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.
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