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Molecular Mechanisms That Could Explain Unique Adverse Events Observed in Patients Treated With the Antibiotic Telithromycin (Ketek) is Reported in Antimicrobial Agents and Chemotherapy

- Inhibition of nicotinic acetylcholine receptors by telithromycin may cause exacerbation of myasthenia gravis, visual disturbances and hepatic toxicity; the pyridine moiety in telithromycin could be linked to nicotinic acetylcholine receptor inhibition

- The pyridine moiety is not found in macrolides, such as azithromycin and clarithromycin, which do not elicit these adverse events nor Cempra Pharmaceutical's novel fluoroketolide, solithromycin (CEM-101), which has significantly lower nicotinic acetylcholine receptor inhibition

CHAPEL HILL, N.C., Dec. 1, 2010 /PRNewswire/ -- Cempra Pharmaceuticals and HiQScreen today announced the publication of research revealing the molecular mechanisms that could explain certain unique adverse events associated with the ketolide, telithromycin (Ketek™), which led to its restricted use.  The study also showed that Cempra's novel fluoroketolide, solithromycin (CEM-101) is unlikely to generate the adverse events seen with telithromycin.  The report was published in the (December) issue of Antimicrobial Agents and Chemotherapy (volume 54: pages 4961 to 4970).

Adverse events ranging from mild to life-threatening have been reported in patients administered telithromycin to treat respiratory or other infections.  These "Ketek or telithromycin effects" resulted in highly restricted use of the drug and an adverse regulatory environment for the development of new and novel macrolides.

The report by Professor Daniel Bertrand et al. revealed that the "Ketek effect" may be caused by the inhibition of specific nicotinic acetylcholine receptors found in the neuromuscular junction, retina and parasympathetic innervation of the liver.  In each case, telithromycin showed higher binding affinity to the receptors and greater inhibitory activity of acetylcholine-induced electrical activity than the currently marketed macrolides, azithromycin and clarithromycin, as well as the new fluoroketolide, solithromycin, which is in Phase 2 trials for community-acquired bacterial pneumonia (CABP).

"The FDA has raised safety concerns regarding the ketolide class of macrolides following the emergence of these unique adverse events with telithromycin," said Professor Daniel Bertrand, Ph.D., president and chief executive officer of HiQScreen and the lead author of the paper.  "The macrolide class had been previously considered safe.  For drug development to continue with this important antibiotic class, it is important to understand the underlying mechanism that generates telithromycin toxicity.  The results of our research show that the pyridine moiety of the telithromycin molecule is the likely cause of its toxicity. Our work also provides an avenue for future macrolide candidates to avoid telithromycin's toxic effects."

Prabhavathi Fernandes, Ph.D., chief executive officer of Cempra and co-author of the paper added, "Cempra's mission is to develop next generation antibiotics that confront the infectious disease challenges of today, particularly drug resistant bacterial pathogens.  One of our lead candidates, solithromycin, is a fluoroketolide with a broad spectrum of activity against a variety of respiratory pathogens including macrolide-resistant strains.  Solithromycin does not contain the pyridine moiety in its structure. Its activity on nicotinic acetylcholine receptors mirrors the profiles of other macrolides that do not elicit telithromycin's adverse effects."

Jennifer Schranz, vice president of clinical affairs research commented, "Solithromycin's tissue distribution profile, particularly in lung, once-daily dosing and ability to be administered both orally and intravenously makes it possible to develop this antibiotic for bacterial pneumonia using the moderate-to-severe CABP criteria defined by the FDA guidance document.  Demonstration of a possible cause for telithromycin's toxicity being specific to the molecule increases our confidence in the safety profile of solithromycin."

About solithromycin 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, beta-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.  

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.

About HiQScreen

HiQScreen is an innovative Swiss based biotech company specialized in the functional screening of membrane proteins, technological development and drug discovery. The company is dedicated to provide unique in vitro drug testing services to the pharmaceutical and biotechnology industries in the area of drug research discovery as well as academia.

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SOURCE Cempra Pharmaceuticals

CONTACT: Russo Partners, LLC, Robert E. Flamm, Ph.D., +1-212-845-4226,, or Tony Russo, Ph.D., +1-212-845-4251,

Posted: December 2010