Update on Experimental Therapies for Chronic Hepatitis C Infection

Like HIV, hepatitis C is often referred to as a “silent killer.” This is because in both life-threatening diseases, most individuals do not become aware of their infection for many years following their exposure to the virus. Some first learn of their infection after being admitted to a hospital for critical care of an HIV- or HCV-related infection or condition (e.g., Pneumocystis pneumonia with HIV or liver cirrhosis with HCV).

Most HIV positive individuals do not display clinical symptoms of chronic HIV disease for several years following initial infection (unless they experience the symptoms of acute HIV infection soon after initial infection). Among individuals with HCV infection, the “incubation” period is much longer than for HIV--clinical symptoms of chronic hepatitis C do not appear for 20-30 years after initial HCV infection (again, with the exception of those who experience acute HCV infection soon after initial infection with the virus).

The optimal time for initiating anti-HCV therapy is not yet known, and for many HCV-infected individuals, especially those with HCV genotypes 1 or 4, early diagnosis and treatment may not be all that helpful, because about 50% or fewer of these individuals will not respond to the current standard of care for chronic HCV—peginterferon alfa plus ribavirin. In addition, many patients for whom therapy is working to eradicate HCV, cannot tolerate the toxicities and side effects of these therapies and they are forced to stop treatment.

It is hoped that one or more of several experimental therapies now in development for HCV infection will prove both more effective and less toxic than current treatments for these difficult-to-treat patients.

Further, it is hoped that there will be a significant breakthrough in therapy for chronic hepatitis C in the not too distant future, as about 10,000 Americans die of the disease annually. Death rates from hepatitis C are estimated to triple over the next 10 years in the US and are expected to surpass the number of fatalities from AIDS.

Promising Experimental Drugs in the Pipeline

There are currently more than 30 experimental monotherapies or combinations of drugs currently being evaluated in clinical studies for the treatment of chronic hepatitis C. A few show promise in terms of both efficacy and safety. These include valopicitabine from Idenix Pharmaceuticals, SCH 503034 from Schering-Plough, VX 950 from Vertex Pharmaceuticals, and viramidine from Valeant Pharmaceuticals.

Valopicitabine

Valopicitabine, an RNA polymerase inhibitor, is the farthest along in clinical trials of these drugs. In a montherapy study of valopicitabine, the drug reduced serum HCV RNA by a mean 1.2 log ₁₀ (94%) in a 15-day trial in HCV patients, most of whom had previously failed antiviral therapy for HCV infection.

In a multicenter, open-label Phase IIa trial, researchers evaluated whether valopicitabine plus peg-IFN alfa-2b (PegIntron) enhanced antiviral activity compared to valopicitabine alone in HCV-infected patients. The treatment has been well tolerated, with no serious adverse events reported, and only one case of grade 3 / 4 laboratory abnormality (ANC decreased to 620 cells/mm³).

At week 12, patients receiving combination therapy had a mean reduction in HCV RNA levels of -3.01 log₁₀compared to -0.87 log₁₀ in the valopicitabine monotherapy arm. At week 24, the 9 patients receiving combination therapy had a mean reduction of -4.5 log₁₀ IU/mL. By Amplicor and TaqMan 8/9 and 6/9 subjects, respectively, had undetectable HCV RNA.

Those patients allocated to the combo arm who had detectable HCV RNA at week 12 experienced subsequent drops in their HCV RNA levels by week 24. Breakthroughs have not occurred in any patient.

In their conclusion, the authors state that combination therapy with valopicitabine plus pegylated interferon alfa for the treatment of patients with chronic hepatitis C, especially those carrying genotype 1, seems to produce superior responses than pegylated interferon alone by historical comparisons.

At the upcoming AASLD conference in San Francisco (November 11-14, 2005), interim results of another valopicitabine trial involving 190 patients are expected to be released.

SCH 503034 and VX 950

Two other experimental hepatitis C drugs have recently completed early stage clinical trials: SCH 503034, made by Schering-Plough, and VX-950, made by Vertex Pharmaceuticals. Both compounds are inhibitors of the HCV protease enzyme, which the virus uses to replicate itself.

Promising results from a Phase II clinical study of SCH 503034 will be presented in November at the AASLD meeting in San Francisco (November 11-14, 2005).

The data to be presented represent results of Phase I studies of SCH 503034 as monotherapy and in combination with peginterferon alfa-2b (PegIntron) in genotype 1 patients who are non responders to peginterferon/ribavirin combination therapy. These Phase 1 studies were conducted with an oral (capsule) formulation of the drug that is suitable for use in larger clinical studies and potentially for commercial development of the drug.

Schering will initiate a Phase II dose-finding study of SCH 503034 that will provide the dosing information required to conduct a complete clinical development program. The full study title is “PEG-Intron/Rebetol vs PEG-Intron/SCH 503034 with and without Ribavirin in Chronic Hepatitis C HCV-1 Peginterferon Alfa/Ribavirin Nonresponders: A SCH 503034 Dose-Finding Phase 2 Study.”

Please note that this study is not yet recruiting patients for enrollment. Look for an announcement soon on this website of the date for open recruitment, location of study sites, and study entry and exclusion criteria.

VX 950

VX-950 is an investigational oral HCV protease inhibitor being developed by Vertex Pharmaceuticals. VX 950 has demonstrated good tolerability and a decline of 4 log₁₀ IU/mL in HCV RNA after 14 days of treatment in subjects infected by HCV genotype 1.

A Phase Ib study of 34 patients with chronic hepatitis C genotype 1 showed that every patient receiving VX-950 achieved greater than a 2 log ₁₀ reduction in HCV-RNA within the first three days of treatment, according to Vertex.

The authors of the study concluded that the rapidity in decreasing HCV RNA levels, the undetectable viral loads achieved, and the slow return to baseline levels of HCV replication off therapy suggest that VX-950 should be explored as monotherapy.

Studies of VX-950 in combination therapy are awaited as well.

New data on the drug are expected to be presented at the 56^th annual AASLD meeting in San Francisco (November 11-14, 2005).

Viramidine

Viramidine (VD) is a prodrug of ribavirin (RBV). It is converted to RBV mainly in the liver, and as a consequence produces less anemia, the most limiting side effect of RBV.

Early study results show a significantly reduced incidence of anemia with viramidine compared to RBV during HCV treatment in combination with pegylated interferon while having comparable efficacy. However, given the small sample and the substantial number of drop-outs from the study, it is not possible to draw firm conclusions regarding efficacy.

Results of Phase III studies of viramidine now underway are anxiously awaited.

Although the drug, like ribavirin, has no direct antiviral effects on the hepatitis C virus, it could act to strengthen the anti-HCV activity of interferon. Perhaps more importantly, it could be safer to use (causing less anemia) than ribavirin and thus would be a welcome adjunct to interferon therapy.

Preliminary results of Phase III studies of viramidine should be available by the end of December 2005.

Other Compounds

There are many other mono- and combination therapies under study for chronic hepatitis C that are in various stages of testing. These include the following agents (in alphabetical order, monotherapies and combination treatment):

Experimental HCV Treatments (HIV and Hepatitis.com)

HCV Experimental Treatments
- Monotherapy -

HCV Experimental Treatments
- Combination Therapy -