Actelion is initiating Phase III clinical development of the novel antibiotic cadazolid in patients suffering from Clostridium difficile associated diarrhea

Tue Sep 10, 2013 1:30pm EDT

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Actelion Pharmaceuticals Ltd / Actelion is initiating Phase III clinical development of the novel antibiotic cadazolid 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 - 10 September 2013 - Actelion (SIX: ATLN) announced today that it will initiate a Phase III clinical development program to assess the efficacy and safety of cadazolid in patients with Clostridium difficile-associated diarrhea (CDAD).

ABOUT THE PHASE III PROGRAM

The Phase III program consists of two identical multi-center, randomized, double-blind studies comparing the efficacy and safety of cadazolid, (250 mg administered orally twice daily for 10 days) versus vancomycin, (125 mg administered orally four times daily for 10 days) in subjects with Clostridium difficile-associated diarrhea (CDAD).

The program is designed to determine whether the clinical response after administration of cadazolid is non-inferior to vancomycin in patients with CDAD, and whether administration of cadazolid is superior to vancomycin in the sustained clinical response.

The program is expected to enroll more than 1'250 patients worldwide, and is planned to commence enrollment in the fourth quarter of 2013.

Dr. Dale Gerding, Professor of Medicine at Loyola University Chicago Stritch School of Medicine, Maywood, IL, Research Physician at Hines, VA Hospital, Hines, IL and Chairman of the cadazolid Steering Committee, commented: "The results from the exploratory Phase II study indicate that cadazolid was numerically similar to, or better than vancomycin on CDAD clinical cure rates as well as sustained cure rates. These results support initiating the Phase III program in a larger population, including patients with CDAD due to epidemic strains."

Jean-Paul Clozel, M.D. and Chief Executive Officer of Actelion commented: "The cadazolid Phase III program will address the essential clinical and commercial requirements for a novel CDAD therapy to be successful, with a focus on making a meaningful difference for patients. Evidence of a superior sustained cure compared to vancomycin, including in hypervirulent strains, would go a long way to meeting the most pressing current medical need. The promising profile of cadazolid underlines Actelion's commitment to finding new classes of antibiotics which have a reduced risk of developing resistance."

The results of these Phase III studies are expected to form the basis for regulatory submissions for marketing approval throughout the world.

CADAZOLID DATA AT ICAAC 2013

Data on cadazolid are currently being presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2013), in Denver, CO:

Prof. Dale N Gerding, Loyola University, Maywood, Illinois, USA, will present a poster (K-168) on the "Susceptibility and typing of Clostridium difficile (CD) isolates from a phase 2 study of the novel antibiotic, cadazolid (CDZ), in CD-Associated Diarrhea (CDAD)" during the Poster Session 018: Clostridium difficile. Tuesday, September 10, 2013 12:00 - 2:00 PM

Dr. Alison Mackie, Actelion Pharmaceuticals Ltd, will present a poster (A-008) on the "Cadazolid, a Novel Potent Antibiotic against Clostridium Difficile: Minimal Systemic Cadazolid Exposure in Subjects with Clostridium Difficile Associated Diarrhea" during the Poster Session 004: Pharmacokinetics/Pharmacodynamics of New Anti-Infective Agents. Tuesday, September 10, 2013 12:00 - 2:00 PM

Dr. Rodrigo E Mendes, JMI Laboratories, North Liberty, Iowa, USA, will present a poster (E-144) on the "Activity of cadazolid against Gram-positive clinical isolates, including linezolid-resistant subsets with defined resistance mechanisms" during the Poster Session 016: Antimicrobial Activity against Gram-Positive Bacteria. Tuesday, September 10, 2013 12:00 - 2:00 PM

  

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Notes to the Editor

ABOUT CADAZOLID

The novel antibiotic cadazolid is a strong inhibitor of Clostridium difficile protein synthesis leading to strong suppression of toxin and spore formation. In preclinical studies cadazolid showed potent in vitro activity against Clostridium difficile 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 the further clinical development.

ABOUT CADAZOLID IN PHASE II INVESTIGATION

Cadazolid was studied in a Phase II multi-center, double-blind, randomized, active reference, parallel group, therapeutic exploratory 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 subjects 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 subjects with mild to severe CDAD.

The results of the Phase II study indicate that the effect of all doses of cadazolid were numerically similar to, or better than vancomycin on key endpoints including CDAD clinical cure rates as well as sustained cure rates. Clinical 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 clinical cure with no recurrence of CDAD up to 4 weeks post-treatment. 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.

