Monday, February 27, 2017

The FDA, Ketolides and the Cempra Decision

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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