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HCV hope on the horizon

There is a formidable pipeline of drugs in late-stage clinical trials for treating hepatitis C

A cross-sectional view of human organs, highlighting the liverChronic infection with the hepatitis C virus (HCV) is a major cause of serious liver disease. HCV infection is five times more prevalent globally than HIV, with about 3 per cent of the population worldwide infected. Risk factors include injection drug use and sexual infection. HCV is the most common blood-borne pathogen and is particularly difficult to control because it is highly infectious and has a long latency period. HCV infection can lead to liver cirrhosis and hepatocellular carcinoma, which may mandate liver transplantation. Furthermore, the chance of developing significant liver disease increases with duration of infection. 

In the US, France, Germany, Italy, Spain, the UK and Japan, the incidence of HCV infection is rising and the cost of therapy is expected to grow to more than $10bn by 2017. The primary goal of treatment is viral eradication. 

Standard therapy for HCV infection at present is combination therapy with peginterferon α (a pegylated form of the immunomodulator interferon α) and ribavirin (a ribonucleoside antiviral agent). However, treatment response is dependent upon the particular HCV genotype causing the infection, with viral eradication rates of just 40-50 per cent in patients infected with HCV genotypes 1 or 4 and around 70-80 per cent in those infected with HCV of other genotypes. Moreover, this therapy has some significant adverse effects such as fatigue, neurological disorders, thyroid dysfunction, influenza-like illness, haemolytic anaemia and gastrointestinal disorders that often result in patients discontinuing treatment.

In the pipeline
Approximately 30 new therapies for HCV infection have progressed into phase II or phase III clinical trials. These treatments either specifically target the biology of the HCV and are usually intended for use in conjunction with peginterferon α plus ribavirin, or are immunomodulatory agents comprised of interferon and are intended as replacements for, or for use with, peginterferon α. 

Immunomodulatory agents have a crucial role in therapy because evidence suggests that T-cell effector function is impaired in individuals who are chronically infected with HCV, and the aim of immunomodulation is to restore the innate and adaptive immune response.

HCV-targeted antiviral therapies in development include protease inhibitors, polymerase inhibitors, HCV NS5A inhibitors and cyclophilin inhibitors. The NS3/4A protease is critical for HCV replication, and NS5A is an HCV protein that appears to be necessary for production of viral DNA. Nucleoside analogue polymerase inhibitors are incorporated as chain terminators in the viral RNA strand, whereas non-nucleoside polymerase inhibitors fix the HCV RNA-dependent RNA polymerase enzyme in its inactive configuration. Cyclophilin B is a host cell protein that functions as a co-factor of HCV RNA-dependent RNA polymerase.

Two protease inhibitors have progressed into phase III trials – Schering-Plough's boceprevir and Vertex Pharmaceuticals' telaprevir. These are competing to be the first orally administered small-molecule protease inhibitors for HCV infection. Both drugs are being developed for use in combination with standard therapy and both have been granted fast-track status by the US Food and Drug Administration (FDA). Phase II data in treatment-naïve patients with HCV genotype 1 show that both drugs improved the sustained virological response rate when added to standard therapy and both were well tolerated. Phase III data are expected to be available for both drugs in mid- to late 2010. At phase II there are several other protease inhibitors such as BI 201335 (Boehringer Ingelheim), ITMN 191 (InterMune and Roche), MK 7009 (Merck & Co), SCH 900518 (Schering-Plough) and TMC 435 (Tibotec). 

Among the polymerase inhibitors, the most advanced in development is Pfizer's non-nucleoside compound filibuvir at phase II. When this drug was added to standard therapy in patients chronically infected with HCV, it was not only well tolerated but there was a marked increase in the percentage of patients achieving rapid viral response (undetectable HCV RNA by week 4) compared with placebo. Other polymerase inhibitors that have progressed to phase II and are competing for a niche in this marketplace are the non-nucleosides ABT 072 and ABT 333 (Abbott Laboratories) and GS 9190 (Gilead Sciences), and the nucleoside analogues IDX 184 (Idenix Pharmaceuticals) and R 7128 (Pharmasset and Roche).

The ciclosporin analogue DEBIO 025 (Debiopharm) is a first-in-class cyclophilin inhibitor that has been generally well tolerated in clinical trials to date and may have potential as an addition to standard therapy. Phase II trial data in treatment-naïve patients with HCV infection showed that the combination of DEBIO 025 and peginterferon α-2a significantly reduced viral load compared to DEBIO 025 or peginterferon α-2a alone. Since DEBIO 025 targets host cell proteins rather than viral proteins, it may not be as susceptible to drug resistance mutations compared to drugs targeting viral proteins.

Taribavirin (Viramidine; Valeant Pharmaceuticals International) is being developed as a possible replacement for ribavirin. The drug is rapidly absorbed and extensively taken up by the liver for conversion into ribavirin. The liver, being the site of HCV replication, has greatly increased exposure to the drug, with substantially less circulating in the plasma. Phase II and III data show that weight-based doses of taribavirin had similar efficacy to ribavirin in reducing HCV viral load, but the rate of haemolytic anaemia was significantly lower than with ribavirin.

Several interferon-based agents are in development as replacements for peginterferon α. Albinterferon α-2b or Albuferon (Human Genome Sciences and Novartis) was created by fusing the genes of interferon α and albumin. It was designed to prolong the activity of the therapeutic protein so as to reduce dosing frequency and minimise adverse events. However, although phase III efficacy data demonstrate non-inferiority of Albuferon to peginterferon α, the adverse event profiles of the two agents were similar. 

Interferon-based agents undergoing phase II trials are the controlled-release interferon α agents Locteron (Biolex) and HDV-interferon (Hepasome Pharmaceuticals), the low-dose oral interferon α product Veldona (Amarillo Biosciences) and interferon ω (Intarcia Therapeutics). HDV-interferon and Veldona offer the advantage of oral administration; interferon-based therapeutics are normally administered subcutaneously.

Various immunomodulators are progressing through clinical trials as potential adjunctive therapies for HCV infection. The tumour necrosis factor-inhibiting monoclonal antibody infliximab (Remicade; Schering-Plough), when administered seven days prior to standard therapy, improved viral eradication at week 8 but not week 12 in phase III trials. The synthetic dipeptide golotide (Verta and SciClone Pharmaceuticals) may enable a dose reduction of peginterferon α and has been approved in Russia, while phase II trials are in progress in the US. Others in phase II trials are the T-lymphocyte stimulants GI 5005 (Tarmogen; GlobeImmune), a recombinant yeast product, and IPH 1101 (Phosphostim; Innate Pharma), a small molecule compound that is administered intravenously. Romark Laboratories has a small molecule signal transduction pathway modulator nitazoxanide (Alinia) that is designed to assist the host cell's innate defence mechanism against viral infection.

In the 20 years since HCV was discovered, a prodigious R&D effort has been in progress. This has resulted in a small number of new therapies reaching the market and a formidable pipeline of potential treatments that are in late-stage clinical trials. In the next few years, this should be translated into more new agents reaching patients, with better choice for treatment options tailored to disease characteristics. The impending phase III trial results for boceprevir and telaprevir will be a milestone of particular interest.


The Author
Pipeline was written by Philip Hair of Adis International (Wolters Kluwer Pharma Solutions), using data derived from Adis R&D Insight and Clinical Trials Insight. 
For further information on Adis services, please contact Kuljeet Sohanpal on +44 (0)20 7981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com
To comment on this article, email pm@pmlive.com

16th November 2009

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