Thursday, November 30, 2017

Linezolid - A Case Study

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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