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 ) were presented at the 25th European Congress of Clinical Microbiology and Infectious Diseases ( ECCMID ).
IGNITE1 - Clinical trial in complicated intra-abdominal 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 FDA ( Food and Drug Administration ) guidance was conducted using a 10% 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% non-inferiority margin of the clinically evaluable ( CE ) patient population ( n=477 ).
In the micro-ITT population, 86.8% of patients receiving Eravacycline achieved a clinical cure compared to 87.6% of patients receiving Ertapenem.
The lower and upper bounds of the 95% confidence interval were -7.1% and 5.5%, respectively.
In the CE population, 92.9% of patients receiving Eravacycline achieved a clinical cure compared to 94.5% of patients receiving Ertapenem.
The lower and upper bounds of the 99% 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 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 ).
Lead-in Portion of IGNITE2 - Clinical trial in complicated urinary tract infections
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 complicated urinary tract infections, 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.
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%, 64.3% and 52.2%, respectively.
Microbiological response was 75.0%, 64.3% and 56.5%, respectively.
In the ME population, the microbiological response, which was a primary endpoint for the EMA, were 83.3% ( n=18 ), 78.2% ( n=23 ) and 61.9% ( 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% for Eravacycline IV-to-oral 200 mg, 72.7% for Eravacycline IV-to-oral 250 mg and 42.9% 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 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.
IGNITE1 is a randomized, multi-center, double-blind, double-dummy, global phase 3 clinical trial designed to assess the efficacy and safety of Eravacycline, dosed intravenously 1.0 mg/kg every 12 hours, compared with Ertapenem, dosed intravenously 1 g every 24 hours, in the treatment of complicated intra-abdominal infections.
Per the trial design, 541 adult patients were enrolled in the trial in 66 centers worldwide.
Under the guidance set by the FDA and the EMA, the primary endpoint of the trial is clinical response at the test-of-cure ( TOC ) visit in the two treatment arms.
For the FDA, the primary analysis is conducted using a 10% non-inferiority margin in the microbiological intent-to-treat ( micro-ITT ) population.
For the EMA, the primary analysis is conducted using a 12.5% non-inferiority margin of the clinically evaluable patient population.
Secondary endpoints include the microbiologic response in the treatment arms at the end of treatment, TOC and follow-up visits in the micro-ITT and microbiologically evaluable populations. The TOC visit takes place 25 to 31 days after the initial dose of Eravacycline. The follow-up visit takes place 38 to 50 days after the initial dose of Eravacycline.
IGNITE2 is a two-part, randomized, multi-center, double-blind, phase 3 clinical trial designed to assess the efficacy and safety of Eravacycline compared with Levofloxacin in the treatment of complicated urinary tract infections at approximately 150 clinical trial sites worldwide.
The two-part trial features a recently completed lead-in portion which was designed to determine the dose regimen to be carried forward into the pivotal portion of the trial.
For the pivotal portion, 720 patients are expected to be enrolled and randomized 1:1 to receive Eravacycline or Levofloxacin ( 1.5 mg/kg intravenously every 24 hours followed by 200 mg orally every 12 hours ) or Levofloxacin ( 750 mg intravenously every 24 hours followed by 750 mg orally every 24 hours ).
This pivotal portion of the trial is designed to be a non-inferiority ( 10% margin ) study.
The primary endpoint for the FDA is the responder outcome ( a combination of clinical cure rate and microbiological response ) in the microbiological intent-to-treat ( micro-ITT ) population at the post-treatment visit ( defined as 6-8 days after the completion of therapy ).
For the EMA, the primary endpoint is the microbiological response in the micro-MITT and microbiologically evaluable populations at the post treatment visit. ( Xagena )
Source: Tetraphase Pharmaceuticals, 2015