IGNITE4: Eravacycline noninferior to meropenem in patients with cIAIs

IV eravacycline was noninferior to meropenem and achieved high clinical cure rates in patients with complicated intra-abdominal infections, according to phase 3 data from the IGNITE4 trial.

Eravacycline (Tetraphase Pharmaceuticals) is a fully synthetic tetracycline antibiotic with activity against multidrug-resistant pathogens, including carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and colistin-resistant bacteria carrying the mcr-1 gene, according to a company press release. In addition to complicated intra-abdominal infections (cIAIs), the antibiotic is also being developed as a treatment for complicated urinary tract infections (cUTIs).

Eravacycline meets FDA, EMA endpoints in IGNITE4

For the IGNITE4 trial, researchers compared the safety and efficacy of twice-daily eravacycline dosed at 1 mg/kg every 12 hours with meropenem dosed at 1 g every 8 hours in 500 patients with cIAIs, including those caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas and Bacteroides. The primary endpoint under FDA guidance was clinical response in the microbiological intent-to-treat population (micro-ITT) at the test-of-cure visit, which was 25 to 31 days after the initial dose. A second primary endpoint under guidance from the European Medicines Agency (EMA) was clinical response in the modified intent-to-treat (MITT) and clinically evaluable (CE) patient populations. The noninferiority margin was set at 12.5% in both analyses.

Tetraphase reported that eravacycline met both primary endpoints under FDA and EMA guidance. Clinical cure rates were 90.8% for eravacycline (n = 195) and 91.2% for meropenem (n = 205) in the micro-ITT population; 92.4% for eravacycline (n = 250) and 91.6% for meropenem (n = 249) in the MITT population; and 96.9% for eravacycline (n = 225) and 96.1% for meropenem (n = 231) in the CE population.

Treatment-emergent adverse events were similar between the two treatment groups. The most common events associated with eravacycline included infusion site reactions, nausea and vomiting, each of which occurred at a rate of less than 5%, according to the release. No drug-related serious adverse events were reported.

Additional phase 3 data

Eravacycline has completed two other phase 3 trials — IGNITE1 and IGNITE2. In the IGNITE1 trial, twice-daily IV eravacycline was well-tolerated and noninferior to ertapenem in patients with cIAIs. The overall clinical cure rates of eravacycline vs. ertapenem were 86.8% vs. 87.6% (–0.8% difference; 95% CI, –7.1 to 5.5) in a micro-ITT population; 87% vs. 88.8% (–1.8% difference; 95% CI, –7.4 to 3.8) in a MITT population; and 92.9% vs. 94.5% (–1.7% difference; 95% CI, –6.3 to 2.8) in a CE population. The cure rates in both treatment arms were similar across all organism types, including cephalosporin-resistant and extended-spectrum beta-lactamase-producing bacteria.

“Complicated intra-abdominal infections are increasingly caused by resistant pathogens, and appropriate antibiotic therapy is critical to successful outcomes,” Joseph Solomkin, MD, professor emeritus in the department of surgery at the University of Cincinnati College of Medicine, said in a press release. “Collectively, the data from the IGNITE program in cIAI versus two widely used comparators, ertapenem and meropenem, provides compelling evidence for IV eravacycline monotherapy and its potential to be a valuable new addition to the limited toolkit currently available to treat serious and often life-threatening MDR infections.”

In the IGNITE2 trial, an IV-to-oral regimen of eravacycline was inferior to IV-to-oral levofloxacin among patients with cUTIs (60.4% vs. 66.9%; difference, –6.5% [95% CI, –14.1 to 1.2]), according to data presented at ASM Microbe 2016. However, researchers noticed higher response rates among patients who stayed on IV eravacycline compared with those who switched to the oral formulation. In a subgroup analysis of micro-ITT patients who received only IV therapy, eravacycline response rates met the primary post-treatment endpoint (54.4% vs. 42.2%; difference, 12.2% [95% CI, –5.7% to 29.3%]), and the treatment continued to be more efficacious against levofloxacin-resistant pathogens. Another subgroup analysis examining independent risk factors for post-treatment visit failure linked receipt of IV drug for 3 or fewer days to poorer outcomes.

Future plans for eravacycline

According to the press release, data from the IGNITE1 and IGNITE4 trials will support a new drug application that Tetraphase plans to submit to the FDA in 2018. The company also plans on submitting a marketing authorization application to the EMA this year.

“In the coming months, along with execution of the U.S. and European regulatory submissions for eravacycline in cIAI, we will also continue to focus on completing the ongoing phase 3 IGNITE3 study for once-daily IV eravacycline in cUTIs,” Guy Macdonald, president and CEO of Tetraphase, said in the release.

In addition, an oral formulation of eravacycline is being further explored in an ongoing phase 1 trial. Results are expected to be announced later this year.

Disclosure: Macdonald is an employee of Tetraphase. Solomkin reports receiving personal fees from Tetraphase, Cubist, Merck, Pfizer, GlaxoSmithKline and Melinta, and nonfinancial support from Tetraphase.

