Novel Fluoroquinolone (JNJ-Q2)
JNJ-Q2 is a Phase III ready novel broad-spectrum fluoroquinolone antibiotic being developed for the treatment of acute bacterial skin and skin-structure infections and community-acquired pneumonia. JNJ-Q2 product is effective in treating methicillin-resistant staphylococcus aureus (MRSA) infections. We are developing both oral and intravenous, or IV, formulations of this compound to allow physicians to select the most appropriate method of delivery. Furiex has completed Phase II clinical trials using the oral formulation for acute bacterial skin and skin-structure infections.
Furiex has a license agreement with Janssen Pharmaceutica N.V., under which Furiex has global rights for development and commercialization of the product.
JNJ-Q2 is a novel fluorinated 4-quinolone. In addition to MRSA, it exhibits a range of antibacterial activities in vitro that support its potential as a new agent for the treatment of skin and respiratory tract infections. In recent laboratory studies, JNJ-Q2 was evaluated for its antibacterial potency against bacterial strains known to be skin and respiratory tract pathogens, including strains exhibiting fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of streptococcus pneumoniae, including fluoroquinolone-resistant variants, JNJ-Q2 was 32-fold more potent than the popular marketed antibiotic moxifloxacin. Against a collection of 511 recently collected MRSA isolates, including 409 ciprofloxacin-resistant strains, JNJ-Q2 was at least 16-fold more potent than moxifloxacin.
In further studies, JNJ-Q2 exhibited bacteria killing activities at lower doses against clinical isolates of streptococcus pneumoniae and MRSA compared to moxifloxacin. JNJ-Q2 also demonstrated a lower potential for resistance development than that for currently marketed fluoroquinolones ciprofloxacin, levofloxacin and moxifloxacin.
The mechanism of action of fluoroquinolones is against specific bacterial enzymes called topoisomerases, typically topoisomerase II (or DNA gyrase) and topoisomerase IV. Some marketed fluoroquinolones target a single topoisomerase more potently than they do the other. The improved activity of JNJ-Q2 is due to its equipotent activity against both of these topoisomerases instead of just one. Furthermore, this dual activity against both target enzymes is consistent with a lower propensity for resistance selection.
Another reason we believe this fluoroquinolone will have a lower propensity for resistance selection is because preclinical studies have shown that JNJ-Q2 is not transported out of the bacterial cell by efflux pumps. Efflux pumps (such as Nor A) are typically implicated in bacterial resistance.
JNJ-Q2 was tested in a Phase II clinical trial comparing the efficacy, safety and tolerability of JNJ-Q2 with linezolid (Zyvox®). The study used a non-inferiority design to test the efficacy of JNJ-Q2 relative to linezolid. One hundred sixty-one patients with ABSSSI received oral treatment with either JNJ-Q2 (250 mg twice daily) or linezolid (600 mg twice daily) for 7 to 14 days. JNJ-Q2 was statistically non-inferior to linezolid for all clinical test-of-cure and short-term follow-up endpoints in the ITT population. At seven days of therapy, 44.6 percent (37/83) of patients receiving JNJ-Q2 were assessed as cured, compared with 37.2 percent (29/78) of patients receiving linezolid; at 10 to 14 days of therapy, 66.3 percent (55/83) of patients receiving JNJ-Q2 were assessed as cured, compared with 61.5 percent (48/78) of patients receiving linezolid; and at the traditional test-of-cure endpoint (short-term follow-up done 2 to 14 days after treatment was completed) 83.1 percent (69/83) of patients receiving JNJ-Q2 were assessed as cured, compared with 82.1 percent (64/78) of patients receiving linezolid. JNJ-Q2 had a favorable safety profile and was well tolerated. Serious adverse events were infrequent in both treatment groups. Nausea and vomiting were more frequent with JNJ-Q2 than linezolid, however, symptoms were mild for both treatment groups. Nausea rates were 22.9 percent for JNJ-Q2 and 11.4 percent for linezolid; vomiting rates were 12.0 percent JNJ-Q2 and 6.3 percent for linezolid. The vast majority of these events occurred on day one to two of treatment and were self-limiting.
JNJ-Q2 was tested in a Phase I pharmacokinetic study in eight healthy volunteers designed to measure the lung penetration of JNJ-Q2, an accepted predictor of efficacy for the treatment of community-acquired pneumonia. Volunteers were dosed orally with JNJ-Q2 and then underwent a bronchoscopic procedure to measure pulmonary drug levels. Levels of JNJ-Q2 in epithelial lining fluid of the lung were, on average, about 50-fold higher than levels in plasma, and levels in alveolar macrophages (which are inflammatory cells in the air sacs of the lung) were 150-fold higher, on average, then levels of JNJ-Q2 in plasma.
We also have results from a double-blind randomized trial where patients with severe community acquired bacterial pneumonia (CABP) received intravenous treatment with JNJ-Q2 (twice daily) versus moxifloxacin (once daily), and were switched from IV to oral therapy as their conditions improved. Although we enrolled only 32 patients, the data from this small study gives us valuable qualitative information about the drug's efficacy and tolerability in this very ill patient population. The results were encouraging, with a clinical cure rate (primary endpoint) of 87.5% for patients receiving JNJ-Q2 versus 81.3% of patients receiving moxifloxacin. For the secondary endpoint of clinical stability at day 4 (determined by patients' vital signs and respiratory status) 50.0% of patients receiving JNJ-Q2 met the endpoint compared with 43.8% of patients receiving moxifloxacin.. Both the IV and oral formulations of JNJ-Q2 had excellent tolerability and safety profiles, with no nausea, vomiting or serious adverse events reported in this treatment arm. These Phase II clinical trial data for CABP, taken together with the excellent lung penetration data, support phase III-readiness for a CABP indication.
View a list of Janssen and Furiex publications.
Fluoroquinolone clinical trials can be accessed at www.clinicaltrials.gov.
The worldwide antibiotics market generated sales of $42 billion in 2009 representing 5 percent of the global pharmaceutical market. The fluoroquinolone class generated $7 billion in global sales. Despite availability of a broad range of treatment options, the growth in antibiotic resistance among potentially life-threating pathogens is creating an increased need for novel products and new classes of antibiotics. Hospital stays for MRSA infections have more than tripled after 2000 and increased nearly ten-fold after 1995, with a 30 percent increase occurring from 2004 to 2005 . Although MRSA had previously been a hospital-acquired pathogen, its incidence has been rising in the community, and it has become the most frequent cause of skin and soft tissue infections presenting to emergency departments in the United States . There are a limited number of antibiotics approved to treat MRSA, and their frequent usage has led to emergence of multi-drug resistant bacteria. Thus, there is significant unmet medical need for new antibiotics such as JNJ-Q2 that provide flexible (hospital and outpatient) treatment options for MRSA.
- New England Journal of Medicine 2006; 355:666-674