BOSTON -- An investigational drug that inhibits programmed cell death could help to prevent fibrosis in hepatitis C-infected livers, even when standard therapies fail to clear the virus, researchers reported here.
BOSTON, Oct. 31 -- An investigational drug that inhibits programmed cell death could help to prevent fibrosis in hepatitis C-infected livers, even when standard therapies fail to clear the virus, reported researchers here.
Patients with chronic HCV infections and liver fibrosis who were treated with the pancaspase inhibitor PF-03491390 at any of three doses had significant reductions in serum aminotransferase levels after 10 weeks of therapy, reported Mitchell L. Shiffman, M.D., of Virginia Commonwealth University in Richmond, and colleagues.
The drug inhibits a wide range of caspases, proteases involved in regulating and promoting inflammation, and in activating apoptosis, or programmed cell death.
It is not, however, an antiviral agent. In a clinical trial of the drug in 200 patients, PF-0349 (for short) did not reduce HCV RNA levels compared with placebo at any of three dosing levels, Dr. Shiffman reported at the American Association for the Study of Liver Diseases here meeting.
Caspase inhibition has the potential to reduce inflammation and prevent hepatocyte apoptosis, thereby reducing or preventing the progression of fibrosis to cirrhosis, Dr. Shiffman said.
In a previous two-week study in patients with chronic HCV, PF-0439 produced significant decreases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), with no apparent safety concerns.
In the double-blind placebo controlled study reported here, Dr. Shiffman and colleagues enrolled 204 patients, who were observed for four weeks to establish baselines aminotransferase levels.
The patients were then randomized to one of four groups: the pancaspase inhibitor at doses of 5, 25 or 50 mg bid for 10 weeks, or placebo, with dose doubling for an additional two weeks for patients who did not have ALT normalization at 10 weeks. All treatments were discontinued after 12 weeks, and patients were followed for an additional four weeks.
The patients were adult men and women with confirmed HCV who were unsuccessfully treated with standard therapy, failed to achieve a viral response, and either could not tolerate standard therapy or failed to maintain a response. All had elevated liver enzymes that were at least 1.5 times the upper limit of normal.
Patients were excluded if they had decompensation or severe liver disease, hepatocellular carcinoma, or concomitant infections such as hepatitis B or HIV, or a recent history of alcohol or drug abuse.
The investigators found that at 10 and 12 weeks there were significant decreases in mean AST levels with all three doses of the inhibitor compared with placebo (P
"PF-03491390 effectively reduced aminotransferase levels in patients with chronic hepatitis C, this effect was evident with seven days, and the effect was maintained for as long as the drug was maintained in this study, up to 12 weeks," Dr. Shiffman said.
Further studies are needed to determine whether the drug influences liver histology and can prevent the progression of fibrosis in patients with chronic HCV infection who are resistant to other treatments, he concluded.
In an interview, Dr. Shiffman noted that there is a theoretical concern that inhibiting apoptosis could lead to malignancies.
"Many people believe that the process of apoptosis rids the body of damaged cells, and is one of the mechanisms of cancer surveillance," he noted. "It's never been proven in animal models, however. In animal models you don't see cancer with this drug."
He said that the compound may also have the potential to prevent or reduce fibrosis in other inflammatory diseases of the liver, such as hepatitis B or non-alcoholic steatohepatitis (NASH). Investigators are planning to test the drug in patients with chronic hepatitis who have undergone a liver transplant, he added.
Dr. Shiffman has received research grant support from Idun Pharmaceuticals, discoverers of PF-03491390, and from Pfizer, which has licensed the compound from Idun and is developing it.