HCV Investigational Therapies
Reports on a number of new drugs in development for treating hepatitis C were presented at EASL. Those which looked the most promising as future HCV medical treatments were viramidine, albuferon, and NM283.

Viramidine
Ribavirin induced hemolytic anemia is reported in about a quarter of HCV patients taking the combination therapy of pegylated interferon plus ribavirin. Preliminary data on the safety and tolerability of viramidine (in combination with pegylated interferon) was presented at the 2004 American Association for the Study of Liver Disease (AASLD). It was reported that the incidence of hemolytic anemia was dramatically lower in the viramidine arm of the study compared to the ribavirin arm (4% vs. 27% respectively).

The data on the sustained virological response (SVR-undetectable HCV during and 24 weeks post treatment) from the same clinical trial was presented at this year’s EASL conference.

One hundred seventy-one previously untreated patients received the full dose of 400 mg (47 patients), 600 mg (43 patients), and 800 mg (44 patients) twice a day (BID) of viramidine versus 1000/1200 mg/day ribavirin (37 patients) in combination with pegylated interferon. Treatment duration was 48 weeks for genotype 1, and 24 weeks for genotypes 2 and 3 with a follow-up period of 24 weeks. The patient characteristics were male (64%), Caucasian (76%), and genotype 1 (72%). The median HCV viral load was 6.5 log10 copies/mL. In the viramidine group, the highest SVR rate was in the patients that received 600 mg BID dose.

It is difficult to draw any concrete conclusions about the SVR rates since the study included a limited number of patients. Phase III trials (with a much larger patient population) of viramidine vs. ribavirin are underway and the results from this study should give us a better understanding of the effectiveness of viramidine compared to ribavirin. However, since the response rates were similar between the different study arms, it does appear that viramidine may produce similar treatment response rates but with less of the ribavirin-induced hemolytic anemia.

Albuferon
Albuferon is a form of time-released interferon that is produced by fusing human serum albumin to interferon. In a previous phase I/II clinical trial of 119 adults (HCV positive non-responders to previous interferon therapy) who received albuferon, it was found that the drug was safe and well-tolerated with no discontinuations due to side effects. The side effects from the treatment were found to be transient (temporary) and mild to moderate in severity. The authors of this study found that the HCV RNA (viral load) decline was dose-dependent and concluded that albuferon has the potential to address an unmet need for HCV therapy with less frequent dosing (injections).

Data from a new phase II trial on 56 previously untreated genotype 1 patients also found that albuferon was safe and well-tolerated. Furthermore, it was reported that after 4 weeks of albuferon therapy there was a 99.9 percent decrease in viral load in the patients who received the two highest doses of albuferon. After 42 days, 23% of the same patients remained HCV negative. The authors concluded, based on this study, that albuferon could be dosed (injected) every 2-4 weeks and that it showed a strong antiviral activity after two doses. A larger 48-week combination study of albuferon plus ribavirin in previously untreated HCV patients is being planned.

Valopicitabine (NM283)
Valopicitabine is an oral nucleoside analog, a new class of drugs that block the hepatitis C virus from replicating (reproducing) by inhibiting the HCV RNA polymerase. HCV polymerase is the enzyme of the hepatitis C virus that is critical in the replication process of hepatitis C. The data presented at EASL on valopicitabine is noteworthy because this is the first time that 24 week data has been reported on an HCV drug with direct antiviral properties against the hepatitis C virus.

Preliminary data from a phase II study was presented at EASL on the genotype 1 patients (previously untreated) who completed 24 weeks of treatment of valopicitabine combined with pegylated interferon. So far 9 out of 30 patients have completed 24 weeks of therapy. It was found that the HCV RNA (viral load) reduction was more than 99.0% in the 9 patients. The HCV viral load declined in 8 out of 9 patients to below the level of detection of < 600 IU/mL (Amplicor PCR)—six of the patients had a reduction of HCV viral load to below the level of detection by a more sensitive viral load test with a lower limit of 10 IU/mL (TaqMan PCR). The authors reported that there were no serious adverse events (side effects) and no patient was required to discontinue therapy due to valopicitabine-related side effects. A larger trial of 171 HCV genotype 1 patients who failed a previous course of pegylated interferon plus ribavirin is currently underway. The patients will receive valopicitabine monotherapy, valopicitabine plus pegylated interferon or pegylated interferon plus ribavirin. Enrollment in the new trial is expected to be completed by June 2005.

PegIntron
The EPIC3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis) is an on-going clinical trial that is evaluating PegIntron plus Rebetol (ribavirin) for previous interferon based treatment non-responders and relaspers. The study will evaluate the effectiveness of PegIntron combination therapy in this patient population. There is also a PegIntron long term maintenance phase in this study that will evaluate whether the use of low dose PegIntron monotherapy can delay or prevent cirrhosis.

Preliminary results from the EPIC study involving over 2,200 HCV patients worldwide were released at EASL. In this study on people who failed a previous course of interferon based therapy, patients were treated with weight based PegIntron (1.5 mcg/kg/week) plus Rebetol (ribavirin-800-1400 mg/day) for up to 48 weeks. Twenty-one percent of the 978 patients who had completed up to 48 weeks of therapy achieved an SVR. Breaking it down by genotype, patients with genotype 1 achieved a 14% SVR compared to a 56% SVR in patients with genotypes 2 or 3. As expected it was found that treatment relapsers achieved higher SVR rates (41% SVR compared to 14% SVR in the treatment non-responders group) and that people with mild to moderate fibrosis achieved a higher SVR compared to people with more advanced scarring (26% vs. 15%).

Pegasys
Generally, people with persistently normal ALT levels have a milder course of HCV disease progression. However, about 30% of people with persistently normal ALT levels will progress on to advanced fibrosis and/or cirrhosis. Clinical trials have found that people with normal ALT levels can be treated successfully and achieve similar treatment response rates as people with elevated ALT levels. Data from a previous study using Pegasys plus Copegus (ribavirin) combination therapy for treatment of HCV in patients with persistently normal ALT levels was analyzed to find out if there was a relationship between the age and baseline characteristics of patients and response to therapy.

In this retrospective study, information on 422 patients was analyzed. It was found that people under 40 years old were more likely to achieve an SVR—54% in the group under 40 years old compared to 34% in the group that was over 40 years old. The authors concluded that age appears to be an important factor in treatment response. It was also pointed out that other confounding factors such as male gender, African American race and high HCV RNA (viral load) play an important role in treatment response.

Adherence to HCV medicines is also an important factor in achieving an SVR and data from another clinical trial was examined. A retrospective analysis of 569 patients who received Pegasys plus Copegus (ribavirin) found that the dose of Copegus was an important factor in treatment response. It was found that 66% of the patients in this group who took greater than 97% of their ribavirin dose achieved an SVR compared to the SVR rate of 33% for patients who took less than 60% of their ribavirin dose. The authors concluded that patients in this trial were more likely to maintain the Pegasys dose compared to the ribavirin dose and that avoiding ribavirin dose reductions and dose discontinuations will likely improve the overall SVR rates.

Weight is also another poor prognostic factor for achieving a successful treatment response, but a study presented at EASL reported that it appears that body weight is not solely responsible for the lower treatment response rates. Studies from two multinational phase III studies of 2,404 patients were analyzed and it was reported that the heavier patients were more likely to be male, black, cirrhotic and infected through intravenous drug use, which are all factors associated with a lower treatment response rate. The authors concluded: “This clustering of poor prognostic characteristics may explain the lower SVR rates observed in heavier patients.”

http://www.hcvadvocate.org/news/newsLetter/2005/advocate0505.html#1