In the Journals

Eravacycline noninferior to ertapenem in patients with cIAIs

Eravacycline, a tetracycline antibiotic with activity against multidrug-resistant pathogens, met both the FDA and the European Medicines Agency primary endpoints of noninferiority to ertapenem in the treatment of patients with complicated intra-abdominal infections, according to recently published phase 3 data from the IGNITE1 trial.

“The incidence of life-threatening infections caused by drug-resistant bacteria is increasing at alarming rates. Without the introduction of new antibiotics, a clear public health threat is evolving,” Joseph Solomkin, MD, professor emeritus in the department of surgery at the University of Cincinnati College of Medicine, said in a press release. “These published data demonstrate eravacycline’s [(Tetraphase Pharmaceuticals)] ability to cure these infections as a monotherapy because of its activity against gram-positive, gram-negative and anaerobic bacteria, including those resistant to commonly used antibiotics. These data support its potential as a novel antibiotic treatment option for serious intra-abdominal infections.”

In the phase 3, double blind, randomized clinical trial, 541 patients from 11 countries with documented complicated intra-abdominal infection (cIAI) were given either 1 mg/kg IV eravacycline (n = 270), administered every 12 hours, or 1 g IV ertapenem, administered daily, for up to 14 days. The primary endpoint for both the FDA and European Medicines Agency (EMA) was clinical response at the test-of-cure (TOC) visit, which was 25 to 31 days after randomization. The FDA analysis was conducted using a 10% noninferiority margin in the microbiological intent-to-treat population (micro-ITT; n = 446), whereas the EMA analysis was conducted using a 12.5% noninferiority margin in the modified intent-to-treat (MITT; n = 538) and clinically evaluable (CE) populations.

According to the results, eravacycline was noninferior to ertapenem in all populations. The clinical cure rates at the TOC visit were 86.8% vs. 87.6% (–0.8% difference; 95% CI, –7.1 to 5.5) in the micro-ITT population; 87% vs. 88.8% (–1.8% difference; 95% CI, –7.4 to 3.8) in the MITT population; and 92.9% vs. 94.5% (–1.7% difference; 95% CI, –6.3 to 2.8) in the CE population. The cure rates in both treatment arms were similar across all organism types, including cephalosporin-resistant and ESBL-producing bacteria. 

The researchers reported that both drugs were well-tolerated. While there were more treatment-emergent adverse events among patients who received eravacycline (113 of 270 vs. 75 of 268); the percentage of those who experienced severe treatment-emergent adverse events were similar (5.6% for eravacycline vs. 6% for ertapenem).

IV eravacycline will be further evaluated in the phase 3, IGNITE4 trial, which will compare the safety and efficacy of the drug with meropenem in patients with cIAIs. Tetraphase Pharmaceuticals also plans to launch another phase 3 trial, IGNITE3, to assess eravacycline in patients with complicated cUTIs. The company is additionally investigating an oral dose formulation in an ongoing phase 1 trial.

“The positive results from IGNITE1 demonstrate that treatment with eravacycline could fill an unmet need in patients with cIAI, particularly those with difficult-to-treat infections,” Guy Macdonald, president and CEO of Tetraphase, said in the release. “These results, along with those from our ongoing phase 3 IGNITE4 trial in cIAI, which are expected in the fourth quarter of 2017, will form the basis of a New Drug Application submission for eravacycline in cIAI.” – by Stephanie Viguers

References:

Tsai L, et al. Abstract L-834. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Tsai L, et al. Abstract L-835. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Disclosures: Solomkin reports receiving personal fees from Tetraphase Pharmaceuticals, Cubist Pharmaceutical, Merck, Pfizer, GlaxoSmithKline and Melinta, and nonfinancial support from Tetraphase. Please see the full study for a list of all other researchers’ relevant financial disclosures.

Solomkin J, et al.

Eravacycline, a tetracycline antibiotic with activity against multidrug-resistant pathogens, met both the FDA and the European Medicines Agency primary endpoints of noninferiority to ertapenem in the treatment of patients with complicated intra-abdominal infections, according to recently published phase 3 data from the IGNITE1 trial.

“The incidence of life-threatening infections caused by drug-resistant bacteria is increasing at alarming rates. Without the introduction of new antibiotics, a clear public health threat is evolving,” Joseph Solomkin, MD, professor emeritus in the department of surgery at the University of Cincinnati College of Medicine, said in a press release. “These published data demonstrate eravacycline’s [(Tetraphase Pharmaceuticals)] ability to cure these infections as a monotherapy because of its activity against gram-positive, gram-negative and anaerobic bacteria, including those resistant to commonly used antibiotics. These data support its potential as a novel antibiotic treatment option for serious intra-abdominal infections.”

In the phase 3, double blind, randomized clinical trial, 541 patients from 11 countries with documented complicated intra-abdominal infection (cIAI) were given either 1 mg/kg IV eravacycline (n = 270), administered every 12 hours, or 1 g IV ertapenem, administered daily, for up to 14 days. The primary endpoint for both the FDA and European Medicines Agency (EMA) was clinical response at the test-of-cure (TOC) visit, which was 25 to 31 days after randomization. The FDA analysis was conducted using a 10% noninferiority margin in the microbiological intent-to-treat population (micro-ITT; n = 446), whereas the EMA analysis was conducted using a 12.5% noninferiority margin in the modified intent-to-treat (MITT; n = 538) and clinically evaluable (CE) populations.

According to the results, eravacycline was noninferior to ertapenem in all populations. The clinical cure rates at the TOC visit were 86.8% vs. 87.6% (–0.8% difference; 95% CI, –7.1 to 5.5) in the micro-ITT population; 87% vs. 88.8% (–1.8% difference; 95% CI, –7.4 to 3.8) in the MITT population; and 92.9% vs. 94.5% (–1.7% difference; 95% CI, –6.3 to 2.8) in the CE population. The cure rates in both treatment arms were similar across all organism types, including cephalosporin-resistant and ESBL-producing bacteria. 

The researchers reported that both drugs were well-tolerated. While there were more treatment-emergent adverse events among patients who received eravacycline (113 of 270 vs. 75 of 268); the percentage of those who experienced severe treatment-emergent adverse events were similar (5.6% for eravacycline vs. 6% for ertapenem).

IV eravacycline will be further evaluated in the phase 3, IGNITE4 trial, which will compare the safety and efficacy of the drug with meropenem in patients with cIAIs. Tetraphase Pharmaceuticals also plans to launch another phase 3 trial, IGNITE3, to assess eravacycline in patients with complicated cUTIs. The company is additionally investigating an oral dose formulation in an ongoing phase 1 trial.

“The positive results from IGNITE1 demonstrate that treatment with eravacycline could fill an unmet need in patients with cIAI, particularly those with difficult-to-treat infections,” Guy Macdonald, president and CEO of Tetraphase, said in the release. “These results, along with those from our ongoing phase 3 IGNITE4 trial in cIAI, which are expected in the fourth quarter of 2017, will form the basis of a New Drug Application submission for eravacycline in cIAI.” – by Stephanie Viguers

References:

Tsai L, et al. Abstract L-834. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Tsai L, et al. Abstract L-835. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy; Sept. 17-21, 2015; San Diego.

Disclosures: Solomkin reports receiving personal fees from Tetraphase Pharmaceuticals, Cubist Pharmaceutical, Merck, Pfizer, GlaxoSmithKline and Melinta, and nonfinancial support from Tetraphase. Please see the full study for a list of all other researchers’ relevant financial disclosures.

Solomkin J, et al.