Cempra Pharmaceuticals today announced poster presentations on its novel fluoroketolide antibiotic, solithromycin (CEM-101), and the Company's proprietary front-loading oral dosing regimen of sodium fusidate, TAKSTA (CEM-102) at the 48th Annual Meeting of the Infectious Diseases Society of America in Vancouver, British Columbia. All presentations are scheduled for 10 a.m. to 6 p.m. PDT on Friday, October 22.
The emergence of serious adverse events with the ketolide antibiotic, telithromycin (Ketek®), has created an impediment for the development of next-generation macrolide antibiotics, as the underlying mechanisms of these off-target effects were not known. Uniquely amongst the macrolides, telithromycin contains a pyridine moiety in its chemical structure. Bertrand et al. (Abst. # 252) hypothesized that the so-called "Ketek effects", such as myasthenia gravis exacerbations, visual disturbances, and acute liver toxicity, could be caused by an interaction of this pyridine moiety with nicotinic acetylcholine receptors.
The investigators expressed several subtypes of nicotinic receptors in a Xenopus oocyte expression model. They found that telithromycin inhibited ganglionic alpha-3-beta-4 and alpha-7 nicotinic receptors at an IC50 of 0.15 micromolar, which is a concentration that can be reached clinically. Other tested macrolides, azithromycin, clarithromycin, and the new fluoroketolide, solithromycin (CEM-101), had little activity at these receptors and all lack the pyridine side-chain. These results suggest that the interactions of telithromycin's pyridine moiety with both peripheral and central acetylcholine receptors may account for the serious adverse events seen with this ketolide. The highly potent fluoroketolide candidate, solithromycin, is not likely to exhibit similar toxicities as it lacks the pyridine side-chain and does not show significant inhibition of these receptors.
In addition, solithromycin has three binding sites on the bacterial ribosome compared to either one or two sites with other macrolides. This additional binding site is believed to strengthen ribosomal binding interactions and, thereby, minimize the potential for resistance development when compared with other macrolides. In a second presentation, Farrell et al. (Abst. # 251) investigated the activity of solithromycin against telithromycin-resistant strains of S. pneumoniae. Ketolide resistance is rare and has been associated with mutations in the region of the chromosome that controls erm(B) gene expression, one of the genes known to cause macrolide resistance. The investigators evaluated 2,123 S. pneumoniae strains from patients with community-acquired bacterial pneumonia in 23 countries. Only five resistant isolates were identified and all mutations were found on the chromosome upstream from the erm(B) gene. Solithromycin was active against all five resistant isolates, with MICs ranging from 0.06 to 0.25 micrograms/mL, indicating that the compound may be an excellent candidate in treating community-acquired bacterial pneumonia including those caused by macrolide-resistant strains.
TAKSTA™ (CEM-102, fusidic acid)
Fusidic acid is a highly potent oral antibiotic used clinically for several decades in Europe, Canada and Australia to treat a variety of skin, bone, and joint infections. The product is in clinical development in the U.S. for the treatment of acute bacterial skin and skin structure infections (aBSSSI). TAKSTA employs a novel PK/PD-based dosing regimen that aims to maximize efficacy and broaden its spectrum, as well as minimize the potential for resistance development.
Castanheira et al. (Abst. # 226) tested the activity of fusidic acid against more than 7,300 S. aureus isolates collected from 51 hospitals in the U.S. in 2008 and 2009. The investigators found that fusidic acid inhibited 99.6% of tested strains at <1 microgram/mL and had an MIC50/MIC90 of 0.12/0.25 microgram/mL. Fusidic acid showed equivalent activity against S. aureus compared to tigecycline and was two- to 16-fold more active than daptomycin, vancomycin, and linezolid.
"Cempra is focused on developing antibiotics for challenging infections," said Prabhavathi Fernandes, president and chief executive officer of Cempra. "These studies add to the growing safety and activity profiles of our two leading candidates, both of which are in clinical development. The studies with solithromycin are particularly encouraging. The Bertrand presentation identifies the potential cause of telithromycin toxicity and therefore helps to alleviate safety concerns with future ketolide antibiotics including the fluoroketolide, solithromycin. The Farrell study adds to the evidence suggesting that solithromycin will be a valuable therapeutic option, particularly against macrolide-resistant S. pneumoniae strains. Finally, the excellent activity profile of TAKSTA against U.S. S. aureus strains further indicates its potential value as an oral option to treat aBSSSI in the U.S."