IV eravacycline was noninferior to meropenem and achieved high clinical cure rates in patients with complicated intra-abdominal infections, according to phase 3 data from the IGNITE4 trial.

Eravacycline (Tetraphase Pharmaceuticals) is a fully synthetic tetracycline antibiotic with activity against multidrug-resistant pathogens, including carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and colistin-resistant bacteria carrying the mcr-1 gene, according to a company press release. In addition to complicated intra-abdominal infections (cIAIs), the antibiotic is also being developed as a treatment for complicated urinary tract infections (cUTIs).

Eravacycline meets FDA, EMA endpoints in IGNITE4

For the IGNITE4 trial, researchers compared the safety and efficacy of twice-daily eravacycline dosed at 1 mg/kg every 12 hours with meropenem dosed at 1 g every 8 hours in 500 patients with cIAIs, including those caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas and Bacteroides. The primary endpoint under FDA guidance was clinical response in the microbiological intent-to-treat population (micro-ITT) at the test-of-cure visit, which was 25 to 31 days after the initial dose. A second primary endpoint under guidance from the European Medicines Agency (EMA) was clinical response in the modified intent-to-treat (MITT) and clinically evaluable (CE) patient populations. The noninferiority margin was set at 12.5% in both analyses.

Tetraphase reported that eravacycline met both primary endpoints under FDA and EMA guidance. Clinical cure rates were 90.8% for eravacycline (n = 195) and 91.2% for meropenem (n = 205) in the micro-ITT population; 92.4% for eravacycline (n = 250) and 91.6% for meropenem (n = 249) in the MITT population; and 96.9% for eravacycline (n = 225) and 96.1% for meropenem (n = 231) in the CE population.

Treatment-emergent adverse events were similar between the two treatment groups. The most common events associated with eravacycline included infusion site reactions, nausea and vomiting, each of which occurred at a rate of less than 5%, according to the release. No drug-related serious adverse events were reported.

Additional phase 3 data

Eravacycline has completed two other phase 3 trials — IGNITE1 and IGNITE2. In the IGNITE1 trial, twice-daily IV eravacycline was well-tolerated and noninferior to ertapenem in patients with cIAIs. The overall clinical cure rates of eravacycline vs. ertapenem were 86.8% vs. 87.6% (–0.8% difference; 95% CI, –7.1 to 5.5) in a micro-ITT population; 87% vs. 88.8% (–1.8% difference; 95% CI, –7.4 to 3.8) in a MITT population; and 92.9% vs. 94.5% (–1.7% difference; 95% CI, –6.3 to 2.8) in a CE population. The cure rates in both treatment arms were similar across all organism types, including cephalosporin-resistant and extended-spectrum beta-lactamase-producing bacteria.

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“Complicated intra-abdominal infections are increasingly caused by resistant pathogens, and appropriate antibiotic therapy is critical to successful outcomes,” Joseph Solomkin, MD, professor emeritus in the department of surgery at the University of Cincinnati College of Medicine, said in a press release. “Collectively, the data from the IGNITE program in cIAI versus two widely used comparators, ertapenem and meropenem, provides compelling evidence for IV eravacycline monotherapy and its potential to be a valuable new addition to the limited toolkit currently available to treat serious and often life-threatening MDR infections.”

In the IGNITE2 trial, an IV-to-oral regimen of eravacycline was inferior to IV-to-oral levofloxacin among patients with cUTIs (60.4% vs. 66.9%; difference, –6.5% [95% CI, –14.1 to 1.2]), according to data presented at ASM Microbe 2016. However, researchers noticed higher response rates among patients who stayed on IV eravacycline compared with those who switched to the oral formulation. In a subgroup analysis of micro-ITT patients who received only IV therapy, eravacycline response rates met the primary post-treatment endpoint (54.4% vs. 42.2%; difference, 12.2% [95% CI, –5.7% to 29.3%]), and the treatment continued to be more efficacious against levofloxacin-resistant pathogens. Another subgroup analysis examining independent risk factors for post-treatment visit failure linked receipt of IV drug for 3 or fewer days to poorer outcomes.

Future plans for eravacycline

According to the press release, data from the IGNITE1 and IGNITE4 trials will support a new drug application that Tetraphase plans to submit to the FDA in 2018. The company also plans on submitting a marketing authorization application to the EMA this year.

“In the coming months, along with execution of the U.S. and European regulatory submissions for eravacycline in cIAI, we will also continue to focus on completing the ongoing phase 3 IGNITE3 study for once-daily IV eravacycline in cUTIs,” Guy Macdonald, president and CEO of Tetraphase, said in the release.

In addition, an oral formulation of eravacycline is being further explored in an ongoing phase 1 trial. Results are expected to be announced later this year.

Disclosure: Macdonald is an employee of Tetraphase. Solomkin reports receiving personal fees from Tetraphase, Cubist, Merck, Pfizer, GlaxoSmithKline and Melinta, and nonfinancial support from Tetraphase.