Meropenem-vaborbactam meets FDA primary endpoint against cUTIs

NEW ORLEANS — An IV regimen of meropenem-vaborbactam was superior to piperacillin-tazobactam in patients with complicated urinary tract infections, including acute pyelonephritis, according to phase 3 results from the TANGO 1 trial.

Vaborbactam is a new class of beta-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC)-producing carbapenem-resistant Enterobacteriaceae (CRE) when used in combination with meropenem. The regimen is being developed as a treatment for gram-negative infections, including complicated urinary tract infections (cUTIs).

“CRE is clearly a growing threat [associated with] high disease burden, high mortality and limited treatment options,” Jeff Loutit, MBChB, investigator for The Medicines Company in San Diego, said during a press conference at IDWeek 2016. “So, we developed vaborbactam, which is a new cyclic boronic acid beta-lactamase inhibitor, and we optimized it essentially to inhibit serine carbapenemases and to be given with a carbapenem.”

Loutit and colleagues randomly assigned 550 adult participants with cUTIs or acute pyelonephritis in a 1:1 ratio to receive a 3-hour infusion of meropenem-vaborbactam (2g/2g) or a 30-minute infusion of piperacillin-tazobactam (4g/0.5g) every 8 hours. The total treatment duration was 10 days; however, after receiving at least 15 doses, certain patients in both arms whose symptoms had improved were switched to an oral regimen of levofloxacin.

The FDA’s primary endpoint was overall success at the end of IV therapy, which was based on clinical cure and microbial eradication in the modified intent-to-treat (mMITT) population (n = 545). The European Medicine Agency’s primary endpoint was microbial eradication at the test-of-cure visit 5 to 9 days after treatment completion. The prespecified noninferiority margin for both agencies was less than 15%.

In the mMITT population, the overall success rate at the end of IV therapy was 98.4% in the meropenem-vaborbactam arm (n = 192) and 94% in the piperacillin-tazobactam arm (n = 182) — a 4% difference (95% CI, 0.7-9.1). The overall success rate at the test-of-cure visit was 74.5% and 70.3% (4% difference; 95% CI, –4.9 to 13.2), and the microbial eradication rate was 66.7% and 57.7% favoring meropenem-vaborbactam (9% difference; 95% CI, –0.9 to 18.7).

Adverse events were similar among patients receiving meropenem-vaborbactam (39%) and piperacillin-tazobactam (35.5%). The severity of adverse events was usually mild or moderate. Serious adverse events occurred in 11 patients receiving meropenem-vaborbactam and 12 receiving piperacillin-tazobactam. Seven patients receiving meropenem-vaborbactam and 14 receiving piperacillin-tazobactam discontinued treatment. Each study arm had two deaths.

“[There were] consistent efficacy results across clinical and microbiologic endpoints and populations,” Loutit said. “The safety of meropenem-vaborbactam was comparable to piperacillin-tazobactam, which is a relatively safe drug. Importantly, even though we’re only using 2g of meropenem plus the vaborbactam, the types and severity of the adverse events that we saw in the meropenem-vaborbactam arm are similar to both the label and published reports with respect to meropenem.”

The researchers will continue to investigate meropenem-vaborbactam by comparing the regimen with the best available therapy for known or suspected CRE infections during the ongoing TANGO 2 trial. – by Stephanie Viguers

Reference:

Loutit, et al. Abstract LB-7. Presented at: IDWeek; Oct. 26-20, 2016; New Orleans.

Disclosures: Loutit is an employee of the Medicines Company.