Zolyd Meets Primary Endpoint in Pivotal UTI Trial

Treatment noninferior to piperacillin/tazobactam

Fosfomycin for injection (Zolyd, Zavante Therapeutics) has met the primary endpoint of statistical noninferiority to piperacillin/tazobactam in a pivotal study of patients with complicated urinary tract infections (UTIs), including acute pyelonephritis (AP). Fosfomycin is a first-in-class injectable epoxide antibiotic with a differentiated mechanism of action and broad spectrum of activity against gram-negative and gram-positive pathogens, including multi-drug resistant (MDR) pathogens.

The ZEUS trial was a phase 2/3, multicenter, randomized, double-blind study designed to evaluate the safety and efficacy of fosfomycin in the treatment of 465 hospitalized adults with complicated UTIs or AP. The patients were randomly assigned to receive 6 grams of fosfomycin as a one-hour intravenous (IV) infusion three times daily (18 g/daily) or 4.5 grams of piperacillin/tazobactam as a one-hour IV infusion three times daily (13.5 g/day) for seven days. Oral step-down therapy was prohibited. Patients with concurrent bacteremia received up to 14 days of therapy. The study’s primary endpoint of overall success––defined as clinical cure plus microbiologic eradication––was assessed in the microbiologic-modified intent-to-treat population at the test-of-cure visit (day 19).

Fosfomycin met the study’s primary endpoint of statistical noninferiority to piperacillin/tazobactam, with an overall success rate of 64.7% (119/184 patients) compared with 54.5% (97/178 patients), respectively––a treatment difference of 10.2%.Clinical cure rates were similar between the two treatment groups (90.8% vs. 91.6%).

Treatment-emergent adverse events (TEAEs) occurred in 42.1% of patients in the fosfomycin arm compared with 32.0% of patients in the piperacillin/tazobactam arm. Most TEAEs were mild and transient, and most events did not lead to premature discontinuation of the study drug. Serious adverse events were uncommon, occurring in five patients in the fosfomycin arm and in six patients in the piperacillin/tazobactam arm. No deaths were reported during the study.

The FDA granted fast track and qualified infectious disease product (QIDP) designations for the investigation of fosfomycin for the following indications: complicated UTIs; hospital-acquired bacterial pneumonia; ventilator-associated bacterial pneumonia; acute bacterial skin and skin-structure infections; and complicated intra-abdominal infections.

Zavante expects to submit a new drug application to the FDA for the UTI indication in early 2018.

Source: Zavante Therapeutics; April 5, 2017.