A potential new tool in the war on gram-negative pathogens, The Medicines Co.’s Carbavance (meropenem-vaborbactam) met both FDA and EMA primary endpoints in a pivotal phase III trial testing the therapy in patients with complicated urinary tract infections (cUTIs).
Results of Tango 1 trial positioned Medicines to submit an FDA new drug application for Carbavance in early 2017 while also delivering data in which it showed statistical superiority to Pfizer Inc.’s Zosyn (piperacillin-tazobactam), giving regulators a benchmark with which to judge its utility.
A second study, Tango 2, is testing Carbavance’s strength vs. “best available therapy” in tough-to-treat carbapenem-resistant Enterobacteriaceae (CRE) infections, designated in the U.S. by the Centers for Disease Control and Prevention as the most urgent antimicrobial resistance threat responsible for systemic infections in hospitalized patients.
“While we had assumed a high probability of success, today’s data nonetheless derisks MDCO’s pipeline,” wrote J.P. Morgan analyst Jessica Fye. “Commercially, TANGO-2 data in more complicated/resistant cases will be key, however TANGO-1 alone will be sufficient for filing/approval.”
Acquired in the Parsippany, N.J.-based company’s 2013 buyout of Rempex Pharmaceuticals Inc., Carbavance combines beta-lactamase inhibitor (BLI) RPX7009 with widely used meropenem. The idea is that adding the BLI could restore the usefulness of the carbapenem antibiotic in treating resistant infections. The BLI component is designed to inhibit Klebsiella pneumoniae carbapenemases (KPC), the enzyme that acts as the primary resistance mechanism to carbapenems. (See BioWorld Today, Dec. 5, 2013.)
For the FDA endpoint, positive top-line data in the randomized, double-blind, double-dummy Tango 1 study showed 98.4 percent of patients in the Carbavance group achieved overall success – defined as either cure or improvement and microbiologic outcome of eradication (baseline bacterial pathogen reduced to < 104 CFU/ml) – vs. 94 percent for patients treated with Zosyn.
For the EMA, the primary assessment was defined as microbiologic outcome of eradication (baseline bacterial pathogen reduced to < 103 CFU/ml) at the test-of-cure visit in the microbiologic modified intent-to-treat (microbiologic modified intent-to-treat) and microbiologic evaluable patient populations. For the mMITT patient population, the microbiological eradication was 66.7 percent in the meropenem-vaborbactam group and 57.7 percent of patients in the Zosyn group.
Speaking to the the importance of the superiority data on a conference call held to discuss the Tango 1 data, Mike Dudley, Medicines’ head of R&D and co-leader of its infectious disease group, said that “superiority does help. But superiority without having a better spectrum isn’t necessarily going to get you there.”
The trial enrolled 550 adult patients who were randomized 1:1 to receive Carbavance as a three-hour IV infusion every eight hours or piperacillin 4 g-tazobactam 500 mg as a 30-minute IV infusion every eight hours, each for up to 10 days. After a minimum of five days of IV therapy, patients who met protocol-defined criteria of improvement were transitioned to oral levofloxacin.
In the safety population, which include about 270 patients in each group, 39 percent reported treatment emergent adverse events (TEAEs) in the Carbavance group and 35.5 percent reported TEAEs in the Zosyn group. Drug-related TEAEs were also slightly higher in the Carbavance group (15.1 percent of patients) vs. the Zosyn group (12.8 percent of patients). Study drug discontinuation due to adverse events occurred in just 2.6 percent of patients that received Carbavance vs. 5.1 percent that received Zosyn. Serious adverse events occurred in 4 percent of patients that received Carbavance vs. 4.4 percent that received Zosyn. There were two deaths in each treatment group.
Another carbapenem-BLI antibiotic in development, Merck and Co. Inc.’s relebactam (imipenem/cilastatin), also had new data which were released during the recent American Society for Microbiology Microbe meeting in Boston. Relebactam met its primary endpoint in a phase II test in cUTIs. Two pivotal phase III studies of relebactam in combination with imipenem/cilastatin are currently ongoing and recruiting patients. One of them is comparing treatment with imipenem/relebactam, as a fixed-dose combination, with piperacillin/tazobactam in patients with hospital-acquired bacterial pneumonia or ventilator-associated bacterial pneumonia.
As analysts await Merck’s data to enable further comparisons, they’ll also be waiting for Medicines’ next move, likely to come in the form of data from the phase II Milano trial for MDCO-216, an agent modulating lipids which contains ApoA-1. Data on that trial are expected within the next couple months.