Thursday, August 21, 2014

Ceftazidime-Avibactam - At Long Last?

This week AstraZeneca announced its top line results from two pooled clinical trials of ceftazidime-avibactam in complicated intraabdominal infection. The combination of ceftazidime with the novel B-lactamase inhibitor avibactam is an important piece of AZ’s antibiotic pipeline and is one of three avibactam-containing combinations being developed (we all hope) by the company. Avibactam was acquired by AZ when they purchased Novexel, a biotech that had been spun out of Sanofi-Aventis.  Avibactam (then called NXL-104) was part of the preclinical assets from Sanofi-Aventis upon which Novexel was based. 

When I was at Novexel, I was pleased and surprised that the early clinical and pre-clinical safety profile of the drug was so promising.  In addition, avibactam inhibits several  classes of B-lactamase beyond the single class (A) inhibited by the currently marketed inhibitors like clavulanate and tazobactam. One of these is the KPC carbapenemase responsible for so much carbapenem resistance among the Enterobacteriaceae. Thus, avibactam combinations hold out the possibility of effective therapy for these highly resistant infections.

According to the press release, the pivotal phase III trials, RECLAIM-1 and RECLAIM-2 demonstrated non-inferiority of ceftazidime-avibactam plus metronidazole to meropenem in complicated intraabdominal infection.  The statistical analysis demonstrated that the non-inferiority margins of 12.5% in Europe and 10% in the US had been achieved.   AZ and their partner Actavis (ex-Forest-Cerexa) are pursuing other indications for ceftazidime-avibactam including complicated urinary tract infection, hospital acquired pneumonia and efficacy in the treatment of ceftazidime-resistant infections.

Based on current guidelines in both Europe and the US, a single trial would not be sufficient to support approval for marketing the compound.  It seems like an additional trial, most likely cUTI or the ceftazidime-resistant infection study, will have to be submitted along with the RECLAIM data to garner approval.  When I queried John Rex (Vice President and Head of Infection, Global Medicines Development at AstraZeneca) on this, he provided little in the way of information beyond what is available in the press release. But the timeline for submission of the dossier for Europe is first quarter 2015.  I surmise, therefore, that at least one of the other studies will have to complete for submission to occur. I also presume the same would be true for the submission by Actavis to the US FDA.  (Actavis is responsible for the US filings and marketing according to the agreement between the two companies).

The two companies also are developing two other avibactam combinations. When I asked John for an update on ceftaroline-avibactam he just noted that it is in phase II development for complicated urinary tract infection. But it has been there forever.  Unlike ceftazidime-avibactam, the cefaroline combination would not have activity against most strains of Pseudomonas, but would be active against MRSA.  It could thus be positioned as more of a hospital workhorse type drug while ceftazidime-avibactam could be more of a Gram-negative ICU type antibiotic.  Is this too much overlap?  I suspect the partners are cogitating this and that his accounts for some of the delay.

The other combination in development is aztreonam-avibactam that John notes is in phase I where it has also been for slightly less than forever. This is a particularly important drug since it could offer activity against the metallo-beta-lactamase producing pathogens such as those expressing NDM-1.

While I rejoice at the prospect that AZ and Actavis will soon be submitting a dossier for ceftazidime-avibactam, I am at the same time led to question their dedication to the avibactam combinations and to antibacterial development in general.  Its generally a bad sign when your CEO says that he will reduce resources for your therapeutic area and then tries to sell you off or partner you with someone else.

Novexel was purchased at the end of 2009.  The phase II data for ceftazidime-avibactam were available by the end of first quarter 2010. The phase III dossier won’t even be filed until first quarter of 2015 and approval will not occur until the end of that year if all goes well. I count over five years here. What have they been doing for five plus years?  If this were a promising oncology drug, it would be approved and marketed by now.  If the drug were being developed by another company (which one???), it would already be approved and marketed.

AZ and Actavis are entrusted with these very important weapons against resistant pathogens. Now is not the time for them to drop the ball!

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