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Actelion's novel antibiotic cadazolid to move into Phase III clinical development in patients suffering from Clostridium difficile associated diarrhea


December 21, 2012 - London

Actelion Pharmaceuticals Ltd /Actelion's novel antibiotic cadazolid to move into Phase III clinical development in patients suffering from Clostridium difficile associated diarrhea . Processed and transmitted by Thomson Reuters ONE.The issuer is solely responsible for the content of this announcement.

ALLSCHWIL/BASEL, SWITZERLAND - 21 December 2012 - Actelion (SIX: ATLN) announced today that it has decided to move forward with Phase III clinical development of cadazolid in patients suffering from Clostridium difficile associated diarrhea (CDAD).

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."

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Notes to the Editor

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.

About cadazolid

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.

Reference

  1. D. Baldoni,et al, Cadazolid, a novel quinolonyl-oxazolidinone antibiotic with potent activity againstClostridium difficile: safety, tolerability, and pharmacokinetics in healthy subjects following single and multiple oral doses.  Poster (A-1273) presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 Septmber 2012, San Francisco. 

Actelion Ltd.

Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion's first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer® through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium - the single layer of cells separating every blood vessel from the blood stream. Actelion's over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).

For further information please contact:

Roland Haefeli
Senior Vice President, Head of Investor Relations & Public Affairs
Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, CH-4123 Allschwil
+41 61 565 62 62
+1 650 624 69 36
www.actelion.com

The above information contains certain "forward-looking statements", relating to the company's business, which can be identified by the use of forward-looking terminology such as "estimates", "believes", "expects", "may", "are expected to", "will", "will continue", "should", "would be", "seeks", "pending" or "anticipates" or similar expressions, or by discussions of strategy, plans or intentions. Such statements include descriptions of the company's investment and research and development programs and anticipated expenditures in connection therewith, descriptions of new products expected to be introduced by the company and anticipated customer demand for such products and products in the company's existing portfolio. Such statements reflect the current views of the company with respect to future events and are subject to certain risks, uncertainties and assumptions. Many factors could cause the actual results, performance or achievements of the company to be materially different from any future results, performances or achievements that may be expressed or implied by such forward-looking statements. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected.


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