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NEW DRUGS
Reported by Jules Levin
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There were several discussions of new drugs for HCV and there are a number of them. There appear to be a bunch of antiviral drugs in various stages of very early development including polymersase and helicase inhibitors. There was a brief presentation on the first HCV protease inhibitor to reach clinical trials, BILN 2061. This drug is being developed by Boerhinger Ingleheim and is the subject of 4 studies being presented at the upcoming AASLD. These presentations are the first publicly revealed data on this drug. Researchers will report initial study results from HCV-infected patients. There were also a few talks here on early results from studies exploring the potential use of certain non-nucleosides and nucleosides in HCV. The development of any drug is subject to the vagaries of development: will it prove to be safe and effective. Many drugs do not make it past the early stages of development.
Interferon Plus Pegylated Interferon
There was an interesting pilot study presented here by a Brazil research group (abstract 36) that raises a question I feel is worthy. They used Consensus Interferon (CIFN) in this study but I think that any interferon could be used. The notion is that starting therapy with interferon for a day or more and then using pegylated interferon may yield better results for hard to treat patients such as genotype 1, previous non-responders, and HIV-infected patients. This approach is experimental and needs further study and refinement. For example, do you use one or two days of a daily dose of interferon and how much do you use? Do you then use pegylated interferon on the following day or do you start both together? Although this concept makes sense I'd like to see studies showing it improves the sustaimed response. An initial loading dose of interferon may improve the initial reduction in viral load but studies need to explore if the sustained response rates are improved.
The purpose of this study was to analyze early HCV viral load decrease after CIFN on the first day followed by 180 ug of peg-IFN/weekly + 1000 mg of ribavirin per day. HCV RNA was determined by qualitative and/or quantitative PCR (Amplicor Roche Monitor) pre-treatment, 24 hour and at weeks 2, 4, and 12. 5 patients, a small study, were treated with 24-30 ug of CIFN on the first day followed by peginterferon. The researchers reported that the median HCV viral loads at pretreatment were 6.3 log and 4.2 log after 24 hours (after the initial CIFN dose). At week two the median HCV RNA viral load was 2.1 log and it was 2.5 log at week 4. At weeks 2 and 4, 2/5 and 2/5 patients had negative viral load, respectively. The researchers concluded that the use of a "fast acting" interferon (CIFN) at the first day of treatment resulted in a profound viral load decrease in 24 hours. All patients showed an absolute count less than 5 log, including a decrease of more than 1.7 log (mean drop 2.1 log) in all but one patient. In the opening session in a talk on viral load kinetics after starting HCV therapy, Avidan Neumann (a noted HCV viral kinetics researcher), also suggested that for some hard to treat patients such as non-responders or genotype 1 using a brief loading dose approach with daily interferon may help improve responses.
Cirrhosis
This morning Jenny Heathcote (University of Toronto) talked about treating patients with cirrhosis and chronic HCV. She said that non-responders to HCV therapy can slow or reduce fibrosis rate of progress and reduce risk of hepatocellular carcinoma (liver cancer). Of course sustained responders have a better chance of slowing or reversing disease. She referred to a study where 56% of sustained responders reversed fibrosis and 30% of non-responders reversed fibrosis. She spoke in support of the findings from Poynard and McHutchison reported at AASLD last year and archived on my website that 49% of patients with cirrhosis showed reversal of fibrosis with paired biopsies 20 months apart. In that study, Poynard suggested that with longer term followup the percent of patients with improved fibrosis might increase.
Alternatives to Ribavirin
Johnson Lau and colleagues from Ribapharm reported early results from their research into 2 alternatives to ribavirin that appear more effective than ribavirin but still need further study in HCV-infected individuals. Here is the information presented by Lau. Ribavirin, in combination with a long-acting interferon, is currently the recommended therapy for patients with chronic hepatitis C. The mechanism of action of ribavirin is unknown but proposed mechanisms include (1) switching the host immune response through tilting the Th1/Th2 balance, (2) inhibition of host IMPDH, (3) direct inhibition of hepatitis C virus, and (4) inducing replication error catastrophies. Another important feature of ribavirin is that it accumulates in erythrocytes, and haemolytic anemia is one of the dose limiting features. As well, the anemia causes difficult to tolerate toxicities and side effects often leading to drug discontinuation by patients.
Two ribavirin analogues (similar in molecular makeup to ribavirin but slightly different) are currently being developed by Ribapharm researchers. In in vitro and in vivo studies, levovirin also switches the Th1/Th2 balance, similar to ribavirin. However, levovirin does not undergo phosphorylation and hence there are no monophosphate and triphosphate metabolites; therefore, the haemolytic anemia side effect as well as the weak direct antiviral effect is also absent. The safety profile of levovirin has been confirmed in a number of animal studies. Phase I studies have also confirmed the safety of levovirin in humans. Lau said that if switching Th1/Th2 is the main mechanism of action of ribavirin, levovirin will be an excellent compound with similar or better efficacy (with more effective dosing) and a much improved safety profile compared with ribavirin. Further studies are ongoing. Ribapharm has a development agreement for levovirin with Roche.
The second compound, viramidine, is a liver-targeting version of ribavirin. This is based on the premise that not enough ribavirin is delivered to the liver and too much ribavirin is delivered to the erythrocytes. Preclinical studies presented at this meeting showed that viramidine is concentrated at a much better ratio between the liver versus the erythrocyte compartments. Clinical results from Phase I study in healthy volunteers based on similar doses of viramidine versus ribavirin have confirmed the improved safety profile of viramidine when compared with similar dosing of ribavirin, and these data will be presented in a few days at the AASLD meeting. Further clinical studies are required to establish that this drug has similar effectiveness in reducing HCV viral load in combination with interferon, as well as in establishing safety in HCv-infected individuals.
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