Shanghai-based Micurx Pharmaceuticals Inc. is preparing to file an NDA for its lead antibacterial candidate, contezolid, with China's National Medical Products Administration after results of a pivotal phase III trial there showed the drug providing comparable clinical cure rates to linezolid for complicated skin and soft tissue infections (cSSTI). Reduced hematologic toxicity for the tablet-based antibiotic vs. linezolid was also seen, highlighting one of contezolid's key advantages.
The data echoed findings of a recent U.S.-based phase II study that compared an I.V.-to-oral regimen of contezolid acefosamil, a prodrug, to linezolid, a long-standing therapy for gram-positive infections marketed as Zyvox by Pfizer Inc., though also sold in generic form. The phase II trial also focused on treatment for cSSTI.
The trans-Pacific biotech, with bases in Shanghai's Zhangjiang Hi-tech Park and Foster City, Calif., is focused on combating pathogens on the World Health Organization's daunting list of 12 multidrug-resistant "superbugs," including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci, the targets of contezolid and contezolid acefosamil, sometimes referred to as MRI-1 and MRX-4, respectively.
Linezolid was a first-in-class antibacterial agents among oxazolidinones and remains in wide use due to advantages such as a lack of cross-resistance with other antibiotic classes due to its mechanism of action and a broad label covering a range of serious gram-positive bacteria. But prescribing information for the drug has long highlighted a risk of myelosuppression, requiring complete blood counts to be monitored weekly during therapy. Also, it has demonstrated a significantly higher incidence of gastrointestinal adverse events and thrombocytopenia compared with Merck & Co. Inc.'s second-generation oxazolidinone, Sivextro (tedizolid phosphate).
Meeting the margin
In the China-based phase III study, contezolid met the primary endpoint of noninferiority vs. linezolid for the clinical cure rate at the test-of-cure visit (TOC), one to two weeks after the last dose of study drug. The double-blind study was conducted at 50 sites. Once started, investigators randomized 719 adults with cSSTI to receive oral contezolid 800 mg or oral linezolid 600 mg twice daily for seven to 14 days. Of the total group, 589 patients were clinically evaluable at the TOC visit. Among them, the clinical cure rates at the TOC visit were comparable for contezolid (93%) and linezolid (93.4%) (treatment difference -0.4% [95% confidence interval (CI) -4.4%, 3.7%]), meeting the noninferiority margin of -10%.
In addition, all lower boundaries of the 95% CI were above the -10% margin for all secondary efficacy endpoints, including the clinical cure rates at the end-of-therapy visit, microbiological clearance rates at the TOC visit, and overall response rates at the TOC visit. Those readings indicated similar treatment outcomes between contezolid and linezolid, Micurx said.
While both the overall and study drug-related rates of treatment-emergent adverse events (TEAEs) were comparable between the study arms, there were fewer hematologic-related events for contezolid than linezolid.
White blood cell-related TEAEs occurred in 0.28% of evaluable patients with contezolid vs. 3.42% for linezolid (p=0.002). Neutrophil-related TEAEs occurred in 0.28% of evaluable patients with contezolid vs. 1.71% on linezolid (p=0.068). Reticulocyte-related TEAEs occurred in 0.28% of evaluable patients with contezolid vs. 1.42% for linezolid (p=0.123). And there were no platelet-related TEAEs in the contezolid arm vs. 2.28% in the linezolid arm (p=0.004).
Of the 405 patients that received more than 10 days of therapy, 25.4% of linezolid patients experienced more than a 30% reduction in platelet counts at the end of therapy visit relative to baseline visit, while only 2.5% of contezolid patients had a similar decrease.
Both MRI-1 and MRX-4 have qualified infectious disease product and fast track designations from the FDA. The company is also developing MRX-8, a polymyxin antibiotic program, for the potential I.V. treatment of multidrug-resistant gram-negative bacterium infections, including E. coli, P. aeruginosa, K. pneumoniae and A. baumannii. According to the company's website, an NDA filing is expected to be submitted globally in the U.S., China and the EU in 2020.