In thinking about pricing of antibiotics as it relates to
revenues, I wanted to go back and think about linezolid as a case example.
Linezolid was approved in 1999, at the very height of the global pandemic of
MRSA (methicillin-resistant S. aureus) infection and during endemic levels of
VRE (vancomycin-resistant enterococcus) infection especially in the US. At the time, the only recognized effective
therapy for serious MRSA infection was vancomycin. Vancomycin has always been thought to be
inferior to B-lactams for the treatment of staphylococcal infections based on
scanty data. But I was certainly
convinced. Vancomycin also had its problems with safety – especially
nephrotoxicity- mainly when used with other potentially nephrotoxic agents such
as furosemide or aminoglycosides. Linezolid was associated with anemia and
thrombocytopenia – but this was related to therapy that went beyond the usual
7-10 days for most infections. Vancomycin could only be used intravenously for
MRSA infections, while linezolid was available both in intravenous and oral
formulations. This allowed earlier
discharge from hospital for many patients. Based on this major advantage, and
based on the availability of generic vancomycin at the time, linezolid was sold
as the highest priced antibiotic in history at around $1800 for a course of
therapy. And, its peak year sales reached somewhere between $1.5 and 2 billion
in spite of it being reserved because of its high price. One analysis I did showed that in North
America, oral linezolid was an important driver of revenues while IV linezolid
was the main driver in Europe. I was at first surprised that the oral form was
not more important in Europe, but I realized later that in those days, rapid
hospital discharge was not such an important issue for the Europeans as it was
in the US.
One of the great debates of the day was bactericidal vs
bacteriostatic therapy. Vancomycin kills
bacteria, albeit slowly compared to B-lactam antibiotics. Linezolid inhibits bacterial growth without
killing them. The worry always was that linezolid would be an inferior therapy
of very serious infections like nosocomial pneumonia because of this
difference. But linezolid was better at penetrating into respiratory secretions
than vancomycin and in clinical trials was always easily shown to be
non-inferior to vancomycin.
To address this potential shortcoming head-on, Pfizer
undertook a randomized, controlled, double blind trial of linezolid vs.
vancomycin in MRSA pneumonia. The trial
(Zephyr) included
all comers including those who had acquired their infections outside the
hospital (HCAP) who accounted for about 15% of the patients in this trial. By
way of background, it is important to understand that about 30% of all
staphylococcal infections in US hospitals at the time of the trial were caused
by MRSA. A study in emergency rooms showed that up to 70% of staph infections
were caused by MRSA. This is probably
the most dominant form of multiple antibiotic resistance ever seen before or
since. In spite of the extent of spread of MRSA, the trial was slow to enroll
taking over 5 years to enroll 1184 patients from 156 centers globally. Patients
were required to have a positive culture for MRSA. The endpoint was clinical
cure or improvement at End of Study (7-30 days after end of therapy). Mortality at 60 days was also an endpoint, but
I view that as irrelevant since at that point, most mortality is probably
related to underlying disease and not the pneumonia. Therefore this would always tend to be
similar across groups assuming that the distribution of underlying disease was
similar as was the case for this trial. Clinical
cure was defined as resolution of clinical signs and symptoms of pneumonia,
compared with baseline; improvement or lack of progression in chest imaging; and
no requirement for additional antibacterial treatment. The trial was designed
as a non-inferiority trial (NI margin 10%) with a possibility for nested
superiority. Of the 1184 patients enrolled, only 348 were evaluable at the end
of the study.
The
results of the study showed that 57% of linezolid treated patients had a
positive clinical response compared to 47% of vancomycin-treated patients. This
is a statistically significant and a clinically relevant difference (p=0.04).
Similar differences were observed when looking at microbial eradication or
presumed eradication where linezolid was also superior. Kidney toxicity was
twice as common in the vancomycin group but anemia and thromobocytopenia were
equal between the treatment groups.
When
this study was published in 2012, I thought that this would be followed by
greater use of linezolid. Wrong. Why? Well, several economic analyses based on
the results of the trial were carried out and came to varied conclusions. The main driver for an economic advantage for
linezolid was the kidney toxicity associated with vancomycin in the trial. But
for some analyses (in Europe), this was not enough to overcome the increased
drug costs of linezolid. Early discharge from the hospital in these studies did
not seem to be all that important. The
one analysis where a
clear economic advantage was shown was done in the US where shorter length of
stay coupled with lower nephrotoxicity supported an advantage for linezolid.
The
other issue might have been the statistical “fragility” of the data. Just a few patients either way would have
swayed the data and superiority for linezolid would have been lost.
The other
lesson, if there is one here, is that the trial was extremely expensive and took over five
years in over 150 centers. And this occurred in the face of high resistance rates. Carrying out
trials targeting resistant pathogens with lower rates of resistance is going to
be harder and we hope unnecessary.
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