The development of antibiotic resistance and the emergence of new pathogenic bacterial strains mean that infections that were once treatable with antibiotics are becoming increasingly difficult or impossible to treat. This makes new antibiotics based on new chemical scaffolds and with new mechanisms of action highly sought after.

Cadazolid, a quinolonyl-oxazolidinone is a new chimeric antibiotic with structural elements of the oxazolidinone as well as the quinolone class of antibiotics. It is a strong inhibitor of Clostridium difficile (C. diff) protein synthesis leading to strong suppression of toxin and spore formation.

Actelion's first potent, novel antibiotic, cadazolid, is to move forward with Phase III clinical development in patients suffering from Clostridium difficile associated diarrhea (CDAD).

The decision to enter Phase III is based on the results of a therapeutic exploratory Phase II dose-finding study randomizing 84 patients. The study evaluated the efficacy, safety and tolerability of 3 doses of cadazolid (administered orally, twice-daily) versus vancomycin, as an active reference, (125 mg administered orally, four times daily) for 10 days. The study, with a limited sample size, was not designed to compare statistically cadazolid versus vancomycin.

The results of this Phase II study indicate that the effect of all doses of cadazolid are numerically similar to, or better than vancomycin on key endpoints including CDAD cure rates as well as sustained cure rates.

Recurrence rates were numerically lower for all doses of cadazolid as compared to vancomycin.

Cadazolid was safe and well tolerated, at present no safety signals have been identified.

Once full data analysis of this exploratory dose-finding study for cadazolid has been completed, Actelion will discuss the details of a Phase III program with Health Authorities.

In preclinical studies cadazolid showed potent in vitro activity against C. diff clinical isolates and in a human gut model of Clostridium difficile associated diarrhea (CDAD), while having only a very limited impact on bacteria of the normal gut microflora. In addition, cadazolid demonstrated a low propensity for resistance development.

Cadazolid absorption is negligible resulting in high gut lumen concentrations and low systemic exposure, even in severe cases of CDAD where the gut wall can be severely damaged and permeability to drugs potentially increased. The observed preclinical and clinical pharmacology and safety profiles of cadazolid supported further clinical development in CDAD.

2012 - Completion of Phase II development

2009 - Actelion's first antibiotic enters man

Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 Septmber 2012, San Francisco.:

H. H. Locher, et al, Abstract/poster C1-1346

H. H. Locher, et al, Abstract/poster C1-1347

D. Baldoni, et al, Poster A-1273

Lo Vecchio A, Zacur GM. Clostridium difficile infection: an update on epidemiology, risk factors, and therapeutic options. Curr Opin Gastroenterol 28 (1):1–9, 2012.

Khanna S. and Pardi DS. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Rev. Gastroenterol. Hepatol 4(4), 409–416, 2010.