WATERTOWN, Mass.—Tetraphase Pharmaceuticals, Inc., a clinical stage biopharmaceutical company developing novel antibiotics to treat life-threatening multidrug-resistant (MDR) infections, has announced the first detailed results from phase 3 clinical trials of its lead drug candidate, eravacycline, in development to treat complicated intra-abdominal infections (cIAI) and complicated urinary tract infections (cUTI). The results are being presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), taking place on April 25-28 in Copenhagen, Denmark.
"The detailed clinical data presented this year at ECCMID continues to support eravacycline's potential as a potent antibiotic option to treat both cIAI and cUTI infections," said Guy Macdonald, president and CEO of Tetraphase. "We believe that eravacycline will offer physicians additional options when treating bacterial infections given its activity against a wide variety of bacterial pathogens, including multidrug-resistant gram-negative bacteria, and, in cUTI, its potential as an IV-to-oral transition therapy. We are encouraged by the results achieved in both IGNITE1 (cIAI) and the lead-in portion of IGNITE2 (cUTI) and we look forward to reporting top-line results from the pivotal portion of IGNITE2 in mid-2015."
Macdonald continued: "Beyond the phase 3 eravacycline program, preclinical data were also presented at ECCMID from our earlier-stage antibiotic programs. For TP-271, IND-enabling data were presented demonstrating significant in-vivo activity against methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae in a preclinical lung infection model. For TP-6076, the lead candidate from our second-generation discovery program, we reported promising preclinical data supporting its potential as a treatment for serious MDR gram-negative infections."
In IGNITE1, eravacycline met the primary endpoint of statistical non-inferiority of clinical response at the test-of-cure (TOC) visit. The primary analysis under the U.S. Food and Drug Administration (FDA) guidance was conducted using a 10 percent non-inferiority margin in the microbiological intent-to-treat (micro-ITT) population (n=446). Under the European Medicines Agency (EMA) guidance, the primary analysis was conducted using a 12.5 percent non-inferiority margin of the clinically evaluable (CE) patient population (n=477).
In the micro-ITT population, 86.8 percent of patients receiving eravacycline achieved a clinical cure compared to 87.6 percent of patients receiving ertapenem. The lower and upper bounds of the 95 percent confidence interval were -7.1% and 5.5%, respectively. In the CE population, 92.9 percent of patients receiving eravacycline achieved a clinical cure compared to 94.5 percent of patients receiving ertapenem. The lower and upper bounds of the 99 percent confidence interval were -7.9% and 4.4%, respectively.
The most common gram-negative pathogens in the study included Escherichia coli, Klebsiella pneumonia and Pseudomonas. Eravacycline achieved high cure rates against these pathogens, as well as in patients with Acinetobacter baumannii and in patients with suspected ESBL-producing [extended-spectrum beta-lactamase-producing] http://www.tphase.com pathogen isolates.
There were no drug-related serious adverse events in the trial. The most commonly reported drug-related adverse events for eravacycline were gastrointestinal, including nausea (3.3%, n=9) and emesis (2.2%, n=6).
"Eravacycline is a novel antibiotic drug candidate that is being developed for the treatment of common, but serious infections, including complicated intra-abdominal infections that may either be community-acquired or following surgical procedures," said Joseph Solomkin, M.D., professor emeritus in the Department of Surgery at the University of Cincinnati College of Medicine and advisor to Tetraphase. "The data being presented at ECCMID this year show that eravacycline has the potential to be a new treatment option for complicated intra-abdominal infections, and possibly other serious bacterial infections, where new treatments remain urgently needed for infections with multidrug-resistant bacteria."
In the lead-in portion of IGNITE2, both IV-to-oral dosing regimens of eravacycline (1.5 mg/kg IV followed by 200 mg or 250 mg) compared favorably to levofloxacin for the treatment of cUTI, supporting the advancement of the trial into its pivotal portion. Efficacy outcomes were microbiological success and responder rates (defined as subjects with both clinical cure and successful microbiological outcome) in all randomized subjects (n=143) with a baseline pathogen identified (micro-ITT population, n=75) and the microbiologically evaluable (ME) population (n=62) at a post-treatment visit 7 days after the last dose of study drug. Patient demographics were well matched across all treatment groups.
In the micro-ITT population, the responder outcome, which was the primary endpoint for the FDA, for the IV-to-oral 200 mg (n=24), IV-to-oral 250 mg (n=28) and levofloxacin groups (n=23) were 70.8 percent, 64.3 percent and 52.2 percent, respectively. Microbiological response was 75.0 percent, 64.3 percent and 56.5 percent, respectively. In the ME population, the microbiological response, which was a primary endpoint for the EMA, were 83.3 percent (n=18), 78.2 percent (n=23) and 61.9 percent (n=21), respectively. The pharmacokinetics for both oral doses of eravacycline were comparable to the IV formulation. The spectrum of pathogens in this trial was similar to that seen in other pivotal trials in this patient population. The most common gram-negative pathogens in the study included Escherichia coli, Klebsiella pneumoniae and Enterococci. Responder rates for levofloxacin-resistant isolates (n=24) were 83.3 percent for eravacycline IV-to-oral 200 mg, 72.7 percent for eravacycline IV-to-oral 250 mg and 42.9 percent for levofloxacin.
There were no drug-related serious adverse events. The most common drug-related treatment emergent adverse events in all arms were gastrointestinal and were mild to moderate. In the eravacycline IV-to-oral 200 mg group the gastrointestinal disorders included nausea (6.4%; n=3), emesis (4.3%; n=2), and nausea and emesis (6.4%; n=3) with only one of these events leading to discontinuation of the study drug.
Based on these data, Tetraphase selected the 200 mg eravacycline oral dose for the pivotal portion of the phase 3 study that is currently underway.
Tetraphase's lead product candidate, eravacycline, is being developed as a broad-spectrum intravenous and oral antibiotic in the IGNITE program (Investigating Gram-negative Infections Treated with Eravacycline). This program includes two phase 3 clinical trials: IGNITE1 for the indication of complicated intra-abdominal infections (cIAI) and IGNITE2 for complicated urinary tract infections (cUTI). Eravacycline has been designated by the FDA as a Qualified Infectious Disease Product (QIDP) for both the cIAI and cUTI indications. This designation, which is assigned to qualifying new antibiotic product candidates, makes eravacycline eligible to benefit from certain development and commercialization incentives, including priority review, and eligibility for both fast-track status and an additional five years of U.S. market exclusivity.
Tetraphase is a clinical-stage biopharmaceutical company using its proprietary chemistry technology to create novel antibiotics for serious and life-threatening MDR bacterial infections, including those caused by many of the MDR gram-negative bacteria highlighted as urgent public health threats by the CDC. Tetraphase has created more than 3,000 novel tetracycline analogs using its proprietary technology platform. Tetraphase's pipeline includes eravacycline, a broad-spectrum intravenous and oral antibiotic that is being evaluated in phase 3 clinical trials, and two preclinical antibiotic candidates, TP-271 and TP-6076.