 |
|
|
| |
New Drug Lowers AST/ALT Levels in Chronic HCV
|
| |
| |
Study reported at AASLD finds new drug, 28% to 36% for AST in patients treated with the pancaapase inhibitor, and from 37% to 48% for ALT.... The drug "is incredibly well tolerated," Dr. Shiffman said... this effect was evident with seven days... Further studies are needed to determine whether the drug influences liver histology and can prevent the progression of fibrosis.... there is a theoretical concern that inhibiting apoptosis could lead to malignancies....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...
By Neil Osterweil, Senior Associate Editor, MedPageToday.com
Reviewed by Rubeen K. Israni, M.D., Fellow, Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine
October 31, 2006
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.
-- about half of all patients with chronic hepatitis C viral infections do not have sustained viral responses from currently available therapies. The investigational drug described here has the potential to prevent or reduce damage to the liver from HCV infection in such patients, and, potentially, in patients with other inflammatory liver diseases.
-- This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary as they have not yet been reviewed and published in a peer-reviewed publication.
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 at AASLD.
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<0.0001 for each), but no significant differences between the dosing groups.
The same patterns was seen with ALT, with patients on placebo having no significant decline from baseline, whereas all three treatment groups showed similar and significant decreases compared with placebo throughout the treatment period.
The overall decline from baseline was from 28% to 36% for AST in patients treated with the pancaapase inhibitor, and from 37% to 48% for ALT.
ALT levels returned to normal at week 10 in 15% of patients treated on 5 mg bid, 35% of those treated with 25 mg bid, and 19% of those treated with 50 mg bid, compared with only 3% of patients on placebo.
However, doubling the dose in patients who did not have ALT normalization at 10 weeks did not increase the mean reduction in aminotransferase levels in the intent-to-treat population, although a few more patients did have normalization of ALT, Dr. Shiffman said.
The drug "is incredibly well tolerated," Dr. Shiffman said. There were no significant increases in the number of adverse events reported by six or more patients in any of the treatment groups compared with placebo, and none was serious, he said.
"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.
Source reference:
Shiffman ML et al. " PF-03491390, (formerly IDN-6556) a Pancaspase Inhibitor, is Well-Tolerated and Effectively Reduces Raised Aminotransferases (ALT and AST) in Chronic Active Hepatitis C (HCV) Patients." Abstract 95, presented Oct. 30.
|
| |
|
|
|
|
|
