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Hepatitis C Treatment and New Drugs in Development

Two review articles published last month offer an overview of the state-of-the-art in hepatitis C treatment and a look at promising drugs in development.

Treating Hepatitis C

M.P. Manns, H. Wedemeyer, and M. Cornberg, of the Medical School of Hannover in Germany, published their review, "Treating viral hepatitis C: efficacy, side effects, and complications," in the September 2006 issue of Gut.

"The treatment of hepatitis C has dramatically improved over the past decade. Unlike any other chronic viral infection, a significant proportion of patients with chronic hepatitis C can be cured," they wrote. "However, the current standard
therapy -- pegylated interferon alpha and ribavirin -- has its limitations."

The authors provided a brief overview of several drugs in the development pipeline, including HCV protease and polymerase inhibitors, antisense oligonucleotides, and small interfering RNAs. Though promising, they predicted, "Drug resistance may become a problem with these new compounds and combination therapies may be unavoidable."

In terms of managing acute HCV infection, the authors noted that immediate treatment of patients with symptomatic acute hepatitis C with conventional or pegylated interferon monotherapy for 24 weeks produced a high rate of virological response (about 90%). However, this approach runs the risk of unnecessarily treating individuals who might spontaneously clear HCV without therapy, leading to the adoption of a "wait and see" strategy to determine with patients still have detectable HCV RNA after 12 weeks.

The authors then reviewed current standard therapy with pegylated interferon plus ribavirin. Among recent advances are the recognition of the importance of weight-based dosing of ribavirin and the need for individualized therapy tailored according to factors such as HCV genotype and pre-treatment HCV viral load. Studies of varying treatment durations -- both shortening treatment for patients with genotype 2 or 3 and lengthening it for those with genotype 1 -- are underway, but thus far have yielded mixed results.

Manns and colleagues devoted considerable attention to managing the side effects of interferon/ribavirin, which can lead to poor adherence, dose reduction, drug discontinuation, and ultimately treatment failure.

Finally, they included a discussion of hepatitis C treatment in "special populations," including patients with persistently normal ALT, those co-infected with HIV or hepatitis B, patients who have received liver transplants, and those undergoing kidney dialysis.

"The main challenge for the future is to improve the success rates for the difficult to treat and non-responsive HCV genotype 1 patients," they concluded.

Future Therapies for HCV

In the September 2006 issue of Nature Reviews Drug Discovery 5: 715-716, Richard E. T. Smith provided an overview of several experimental anti-HCV therapies.

"As with HIV drug development, the first direct antivirals to be developed for HCV were the nucleoside analogues that inhibit the non-structural protein 5B (NS5B) polymerase, an essential enzyme required for viral replication," he wrote.

Ribavirin is a weak inhibitor, but it is effective when used in combination with interferon. Researchers hoped to circumvent ribavirin-induced anemia with the prodrug Viramidine (from Valeant), but "efficacy results have been disappointing so far."

Newer nucleoside analogues now in development include valopicitabine (NM283; Idenix/Novartis), currently in Phase II trials using lower doses in the hopes of reducing the occurrence of gastrointestinal side effects; Phase III trials are expected to start in 2007. Also in development is Roche's R1626, which recently advanced to a Phase II trial.

Non-nucleoside analogue inhibitors that also target the HCV polymerase are in earlier stages of development. ViroPharma/Wyeth's HCV-796 is the furthest along in the pipeline.

"The early development of resistance is not uncommon with this class, as is evident with non-nucleoside analogue inhibitors for HIV, but like HIV, these drugs will probably have to be used in combination with other therapies," said Smith, echoing Manns and colleagues.

"The HCV NS3-4A serine protease has long been a desirable drug target for HCV; however, its shallow active binding site has made it difficult to design small-molecule inhibitors," Smith continued. Boehringer Ingelheim's BILN 2061 was the HCV protease inhibitor first to enter trials, but was halted due to cardiac toxicity in animals.

Two other protease inhibitors now undergoing trials are Vertex's VX-950 and Schering-Plough's SCH-503034. VX-950 has shown "significant potency" in early studies and is now in Phase II trials. Smith predicted that InterMune's ITMN-191 would enter clinical trials by the end of this year.

Despite progress with novel antiviral agents, "Most experts agree that for the foreseeable future, HCV treatment regimens are likely to include an immunomodulator" such as interferon, Smith wrote.

These included new forms of interferon, such as Albuferon (Human Genome Sciences/Novartis) and Locteron (Biolex/OctoPlus), which may be able to be dosed less often than pegylated interferon. Newer immune-based approaches include toll-like receptor (TLR) agonists such as Coley's Actilon's CPG10101 and Anadys' ANA-975.

"It is evident that the way in which HCV is treated is about to change as new drugs edge towards the market," Smith concluded. "Sustained virological response rates need to be improved, the holy grail being an all oral drug combination that pushes rates into the 80-90% range without the need for interferon injections. This goal remains some distance away, but in the meantime the current treatment market for HCV is likely to grow from approximately US $3 billion per year to more than $8 billion by 2010."

M P Manns, H Wedemeyer and M Cornberg. Treating viral hepatitis C: efficacy, side effects, and complications. Gut 55(9): 1350-1359. September 2006.

R E T Smith. From the analyst's couch: Hepatitis C virus therapies. Nature Reviews Drug Discovery 5: 715-716. September 2006.


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