ABOUT CLOSTRIDIUM DIFFICILE ASSOCIATED DIARRHEA

Clostridium difficile is a Gram-positive, anaerobic, spore-forming bacterium that is the leading cause of nosocomial diarrhea. Clostridium difficile associated diarrhea (CDAD or CDI for Clostridium difficile infection) can be a severe and life-threatening disease and results from the overgrowth in the colon of toxigenic strains of Clostridium difficile, 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 Clostridium difficile 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 clinical cure rates are generally 85-90%, recurrences rates of 15-30 % with either drug are problematic as Clostridium difficile 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 recurrence 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.

ICAAC ABSTRACTS

Gerding D, Best E, Buitrago M, Cornely O, Hecht D, Nord CE, Sambol S, Talbot G, Wilcox M, Charef P, El-Akkad T, Kracker H, Locher HH, Louie T. Susceptibility and typing of Clostridium difficile (CD) isolates from a phase 2 study of the novel antibiotic, cadazolid (CDZ), in CD-Associated Diarrhea (CDAD). Poster (K-168) presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10-13 September 2013, Denver, CO.

Mackie AE, Desnica B, Nicolas LB, Louie T, Dingemanse J. Cadazolid, a Novel Potent Antibiotic against Clostridium Difficile: Minimal Systemic Cadazolid Exposure in Subjects with Clostridium Difficile Associated Diarrhea. Poster (A-008) presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10-13 September 2013, Denver, CO.

Mendes RE, Rhomberg PR, Locher HH, Jones RN. Activity of cadazolid against Gram-positive clinical isolates, including linezolid-resistant subsets with defined resistance mechanisms. Poster (E-144) presented at the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 10-13 September 2013, Denver, CO.

References

  1. Louie T, Buitrago M, Cornely O,  Kracker H, Rangaraju M, Charef P. Multicentre, double-blind, randomised, phase 2 study evaluating the novel antibiotic, cadazolid, in subjects with Clostridium difficile-associated diarrhoea. Late-breaker poster (LB-2956) presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27-30 April 2013, Berlin, Germany.
  2. Rashid M-U, Martinez Lozano H, Weintraub A, Nord CE. Activity of cadazolid against clinical isolates of Clostridium difficile. Oral presentation at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27-30 April 2013, Berlin, Germany.
  3. Caspers P, Ritz D, Locher H, Bruyere T, Schroeder S, Pfaff P, Knezevic A, Dos Santos M, Hubschwerlen C, Keck W. Cadazolid, a new quinolonyl-oxazolidinone antibiotic with potent activity against Clostridium difficile inhibits protein synthesis also in linezolid-resistant strains. Poster (P-1658) presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27-30 April 2013, Berlin, Germany.
  4. Seiler P, Enderlin M, Chen X, Pfaff P, Boehme M, Locher HH, Fournier E, Klenik A, Clozel  M, Kelly CP, Keck W. Activity of Cadazolid in Animal Models of Clostridium difficile Infection. Poster (P-1657) presented at the 23rd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 27-30 April 2013, Berlin, Germany.
  5. Baldoni D, Gutierrez M, Timmer W, Dingemanse J. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability, and pharmacokinetics in healthy subjects following single and multiple oral doses. Poster (A-1273) presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 September 2012, San Francisco.
  6. Baines SD, Crowther GS, Todhunter SL, Freeman J, Wilcox MH. In vitro activity of cadazolid (ACT-179811) against Clostridium difficile and in an in vitro gut model of C. difficile infection. Poster (B-662) presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 September 2012, San Francisco.
  7. Hecht DW, Osmolski JR, Checknis A, Sambol S, Gerding DN. In vitro activity of cadazolid against 209 toxigenic isolates of Clostridium difficile. Poster (E-808) presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 September 2012, San Francisco.
  8. Locher HH, Pfaff P, Schroeder S, Specklin JL, Hubschwerlen C, Keck W. Cadazolid, a new quinolonyl oxazolidinone with potent activity against Clostridium difficile: in vitro antibacterial activity and propensity for resistance development. Poster (C1-1346) presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 September 2012, San Francisco.
  9. Locher HH, Ritz D, Schroeder S, Pfaff P, Knezevic A, Hubschwerlen, C, Keck W. Cadazolid, a novel quinolonyl-oxazolidinone antibiotic: mode of action and effect on Clostridium difficile toxin and spore formation. Poster (C1-1347) presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9-12 September 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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