Delafloxacin

Description

 

Delafloxacin, which recently successfully completed a Phase 2b study in ABSSSI, is a novel hospital-focused fluoroquinolone antibiotic candidate with potency against a variety of quinolone-resistant Gram-positive and Gram-negative bacteria, including quinolone-resistant, methicillin-resistant Staphylococcus aureus (MRSA). Fluoroquinolones are a class of broad spectrum antibiotics which kill bacteria by interfering with DNA replication. Within this class, delafloxacin has a unique three-dimensional chemical structure and properties that enable an increase in potency at acidic pHs found specifically at sites of infection. Our in vitro testing suggests that delafloxacin becomes up to 32 times more potent in acidic environments than in normal pH environments within the human body, in contrast to many other antibiotics which become progressively less potent, as measured by the changes in their minimum inhibitory concentration. The acidic pH enhances the ability of delafloxacin to cross the bacterial cell membrane and exert its effects.  Moreover, delafloxacin kills bacteria more rapidly than Zvyox, Tygacil and vancomycin according to the Journal of Chemotherapy and the Journal of Antimicrobial Chemotherapy. With both IV and oral formulations, delafloxacin has been shown to be more potent than current standards of care against multiple strains of drug-resistant Gram-positive bacteria, including MRSA, and to have improved efficacy when compared to traditional quinolone compounds. Importantly, delafloxacin has consistently demonstrated a favorable safety profile that, unlike other fluoroquinolones, does not further compromise patients.

 

Status

 

Delafloxacin successfully completed a Phase 2b clinical trial and positive top-line data was reported in December 2011. The study was designed to compare the efficacy of delafloxacin for the treatment of ABSSSI, including infections caused by MRSA to Zyvox (linezolid), with and without aztreonam, and vancomycin, with and without aztreonam. Delafloxacin met primary and secondary efficacy endpoints evaluated to date, including endpoints based on the draft guidance from the FDA in ABSSSI. Rib-X plans to enter delafloxacin into a Phase 3 trial in the first half of 2013.

 

Delafloxacin has been tested in more than 1,200 patients and determined to be clinically efficacious and well-tolerated in studies to date, as demonstrated across four Phase 2 trials and 16 Phase 1 trials. Delafloxacin has been shown to be at least 16-fold more potent than levofloxacin, ciprofloxacin, gatifloxacin and moxifloxacin against ciprofloxacin-resistant MRSA (MIC90 of = 0.5 micrograms/ml for delafloxacin versus > 16 micrograms/ml for all other quinolones). Delafloxacin has also been shown to be more potent than existing quinolones against a range of Gram-positive, anaerobic and Gram-negative organisms. 

 

Recent Data

 

The Phase 2b clinical trial was a randomized, double-blind study designed to compare delafloxacin, linezolid and vancomycin for the treatment of acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA). The trial evaluated multiple objective efficacy measures based on the newly updated guidance from the U.S. Food and Drug Administration (FDA) in order to support the design of a Phase 3 program. Delafloxacin met primary and secondary efficacy endpoints evaluated to date, including endpoints based on the draft guidance from the FDA in ABSSSI. Of note, although this Phase 2b trial was not designed to demonstrate statistical significance, for the primary endpoint of Investigators’ Global Assessment of Cure, delafloxacin demonstrated a statistically significant efficacy advantage as compared to vancomycin (95% Confidence Interval -30.3%, -2.3%; p=0.031). Additionally, delafloxacin demonstrated numerical benefit over both Zyvox and vancomycin in the secondary endpoint, cessation of lesion spread and absence or resolution of fever at 48 to 72 hours, with cure rates of approximately 78%, 75%, and 73%, respectively. Furthermore, delafloxacin showed that a greater percentage of patients experience a 30% or greater reduction in the size of the lesion at 48 to 72 hours than either comparator.

 

Overall adverse event rates for the Phase 2b study were statistically equivalent across the study for delafloxacin (74%), Zyvox (72%) and vancomycin (65%). The leading adverse event associated with delafloxacin was gastrointestinal, or GI, disorder with mild to moderate diarrhea as the most common specific event. The other common adverse events in this trial were nausea, vomiting, fatigue, headache, dizziness and infusion site pain. The leading adverse event for Zyvox was also GI disorder, with the most common specific event being nausea. The leading adverse event for vancomycin was disorders of the skin, with the most common specific event being pruritus, or itching. In the Zyvox arm, two subjects experienced thrombocytopenia. In the vancomycin arm, three patients experienced renal issues, including two renal failures. Importantly, as observed in earlier Phase 2 studies, delafloxacin did not demonstrate evidence for the toxicities that have been common in the fluoroquinolone class of antibiotics, such as phototoxicity, elevated liver enzymes, dysglycemia and QT prolongation.

 

Based on this analysis and other data, we believe delafloxacin has demonstrated a level of efficacy that strongly supports our planned initiation of a Phase 3 study of delafloxacin in the first half of 2013.

 

At ICAAC 2010, data were presented that suggest the unique chemical structure and molecular properties of delafloxacin lead to an increase in potency in acidic environments, which are typically found at the site of infection. It is believed that this increased potency may translate to an enhanced clinical benefit with regard to both improved efficacy and an improved resistance profile. In the first presented study, the impact of increasing acidity on the minimum inhibitory concentrations (MICs) of delafloxacin in comparison to the leading approved agents, levofloxacin, ciprofloxacin and moxifloxacin, was explored. Results demonstrated that delafloxacin MICs were reduced as a function of acidity two- to 32-fold at pH concentrations typically found at most sites of infection (pH 5.5 and 6.5) whereas levofloxacin, ciprofloxacin and moxifloxacin MICs increased from those seen at neutral pH. Against fluoroquinolone resistant strains, delafloxacin demonstrated more pronounced reduction in MICs which were approximately two-fold greater than those observed with quinolone-susceptible strains. A second study identified through computational analysis of the three-dimensional structure a set of molecular features unique to delafloxacin that deliver enhanced potency as compared to other quinolones.

 

At ECCMID 2011, data were presented evaluating the in vitro activity of delafloxacin against S. aureus strains isolated from a diverse range of European sources, of which 96% were found to be methicillin-resistant. Delafloxacin activity against MRSA was found to be consistent across European regions and was at least 32-fold more potent than levofloxacin (MIC50/MIC90 = 0.12/>32 mcg/mL), regardless of the geographic region. MIC50/MIC90 values for linezolid and vancomycin, both of which delafloxacin is currently being evaluated against in a Phase 2b clinical trial, were  2/2 mcg/mL and 0.5/1 mcg/mL, respectively.