Thursday, September 10, 2015
I am saddened to report that Tetraphase failed to achieve their primary endpoint in their pivotal phase III study of eravacycline in the treatment of complicated urinary tract infection (the IGNITE 2 trial). This is a very puzzling result to me. Their trial in intraabdominal infection succeeded even with highly resistant pathogens. (Coming clean - I helped design their trials).
I know that Tetraphase did a great deal to assure themselves and everyone else that the UTI trial would succeed and that eravacycline would be an effective new antibiotic for UTI caused by resistant strains of Gram negative pathogens. They studied levels of eravacycline excreted in urine and antibacterial titers in urine of normal volunteers treated with various doses. They carried out a preliminary analysis of the first 143 patients of their phase III trial in order to choose an oral dose of eravacycline (200 vs 250 mg) with which to continue the study. In the lead-in portion, all eravacycline groups appeared to be superior to levofloxacin. Based on these data and safety data, a 200 mg oral dosage was chosen. I was very excited about eravacycline since it was the only orally available antibiotic in late stage trials with activity against resistant Gram negatives.
The primary endpoint of the study was clinical and microbiological cure at the test of cure – about one week following end of therapy. The non-inferiority margin was set at 10%. 908 patients were enrolled in the trial. Apparently, this was not achieved. In their press release and in the investors’ call, Tetraphase did not provide further details such as how wide the margin was. Other details such as an analysis by pathogen was also not available.
Even though eravacycline did not achieve its primary endpoint, it was superior to levofloxacin among those patients whose infecting organisms had elevated MICs of levo. This suggests to me that eravacycline does, indeed, have a reasonable antibacterial effect in the urine.
The announcement of these results prompted me to recall the days when Tetraphase was trying to find partners for their program before they went to the public markets. I was an enthusiastic supporter of this effort and I participated in a number of these meetings. I was surprised and disappointed at the time when none of the companies to whom they were speaking were willing to invest in Tetraphase and eravacycline. It is true that there were some problems in the preclinical data set for eravacycline, but none were anything more than I had seen previously for successful products. I considered that the overall data package as a strong one. Apparently the regulatory authorities agreed with me as Tetraphase progressed through phase II and phase III studies. At the time, and now in retrospect, I thought that this was another indication that the naysayers never take risk. It is only those rare product champions that take the risk.
In the case of Tetraphase, it still remains to be seen whether the naysayers will win the day or not.