Prabhavathi Fernandes, PhD, President and CEO; Cempra Pharmaceuticals, Chapel Hill, N.C.
Drug Discovery & Development - December 01, 2010
There are increasing numbers of treatment failures in community-acquired bacterial pneumonia (CABP). CABP’s primary pathogen is Streptococcus pneumoniae, of which many strains are resistant to currently available macrolides. Over five million people in the United States are diagnosed with CABP each year and more than a million of these require hospitalization.1
More than 30% of S. pneumoniae cases show resistance to macrolides and 15% to 30% are resistant to three or more antibiotic classes.2 Rising treatment-failure rates and the associated mortality increases show a need for new drug options.
The discovery and development of new macrolides has been hampered by serious and poorly understood adverse events associated with telithromycin. Recently, in vitro work has shown that these issues are likely the result of the inhibition of nicotinic acetylcholine receptor subtypes.3 Understanding this mechanism of action will enable drug developers to design around the structural elements that interacted with these receptors and avoid these problems.
Solithromycin (CEM-101) is a new fluoroketolide in Phase 2 clinical development for treatment of CABP. Solithromycin can be administered both orally and intravenously, allowing hospital in-patients to be discharged earlier while remaining on the same antibiotic. Solithromycin is eight to sixteen times more potent than azithromycin and it is active against macrolide-resistant strains. This may be the result of solithromycin binding to three sites on the bacterial ribosome.
FDA guidelines require that clinical studies in CABP be performed on patients with moderate to severe CABP. These patients are treated in the hospital, usually with intravenous antibiotics. Solithromycin’s ability to be given either orally or intravenously means that the drug can be provided to in-hospital patients in accordance with the FDA’s guidelines and then later, after approval, the oral version could expand its use into the community setting.
Moderate to severe CABP patients are currently being enrolled into a Phase 2 trial to test preliminary efficacy and safety of oral solithromycin. A Phase 1 trial of IV solithromycin is enrolling healthy volunteers to determine its tolerability and pharmacokinetic profile.
The need for new macrolides addressing drug resistance is critical to fight the rising treatment failure rate and increasing mortality caused by S. pneumoniae. A fluoroketolide with oral and IV dosing options could give physicians and patients the flexibility to step down to oral therapy and be discharged from the hospital earlier, helping reduce the estimated $8.4 billion to $10 billion spent treating patients with CABP each year.3
Solithromycin is also being developed for pediatric indications. This helps fill a gap between ampicillin and penicillin, which are hampered by increasing resistance, and fluoroquinolones, which are not approved for use in pediatric pneumonia patients because of associated side effects.
References
1. File TM. Community-Acquired Pneumonia. Lancet. 2003;362:1991-2001.
2. Lynch JP III, Zhanel GG, Streptococcus pneumoniae: Does Antimicrobial Resistance Matter? Seminars In Respiratory and Critical Care Medicine, 2009;30:210-238.
3. Restrepo M, Frei CR. Health Economics of use Fluoroquinolones to Treat patients with Community-Acquired Pneumonia. Amer J Med. 2010; 123: S39-46.
More than 30% of S. pneumoniae cases show resistance to macrolides and 15% to 30% are resistant to three or more antibiotic classes.2 Rising treatment-failure rates and the associated mortality increases show a need for new drug options.
The discovery and development of new macrolides has been hampered by serious and poorly understood adverse events associated with telithromycin. Recently, in vitro work has shown that these issues are likely the result of the inhibition of nicotinic acetylcholine receptor subtypes.3 Understanding this mechanism of action will enable drug developers to design around the structural elements that interacted with these receptors and avoid these problems.
Solithromycin (CEM-101) is a new fluoroketolide in Phase 2 clinical development for treatment of CABP. Solithromycin can be administered both orally and intravenously, allowing hospital in-patients to be discharged earlier while remaining on the same antibiotic. Solithromycin is eight to sixteen times more potent than azithromycin and it is active against macrolide-resistant strains. This may be the result of solithromycin binding to three sites on the bacterial ribosome.
FDA guidelines require that clinical studies in CABP be performed on patients with moderate to severe CABP. These patients are treated in the hospital, usually with intravenous antibiotics. Solithromycin’s ability to be given either orally or intravenously means that the drug can be provided to in-hospital patients in accordance with the FDA’s guidelines and then later, after approval, the oral version could expand its use into the community setting.
Moderate to severe CABP patients are currently being enrolled into a Phase 2 trial to test preliminary efficacy and safety of oral solithromycin. A Phase 1 trial of IV solithromycin is enrolling healthy volunteers to determine its tolerability and pharmacokinetic profile.
The need for new macrolides addressing drug resistance is critical to fight the rising treatment failure rate and increasing mortality caused by S. pneumoniae. A fluoroketolide with oral and IV dosing options could give physicians and patients the flexibility to step down to oral therapy and be discharged from the hospital earlier, helping reduce the estimated $8.4 billion to $10 billion spent treating patients with CABP each year.3
Solithromycin is also being developed for pediatric indications. This helps fill a gap between ampicillin and penicillin, which are hampered by increasing resistance, and fluoroquinolones, which are not approved for use in pediatric pneumonia patients because of associated side effects.
References
1. File TM. Community-Acquired Pneumonia. Lancet. 2003;362:1991-2001.
2. Lynch JP III, Zhanel GG, Streptococcus pneumoniae: Does Antimicrobial Resistance Matter? Seminars In Respiratory and Critical Care Medicine, 2009;30:210-238.
3. Restrepo M, Frei CR. Health Economics of use Fluoroquinolones to Treat patients with Community-Acquired Pneumonia. Amer J Med. 2010; 123: S39-46.
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