Cempra Pharmaceuticals Presents New Data on its Next Generation Fluoroketolide, Solithromycin (CEM-101) at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

CHAPEL HILL, N.C., Sept. 9 /PRNewswire/ --

• Phase 1 presentations:
  • Provide evidence of the safe administration of multiple oral doses
  • Demonstrate high levels of pulmonary accumulation in the lung that could provide coverage for macrolide-resistant pneumococci
  • Demonstrate no food effect, unlike other macrolides
• In vivo toxicology and pharmacokinetic studies further define solithromycin's IV and oral safety profile and provide support for dose selection in upcoming clinical trials with an intravenous formulation and oral dosing in community-acquired bacterial pneumonia (CABP)
• In vitro and in vivo activity is demonstrated against Mycobacterium avium complex, including clarithromycin-resistant strains, Listeria monocytogenes, Enterococcus faecalis and macrolide-resistant Streptococcus pneumoniae

Cempra Pharmaceuticals today announced abstracts to be presented on its novel fluoroketolide antibiotic, solithromycin (CEM-101), at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 12 to 15, 2010, in Boston.  The abstracts provide additional data that demonstrate the safety and pharmacokinetics in healthy volunteers as well as additional information from in vivo toxicology and spectrum of activity studies.

Solithromycin is a fluoroketolide belonging to the macrolide class and is the first macrolide since azithromycin with the potential for both IV and oral administration. The compound has potent in vitro activity against respiratory pathogens such as pneumococci, including macrolide- and quinolone-resistant strains.  Bacterial pneumonia caused by multi-drug resistant pneumococci has a significant impact on morbidity and mortality due to high treatment failure rates and subsequently increases in hospitalization and healthcare costs.

"The data presented at this year's ICAAC add to the promising safety and efficacy database of this promising next generation fluoroketolide," said Prabhavathi Fernandes, Ph.D., chief executive officer of Cempra.  "We are encouraged by these results and look forward to completing the Phase 1 study with the intravenous formulation and moving into Phase 2 trials with the oral formulation in CABP patients."

Multiple doses of solithromycin were well tolerated in healthy volunteers in multiple Phase 1 studies

Schranz et al. (Abst. A1-689) investigated the effect of solithromycin in healthy volunteers to determine the tolerability and pharmacokinetics of multiple oral doses of the compound.  Multiple daily doses, from 200 to 600 mg, dosed once-daily for seven days, were found to be safe and well tolerated.  A 400 mg single dose fed/fasted bioequivalence study indicated that dosing was not affected by food.  

Penetration into target tissues is critical for antibiotic efficacy.  Rodvold et al (Abst. A1-690) showed that solithromycin, dosed 400 mg orally once-daily, is well distributed in plasma, lung and lung macrophages.  Importantly, high concentrations were found in the lung reaching levels that are clinically relevant against macrolide-resistant pneumococci.

Population pharmacokinetic modeling performed by Okusanya et al. (Abst. A1-691) predicted reliable pharmacokinetic data when solithromycin is administered orally.  In addition, Phase 1 data applied to a Monte Carlo simulation (Okusanya et al., Abst. A1-692) and a mouse pneumonia model (Andes et al., Abst. A1-688) determined that doses chosen for the Phase 2 study in CABP, including the 800 mg loading dose, will address organisms with MICs as high as 2 ug/ml, such as rare macrolide-resistant strains.  

Solithromycin demonstrates a promising safety profile for both oral and IV administration

Solithromycin has potential to be administered both orally and IV.  This would be an advantage for hospitalized patients being transferred to an out-patient setting.  Fernandes et al. (Abst. F1-2151) conducted a 28-day toxicology study in two animal models with the IV formulation of solithromycin.  The drug appeared safe and well tolerated in both models at doses up to 25 mg/kg.  There was minimal injection site irritation observed and no evidence of pain on infusion, both, common occurrences with IV macrolides.  This study completed the toxicology panel of IV solithromycin.  The formulation has been prepared for the Phase 1 single/multi-dose clinical study.

