OK. So this is a few
months late. Mea culpa. But since the
FDA advisory committee meeting on Cempra’s solithromycin, I have had a number
of questions from readers and colleagues on the FDA decision to request
additional safety information before approving Cempra’s antibiotic for the
treatment of pneumonia. I would point out that Harald Reinhart has already
posted a timely analysis
of the situation. 
To put things in perspective, we must go back to the Ketek
(telithromycin) scandal
of 2006. Ketek was approved in 2004 for the treatment of pneumonia,
exacerbations of chronic bronchitis and sinusitis – by a circuitous route (see
my book Antibiotics the Perfect Storm for details). After several reports of serious liver
toxicity appeared, the FDA re-reviewed their prior approval. It has been
calculated that the rate of liver injury caused by Ketek is 5.5 per 100,00
courses of therapy and the rate for serious liver toxicity is between 0.5 and 1
case per 100,000 courses of therapy. These numbers are similar for what you
would see with other macrolide antibiotics and are better than rates for
serious reactions to other antibiotics like the penicillins as Bob Moellering
and I pointed
out. The FDA withdrew their approval
for bronchitis and sinusitis, but left the approval for treatment of pneumonia
in place judging that the risk benefit for pneumonia was still favorable.
When solithromycin was being studied by Cempra, the company touted
the lack of binding to the nicotinamide acetylcholine receptor as being the key
to its lower levels of toxicity for both the eyes, in cases of myasthenia
gravis and even for liver toxicity. But as it finally became clear in their toxicology studies of solithromycin in animals, the liver was the main target organ for toxicity from this drug. In
their phase 3 clinical trials there was certainly a trend for more liver injury
in the solithromycin treated patients compared to those receiving moxifloxacin
(see FDA briefing
document). Then – the company embarked on longer-term solithromycin treatment
trials for chronic bronchitis and for non-alcoholic steatohepatitis (fatty
liver disease) hoping that the anti-inflammatory effects of the drug would be
beneficial here. They did this knowing
that long-term treatment in monkeys increased the risk for liver injury. Sure enough – the few patients treated in these long-term trials did show
evidence of liver injury. This was
enough to make the FDA advisors hesitate to agree that the company had
demonstrated that the drug was safe – although the majority did agree that the
drug worked for the treatment of pneumonia. The FDA responded with a
requirement that the company carry out additional safety studies to reassure us
that there is not a greater risk of serious liver toxicity than we see with
other antibiotics.
Of course, like telithromycin, solithromycin is active
against pathogens, especially those that cause pneumonia, that are resistant to
other macrolide antibiotics. This is an
important advantage because it could decrease use of the quinolone antibiotics
that are associated with an increased risk of C. difficile diarrhea – a
potentially fatal complication. These ketolides also offer a potentially more
efficacious alternative to the penicillins for penicillin-allergic patients. Did
the FDA over-react here? In the case of Ketek – they left the approval for
pneumonia intact – partly based on evidence obtained post-market over millions
of treatment courses. For solithromycin, we have no such assurance. How do we know that solithromycin is not, in
fact, more toxic than telithromycin or a number of other antibiotics? The animal data certainly gives one pause and
the number of treated patients is too small to judge the extent of clinical
toxicity here. Another bothersome fact is that the arguments of Cempra that
this drug would be much less toxic based on data surrounding a single receptor
and its interaction with various macrolides turned out to be so much hot air.
So, unusually, I must come down on the side of FDA and its
advisors in the case of solithromycin.
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