Actelion’s Novel Antibiotic Cadazolid To Move Into Phase III Clinical Development In Patients Suffering From Clostridium Difficile Associated Diarrhea
The decision 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. Cure rate was defined as the resolution of diarrhea and no further need for CDAD therapy at test-of-cure 24 to 72 hours after the last dose of treatment, while sustained cure rate was defined as cured with no recurrence of diarrhea up to 4 weeks post-treatment.
Recurrence rates were numerically lower for all doses of cadazolid as compared to vancomycin. Recurrence rate was defined as a new episode of diarrhea and a positive Clostridium difficile toxin test.
Guy Braunstein, M.D. and Head of Clinical Development commented: “This is the first time cadazolid has been used to treat patients, delivering very encouraging clinical data with this new class of antibiotics. The results provide clear information to support further evaluation in a Phase III program. Results of microbiology and pharmacokinetic assessments will soon be available allowing us to further characterize cadazolid.”
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. Actelion will present the results of this study through scientific presentations and publications.
Jean-Paul Clozel, M.D. and Chief Executive Officer commented: “This year we, at Actelion, made significant progress to deliver on our strategy. The landmark results for macitentan (Opsumit®) will allow us to sustain and grow our pulmonary arterial hypertension business. Now, with the results from both ponesimod in psoriasis and cadazolid in CDAD, we have laid the foundation for our mid-term goal of building a second specialty franchise.”
About cadazolid in Clostridium difficile associated diarrhea
Cadazolid was studied in a multi-center, double-blind, randomized, active reference, parallel group, therapeutic exploratory dose-finding study. The study evaluated the efficacy, safety and tolerability of a 10-day, twice daily oral administration of 3 doses (250 mg, 500 mg or 1,000 mg b.i.d.) of cadazolid in patients with Clostridium difficile associated diarrhea (CDAD). As the current standard of care for CDAD, oral vancomycin (125 mg qid for 10 days) was used as the active reference. The study was completed in December of 2012, after having enrolled 84 patients.
About the efficacy measurements used in the study
In CDAD, as in most acute infectious diseases, the clinically most relevant parameter for assessing treatment efficacy in a Phase II study is clinical response at the end of therapy (in this case principally resolution of diarrhea), which was evaluated at the Test-of-Cure visit (24 to 72 hours after the last dose of study treatment). In current and past clinical trials in CDAD, clinical cure rate is consistently selected as the primary endpoint.
In CDAD, disease recurrence is an additional important parameter. Recurrence during the 4 weeks after the end of treatment is chosen as the main secondary endpoint.
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. 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.
About Clostridium difficile associated diarrhea
Clostridium difficile (C. diff) is a Gram-positive, anaerobic, spore-forming bacterium that is the leading cause of nosocomial diarrhea. Clostridium difficile associated diarrhea (CDAD or CDI for C. Diff infection) can be a severe and life-threatening disease and results from the overgrowth in the colon of toxigenic strains of C. Diff, generally during or after therapy with broad-spectrum antibiotics. CDAD is a major healthcare problem and a leading cause of morbidity in elderly hospitalized patients. The frequency and severity of CDAD in the western world has increased in recent years, and new hypervirulent and epidemic strains of C. diff have been discovered that are characterized by overproduction of toxins and other virulence factors, and by acquired resistance to fluoroquinolones such as moxifloxacin.
Current antibiotic therapy for CDAD includes vancomycin and metronidazole. While cure rates are generally 85-90%, recurrences rates of 15-30 % with either drug are problematic C. Diff produces spores that are resistant to antibiotic treatment and routine disinfection. Spores surviving in the gut of patients and/or in the hospital environment may play a major role in re-infection and relapse of CDAD after antibiotic treatment, Vancomycin and metronidazole are reported to promote spore formation in vitro at sub-inhibitory concentrations.
Only one new antibiotic, fidaxomicin, has been approved over the last 30 years for this indication, and there remains a need for new drugs with improved properties. In particular, antibiotics that allow effective treatment of infections caused by hypervirulent strains with low recurrence rates.
“Cadazolid, a novel quinolonyl-oxazolidinone antibiotic with potent activity against Clostridium difficile: safety, tolerability, and pharmacokinetics in healthy subjects following single and multiple oral doses.”, D. Baldoni,et al.
Poster (A-1273) presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 Septmber 2012, San Francisco.
Source: Actelion Ltd.