In vivo data demonstrate the potent activity of solithromycin

A comparative metabolic study in mice, monkeys, rats and humans showed that solithromycin metabolism in humans was quite different than in monkeys and rats but was similar in mice (Periera et al., Abst. A1-687), indicating that the mouse might be the most appropriate in vivo model to use in preparation for human studies.  

This study also adds credence to three studies demonstrating the potent activity of solithromycin against several pathogens in the mouse model.  Andes et al., (Abst. A1-688) showed that solithromycin was effective in the pneumococcal mouse model.   Murphy et al., (Abst. F1-2152) confirmed in vitro activity in an in vivo mouse model against L. monocytogenes, E. faecalis and macrolide-resistant S. pneumonia strains.  Shoen et al. (Abst. E-2057) showed that solithromycin demonstrated potent activity against macrolide-resistant and susceptible Mycobacterium avium complex (MAC) isolates.    MAC is a serious problem for HIV patients and resistance has been increasing against clarithromycin, the macrolide used to treat this infection.  Solithromycin has the potential to replace clarithromycin as the antibiotic of choice to treat MAC.

About solithromycin (formerly CEM-101)

Solithromycin is the first fluoroketolide with a number of attributes that may provide clinically important advantages over several comparator products:

• 8 to 16 times more potent than azithromycin and is active against organisms that have become resistant to azithromycin
• Potent in vitro activity against all important respiratory pathogens, including pneumococci, β-hemolytic streptococci, staphylococci, Hemophilus, Legionella, Mycoplasma, Moraxella  and Chlamydophila
• Potent in vitro activity against other medically significant pathogens including CA-MRSA, M. avium, malaria, enterococci and gonococci
• Good tolerability to date as demonstrated in phase 1 trials of the oral formulation
• Low resistance frequency in vitro
• Unlike telithromycin, solithromycin does not inhibit the alpha 7 acetylcholine nicotinic receptor; such inhibition is believed responsible for certain adverse effects observed with telithromycin (Ketek®).
• Excellent tissue distribution and intracellular tissue concentrations including lung epithelial lining fluid and alveolar macrophages
• Oral and IV formulations concurrently in development
• Once-daily dosing
• Potential for indications beyond CABP, including urethritis and other urogenital infections, bioterrorism targets, malaria, M. avium infections and tuberculosis.

The annual incidence for CABP in the United States is over five million of which over 1 million are hospitalized (File, T.M., Lancet, 2003; File, T.M. and Tan, J.S. JAMA, 2005; CDC, National Hospital Discharge Survey, 2006; File, T.M. and Marrie, T., Postgrad. Med., 2010).  There is a growing need for new drugs to address the issues of drug resistance, tolerability, and IV administration associated with currently available treatments.  Cempra has licensed exclusive worldwide rights from Optimer Pharmaceuticals, Inc., except in the Association of Southeast Asian Nations (ASEAN) countries, to discover, develop and commercialize macrolides from a library of more than 500 compounds from Optimer's OPopS drug discovery platform.

About Cempra Pharmaceuticals

Founded in 2006, Cempra Pharmaceuticals is a privately-held, clinical-stage pharmaceutical company focused on developing antibacterials to address critical medical needs. Two lead products, both in late-stage clinical trials, address the urgent and increasing need for new treatments targeting drug-resistant bacterial infections in the hospital and in the community. Cempra is well-funded and is committed to developing commercially and medically differentiated and novel products that reduce development risk and provide a high financial return. The company is also utilizing its proprietary compound library and chemistry technology to develop novel macrolides without antibacterial activity for non-antibiotic uses such as COPD, chronic inflammatory and GI disorders. Additional information about Cempra can be found at www.cempra.com.

SOURCE Cempra Pharmaceuticals