Hepatitis C Treatment and New Drugs in Development

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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, E. T. 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 , 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, " 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.

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, 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, "

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. "

10/20/06