icon-folder.gif   Conference Reports for NATAP  
  American Association for the Study of Liver Diseases 2003 Conference
Boston, MA
Oct 24-28, 2003
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Hepatitis C: new antiviral developments
  Reported by Jules Levin
In Monday afternoon’s oral session on new candidates for HCV treatment several interesting potential therapies were discussed. It appears that companies have reached the point of starting to present data at conferences on their HCV new drug research. Two protease inhibitors were discussed today, both of which appear promising at an early developmental stage. The development of protease inhibitors are exciting for patients, but the best case scenario is it will take at least 3 years or longer to reach availability and Phase III studies.
Caspase Inhibitor, IDN-6556
This drug was designed as an apoptosis inhibitor. Apoptosis is cell death. In pre-clinical study this drug protected against fulminant liver failure in animals. Paul Pockros (Scripps Clinic) presented data from an early oral dose ranging study. 2 patients received placebo and 6 patients received IDN-6556 for 2weeks and were observed for 3 weeks. There were 40 HCV+ patients: 11 treatment naïve and 29 treatment failures. 90% had genotype 1. Average age was 49 and about 50% were men. ALT was reduced by 30-40% at day 14 and rebounded after drug was stopped in all dose regimens. AST also declined 30-50% at day 14 and rebounded after stopping drug. Adverse events were mostly mild, some moderate: dry mouth, fatigue, headache, dizziness, upper abdominal pain, nasopharyngitis.; no serious or severe adverse events, no discontinuations, side effects were no different from placebo. Several patients experienced –0.5 log reduction in viral load. The author concluded IDN-6556 lowers ALT & AST, does not increase viral load, was well tolerated for 2 weeks, and merits further study.
SCH6: new protease inhibitor of the hepatitis C virus
Karm Abid (Schering Plough) discussed preliminary results from early study of this protease inhibitor for HCV. The candidate Schering Plough is currently studying in Phase I is SCH7. SCH6 appears to be a potent inhibitor of HCV RNA subgenomic replication in vitro as consistently shown by various approaches (immunofluorescence, real time PCR, in situ RNA hybridization) (IC90 = 100 ± 40 nM). SCH6 was non-toxic to transfected Huh-7 cells for at least 6 weeks and for concentrations up to 200 nM. Analysis of potential resistant variants is ongoing.
HCV Polymerase Inhibitors for Chronic Hepatitis C Virus
Shlomo Dagan (XTL Pharma) reported on using a unique HCV cell-based assay and an HCV-Trimera mouse model to evaluate drug candidates (HCV polymerase inhibitors) as a potential therapy against chronic hepatitis C. Two different molecules were designed, synthesized, and tested for their ability to inhibit the activity of the HCV polymerase. In a biochemical assay, they both showed good inhibition activity (IC50 < 0.1 ug/ml). The first molecule, BC2125 is water soluble with a good rodent oral PK profile; Tmax=4.0 hr; and Cmax ~ 5 ug/ml for administration of 50 mg/kg in rats. This molecule was proved to be non-cytotoxic (CC50 ~100 ug/ml for HepG2, FLC4 and Huh7 cell lines). It also showed inhibition of HCV replication at concentrations of 2-10 ug/ml using our cell-based assay for both Huh7 and FLC4 cells. In vivo, BC2125 was able to reduce viral loads and percentages of HCV-positive mice in HCV-Trimera mice at 100, 50, and 30 mg/kg/day (treatment oral, b.i.d. for 8 days). These reductions were dose dependent and statistically significant. Fourteen days oral toxicity study in mice showed no toxicity signs (necropsy, histopathology, weight loss) for 50 or 250 mg/kg/day.
The second molecule, BC2329 was administered orally as a suspension in water to rats and gave Tmax of approximately 0.5 hr and Cmax of about 30 ug/ml for 50 mg/kg. The molecule was proved to be non-cytotoxic (CC50 ~ 200 ug/ml for HepG2, FLC4, and Huh7 cells) and demonstrated HCV inhibition in the cell-based assay for both Huh7 and FLC4 cells (IC50 ~ 5-10 ug/ml). This molecule is currently under evaluation in vivo using the HCV-Trimera mouse model.
