Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.
OBJECTIVE
Novel, potent, and well-tolerated hepatitis C virus (HCV) drugs are needed. BILN 2061 is a potent and specific inhibitor of HCV serine protease in vitro. Preclinical toxicology data and studies in healthy volunteers supported the administration of BILN 2061 to patients with HCV infection.


METHODS
The antiviral efficacy, pharmacokinetics, and tolerability of 25, 200, and 500 mg BILN 2061 twice daily given as monotherapy for 2 days in 31 patients infected with chronic genotype 1 HCV infection and with minimal liver fibrosis (Ishak score of 0-2) were assessed in a placebo-controlled, double-blind pilot study. In 2 subsequent placebo-controlled studies of similar design, 200 mg BILN 2061 twice daily was administered for 2 days to 10 patients with advanced liver fibrosis (Ishak score of 3 or 4) and to 10 patients with compensated cirrhosis (Ishak score of 5 or 6).


RESULTS
Viral RNA reductions of 2-3 log 10 copies/mL were achieved in most of the patients. There was a trend toward a higher number of patients receiving 500 mg BILN 2061 achieving a viral RNA reduction > or =3 log(10) copies/mL as compared with patients receiving 25 mg BILN 2061. Advanced fibrosis or compensated cirrhosis did not affect the antiviral efficacy of BILN 2061. BILN 2061 was well tolerated in all studies.


CONCLUSIONS
BILN 2061 is a well-tolerated and very active compound that reduced serum viral RNA concentrations after 2 days of treatment in patients infected with genotype 1 HCV independent of the degree of fibrosis. Nevertheless, further clinical trials are on hold pending resolution of animal toxicity issues.
Hinrichsen
Holger
H
Medizinische Universitätsklinik, Kiel, Germany. hhinrichsen@1med.uni-kiel.de
Benhamou
Yves
Y
Wedemeyer
Heiner
H
Reiser
Markus
M
Sentjens
Roel E
RE
Calleja
José L
JL
Forns
Xavier
X
Erhardt
Andreas
A
Crönlein
Jens
J
Chaves
Ricardo L
RL
Yong
Chan-Loi
CL
Nehmiz
Gerhard
G
Steinmann
Gerhard G
GG
D000998:Antiviral Agents / Q000627:therapeutic use*; D002219:Carbamates / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047028:Macrocyclic Compounds / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood / Q000302:isolation & purification; D012697:Serine Endopeptidases; D013844:Thiazoles / Q000627:therapeutic use*; D019562:Viral Load
D000998:Antiviral Agents; C479555:BILN 2061; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D012367:RNA, Viral; D013844:Thiazoles; D012697:Serine Endopeptidases