American Association for the Study of Liver Diseases'
Single Topic Conference on Hepatitis C
In a Phase I/II clinical trial, the antisense drug ISIS 14803 demonstrated
dose-dependent antiviral activity, decreasing viral titers in patients with
drug-resistant chronic hepatitis C virus (HCV).
All patients in the clinical study had the most common and drug resistant form
of HCV, genotype 1, and all but one patient had failed previous
interferon-based therapy.
John G. McHutchison, MD, medical director of liver transplantation, division of
gastroenterology/hepatology, Scripps Clinic in La Jolla, California, presented
results from this study at the American Association for the Study of Liver
Diseases' Single Topic Conference on Hepatitis C held in Chicago, Illinois.
"The anti-HCV activity demonstrated by this drug at this early stage of
clinical development is impressive. In the trial, we observed responses in
patients who were resistant to currently available treatments," said
McHutchison.
In the study, 11 patients with genotype 1 HCV, 10 of whom had failed interferon
or interferon and ribavirin therapy, were treated with escalating doses of up
to 2 mg/kg intravenous ISIS 14803, three times a week, for one month. Three
patients received 0.5 mg/kg, three were treated with 1.0 mg/kg and five were
given 2.0 mg/kg, of ISIS 14803. The drug works by inhibiting HCV replication.
Two of four evaluable patients in the 2 mg/kg group had greater than one log
(1.4 and 1.5 log), or 30-fold, decrease in viral titers. A third patient
receiving 2 mg/kg experienced a half log, or three-fold, reduction. A fourth
patient, who received 0.5 mg/kg, experienced a 0.7 log reduction in viral
titers. Responses developed after several doses of ISIS 14803 and persisted for
a range of 20 to 50 days.
In most cases, the responses were associated with a transient liver enzyme
"flare," or an increase in alanine aminotransferase (ALT). ALT flares
were not accompanied by changes in bilirubin, albumin, or prothrombin time,
which are measures of liver synthetic function. Liver biopsy results obtained
during an ALT flare did not show evidence of drug-related liver toxicity.
Overall, ISIS 14803 was well tolerated in the Phase I/II clinical trial.
"Based on the results of this study, we plan to continue to evaluate the
potential of ISIS 14803 in single-agent trials, in combination studies with
pegylated interferon and ribavirin as well as through studies that will look at
longer-term dosing with both intravenous and subcutaneous administration,"
said F. Andrew Dorr, MD, Isis.
Studies of the subcutaneous delivery of ISIS 14803 are currently being
conducted. Clinical trials of ISIS 14803 using Elan's MEDIPADTM Drug Delivery
System, a minimally invasive microinfusion pump, are planned for the future.
ISIS 14803 is being developed through a joint venture of Isis Pharmaceuticals,
Inc. (Nasdaq: ISIP) and Elan Corporation plc. (NYSE: ELN) of Dublin, Ireland.
Edward E.
Rylander, M.D.
Diplomat American
Board of Family Practice.
Diplomat American
Board of Palliative Medicine.