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

Fri Dec 21, 2012 1:01am EST

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Actelion Pharmaceuticals Ltd / Actelion's novel antibiotic cadazolid to move into Phase III
clinical development in patients suffering from Clostridium difficile associated diarrhea .
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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(R))
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."

###

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

1Clostridium difficileD. Baldoni,et al, Cadazolid, a novel quinolonyl-oxazolidinone antibiotic
with potent activity against: 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(R), an orally available dual endothelin receptor
antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets
Tracleer(R) 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(R)).

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 http://www.actelion.com/ 

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vary materially from those described herein as anticipated, believed, estimated or expected.

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Actelion Pharmaceuticals Ltd
Gewerbestrasse 16 Allschwil Switzerland

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