The authors concluded that good in vitro and in vivo toxicity profiles and PK data together with antiviral inhibitory activity in both assay systems indicate the potential of BC2125 as oral drug candidates for treatment of chronic hepatitis C. Further in vitro and in vivo evaluation of these two compounds is underway.
BILN-2061: a new HCV protease inhibitor
Markus Resier from Germany and Boehringer Ingelhiem reported at the 2002 AASLD on short term treatment with this drug in patients with genotype 1 HCV. After 48 hours 2-3 log reductions in viral load were observed.
BILN 2061 is a potent and specific inhibitor of the HCV serine protease in-vitro and in patients infected with genotype 1 (GT 1) as recently reported. In a first exploratory trial, the effect of a 2-day oral treatment with BILN 2061 was investigated in genotype 2 and genotype 3 patients with minimal liver fibrosis. In a randomized, double-blind group comparison, 10 male patients with HCV other than genotype 1 and no or minimal liver fibrosis (Ishak 0-2) were administered 500 mg BILN 2061 or placebo in an oral solution (randomized 8:2) b.i.d. over 2 days. Mean age of all 10 patients was 37 years. HCV genotypes were genotype 2 (3 patients) and genotype 3 (7 patients). 9/10 patients were naive for anti-HCV therapy. All patients completed the study and were followed up for 12 days. VL decreased by ≥1 log10 unit in 4/8 patients treated with 500mg BILN 2061 b.i.d., without detectable difference between genotypes 2 and 3. A weak response was observed in 1 BILN 2061-treated patient, whereas 3/8 BILN 2061-treated patients and 2/2 patients given placebo experienced no response. The largest VL decrease was observed in the one patient with genotype 2 HCV that had been previously treated with anti-HCV therapy. However HCV-RNA was still detectable. After end of treatment, VL returned to baseline levels within 1-7 days. No adverse events were reported. Liver function tests did not change during treatment. Vital signs, routine laboratory and ECG did not show relevant drug-induced changes. Tolerability was rated "good" by the investigators in 9 patients and "satisfactory" in 1 BILN 2061-treated patient. The authors concluded that BILN 2061, given orally over 2 days at 500 mg b.i.d., demonstrated antiviral activity in 5/8 non-genotype-1 patients. In contrast to our previous results in genotype-1 patients, the antiviral activity was not uniform and less pronounced. No safety issues were identified among the 8 patients exposed to BILN 2061. Clinical development plans are unclear.
VX-950, an HCV Protease Inhibitor
Ann Kwong (Vertex Pharma) reported on a new HCV protease inhibitor. This protease inhibitor was developed using a structure-based, rational drug design process. VX-950, to BILN-2061, another HCV protease inhibitor in clinical development (2002 AASLD Mtg). VX-950 and BILN-2061 exhibit inhibition mechanisms that appear kinetically distinct from each another. VX-950 appears to be potent: it showed similar antiviral activity in both the HCV replicon assay (cell dish) as well as test carried out in fetal hepatocytes. Over the course of 9 days showed potent HCV inhibition in vitro. The antiviral activity can be sustained in viral clearance assays resulting in continuing decline of HCV RNA for 9 days. VX-950 is metabolized by CYP-3A4. It is not significantly metabolized by CYP-2C19m 2D6, or 1A2. High liver exposures have been achieved. High liver levels of the drug were seen in rats and dogs over an 8 hour period with an average of 10 times higher levels than seen in plasma. Clinically accepted formulations have demonstrated good systemic oral bioavailability. Resistance data was presented in poster at AASLD by Vertex researchers: VX-950 did not suffer as dramatic a reduction in potency (20-40 fold) as BILN (1000-1800 fold) against their respective resistance mutations selected in vitro. VX-950 appears to be equipotent against the major in vitro BILN-2061 resistant mutant, D168V. The major in vitro VX-950 resistant mutant, A156S, remains sensitive to BILN-2061. Clinical trials in humans are planned for early 2004. Clinical trials in humans are planned for early 2004.