IGNITE2: Eravacycline inferior to levofloxacin, but IV formulation shows promise

Issue: August 2016

BOSTON — An IV-to-oral regimen of eravacycline was inferior to IV-to-oral levofloxacin for the treatment of complicated urinary tract infection, according to results from the IGNITE2 trial presented at ASM Microbe 2016.

However, additional analysis of the phase 3 data indicated favorable responses when patients were receiving eravacycline (Tetraphase Pharmaceuticals) intravenously, suggesting that the novel fluorocycline antibiotic’s poor performance could be the result of a faulty oral formulation.

“The longer a subject was on IV, the higher the responder rate of eravacycline relative to levofloxacin, and it really pointed out the fact that it seemed to be an underperformance of the oral product that really drove the overall study results.” Patrick Horn, MD, chief medical officer for Tetraphase, told Infectious Disease News. “The IV for UTI was efficacious, and that supports the efficacy that we’ve seen in a previous intra-abdominal trial [IGNITE1].”

In the IGNITE2 trial, Horn and colleagues randomly assigned patients hospitalized with complicated urinary tract infection (cUTI) to receive IV eravacycline or levofloxacin for 7 days, with an option to transition to oral formulations after 3 days. The researchers’ primary endpoint was composite response rate margin of at least 10% in the microbiological intent-to-treat (micro-ITT) population (n = 600) upon a posttreatment visit 6 to 8 days after completion of antibiotic therapy.

Eravacycline was inferior to levofloxacin at the posttreatment visit (60.4% vs. 66.9%; difference, –6.5% [95% CI, –14.1 to 1.2]), but achieved several secondary outcomes including efficacy against levofloxacin-resistant pathogens and composite response rate at the end of antibiotic treatment.

“If you look at any time when [patients] are on therapy, the responder rate was higher in the eravacycline group than the levofloxacin group,” Horn said. “But the primary efficacy endpoint for both the [European Medicines Agency] and the FDA is the post-therapy visit … and if you look at that visit, then the responder rate is actually higher in the levofloxacin group.”

Notably, Horn said, the researchers noticed higher response rates among patients who stayed on IV eravacycline compared with those who switched. In a subgroup analysis of the 121 micro-ITT patients who only received 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 novel treatment continued to be more efficacious against levofloxacin-resistant pathogens. Further, another subgroup analysis examining independent risk factors for posttreatment visit failure weakly linked receipt of IV drug for 3 or fewer days to poorer outcomes.

Horn and Guy MacDonald, CEO of Tetraphase, said the pharmaceutical company is currently organizing an IV-only study to confirm these data in a larger patient sample. It will be investigating the pharmacokinetics of the oral formulation to better explain and address its underperformance.

“We still very strongly believe in eravacycline, and we think it has a lot to offer,” MacDonald told Infectious Disease News. “Although there are, thankfully, a number of new gram-negatives being developed, they still don’t cover all of the carbapenem resistance and not many cover Acinetobacter, and we work very well against both of those, so we still see there’s an unmet need.” – by Dave Muoio

References:

Tsai L, et al. Intravenous eravacycline with transition to oral therapy for treatment of complicated urinary tract infections including pyelonephritis: Results from a randomized, double-blind, multicenter, phase 3 trial (Ignite2). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Tsai L, et al. Intravenous eravacycline compared to intravenous levofloxacin for the treatment of complicated urinary tract infections: Subgroup analysis from a randomized, double-blind, phase 3 trial (Ignite2). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Tsai L, et al. Risk factors for change in microbiological outcomes between the end of therapy and post-treatment evaluations in patients with complicated uti treated with eravacycline: Analysis from a randomized, double-blind, multicenter, phase 3 trial (Ignite2). Presented at: ASM Microbe; June 16-20, 2016; Boston.

Disclosures: Horn and MacDonald are employees of Tetraphase.