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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