasis. And they formed a fully-fledged business unit out of their antibiotic development group. 

In 2011, Pfizer abandoned antibiotic research entirely. They fired all (or almost all) of their anti-infectives researchers and developers.  They also downsized their entire research effort globally by almost 25%. This occurred in a company with a rich history in antibiotic discovery and development.  Pfizer was one of the first companies to join the antibiotic revolution with penicillin. Then came the first, good, oral tetracycline, doxycycline in the 1960s. Later came the beta-lactamase inhibitor, sulbactam. Diflucan or fluconazole was invented at Pfizer’s facility in Sandwich, UK in the 1990s. They acquired Zyvox through their purchase of Pharmacia. With their acquisition of Wyeth, they had piperacillin-tazobactam and tigecycline. How could a company with this history abandon antibiotics research in the way that it did?

What’s now left at Pfizer? Apparently there is still a small core of antibiotic developers there.   A few of the researchers involved in antibiotics moved over to Pfizer Vaccines (previously Wyeth Vaccines). Some moved to other therapeutic areas within Pfizer.  But the vast majority are long gone.  Many went to AZ and are now either working elsewhere or at Entasis or are unemployed. But – I understand that there will be a significant transition period where the AZ developers will be able to support Pfizer’s efforts and even provide experience and guidance going forward. They may even get a shot at a job in Pfizer. So this might work better than if, say, Pfizer were just to jump back in the way the Roche did.

On the one hand, I want to be excited that Pfizer is getting back into the antibiotics business. Companies that have lost their expertise in antibiotics can struggle for years to regain their footing. My contacts suggest that the transition from AZ to Pfizer is structured such that this will be a smooth process and will avoid this struggle. I take their word for it, but I’ll be watching.

In terms of big pharma companies still doing antibiotics R&D – the numbers haven’t changed.  We’ve just replaced AZ with Pfizer.  It’s a shell game.

I still find it depressing that those who worked so hard to bring exciting, new antibiotics like ceftazidime-avibactam to market at AZ, now, once again, face an uncertain future.

Confounding Aminoglycosides?

I’m still stuck on the recent FDA meetings where pathways to regulatory approval for pathogen-specific antibiotics were discussed. The example chosen to illustrate the challenges in identifying a pathway was a fictional drug called X-1 that was entirely specific for Pseudomonas aeruginosa. I suggested a superiority design trial where patients with a high risk for Pseudomonas infection would be enrolled and treated with a combination of a carbapenem, X-1 and, if desired, an aminoglycoside. Controls would include those treated with only the carbapenem plus (or not) aminoglycoside. As I noted, the centers would have to be those where there was a rate of carbapenem-resistance among Pseudomonas but not at such a high level that physicians would feel uncomfortable with empiric carbapenem therapy.  (Globally, the rate for carbapenem resistance in this organism is in the range of 15-20% range.  In this range, most patients are still treated empirically with a carbapenem, usually in combination with an aminoglycoside).   In my design, I suggested that the evaluable population for analysis of superiority would, in fact, be those with carbapenem-resistant infections.

The response I received was a horrified, “But the aminoglycoside is an active drug.  It will confound your results.  You will never know what to attribute to X-1 vs. the aminoglycoside!” Some insisted this would be true even if the aminoglycoside were only administered for the first few days of therapy. I beg to differ (at least for serious infections outside the urinary tract).

There are a number of studies examining the effect of aminoglycosides on Pseudomonas aeruginosa infections. One, from Leibovici et. al. in Israel.  In their prospective observational study, they were unable to demonstrate an advantage of adding an aminoglycoside to B-lactam therapy outside of those patients who were neutropenic and those with bacteremia. But more interesting was that for patients where the aminoglycoside was the only “appropriate” drug based on susceptibility testing, patients had a 40-100% higher mortality compared to appropriate beta-lactam monotherapy.

Another study looked at bacteremia caused by Pseudomonas aeruginosa. In this study from Spain, it appeared as though a higher mortality among those treated “appropriately” was mostly due to those who received an aminoglycoside as the only active drug.

Several other studies confirm the lack of an advantage for combination therapy of beta-lactam plus aminoglycoside compared to beta-lactam alone in treating these infections. Several, like the two I noted here, suggest that there is a treatment disadvantage when, in fact, an aminoglycoside is the only active drug in the regimen.  These studies suggest to me that a few days of an aminoglycoside in the design I suggested would be anything but confounding.