The hepatitis C drug development pipeline.Current hepatitis C treatment has many drawbacks, including significant side effects, high cost, and the need for injections of pegylated interferon IFN . While the major clinical trials of pegylated
interferon and ribavirin show about a 50% success rate in clearing the
virus--deemed a sustained virologic response (SVR)--in real-life
clinical settings, SVR rates are frequently lower. Moreover, treatment
outcomes are poorer for African-Americans and for people with genotype
1, high viral loads, and/or HIV co-infection. Because of toxicities,
including psychiatric side effects, treatment is often contraindicated
for many people with hepatitis C. As a result, many people avoid or
delay hepatitis C treatment, and only a relatively small proportion of
people with hepatitis C--perhaps 10%--have been treated to date, with
many failing to achieve an SVR. Thus, there is an urgent need for new,
more effective, and better-tolerated treatments. Any of a group of glycoproteins that are produced by different cell types in response to various stimuli, such as exposure to viruses, and that block viral replication in newly infected cells and, in some cases, modulate specific cellular functions. The hepatitis C virus (HCV HCV - Heavy Commercial Vehicle HCV - Hepatitis C Virus HCV - High Capacity Voice HCV - High Conservation Value HCV - HVAC Coolant Valve HCV - Hypersonic Cruise Vehicle (DARPA)) offers a number of potential targets for drug development. HCV undergoes a relatively simple replication cycle: cell entry; translation and cleavage of viral proteins; replication of viral RNA; and assembly and release of new viruses. Each of these stages in the replication cycle are, in theory, susceptible to inhibition by new drugs, though some aspects of replication--particularly cell entry and assembly and release--are still not well understood. In addition, novel treatments could stimulate more effective immune responses targeting HCV and facilitating viral clearance. Finally, in lieu of eradicating HCV, new drugs could benefit people who do not respond to current therapy by slowing or ameliorating liver damage. Most current approaches to HCV drug development focus on one of 2 strategies: targeting the hepatitis C virus itself, or improving on current modes of treatment. Pegylated interferon and ribavirin therapy has both antiviral and immunomodulatory effects, but neither drug was developed specifically as an anti-HCV therapy (unlike, for instance, HIV protease protease /pro·te·ase/ (pro´te-as) endopeptidase. pro·te·ase (pr ![]() t inhibitors, which directly target the HIV protease enzyme).
Primary viral targets for HCV include 2 enzymes: the NS3 NS3 - Netscape 3 serine protease
and the NS5B RNA-dependent RNA polymerase (RdRp; "NS" refers
to "non-structural protein"). Drugs targeting these enzymes
are still in relatively early stages of development. Strategies aimed at
improving current treatment include the addition of a third
(non-HCV-specific) drug to pegylated interferon and ribavirin to boost
their effectiveness, or alternative forms of interferon and ribavirin
intended to show greater efficacy and/or less toxicity. Many of the
drugs focused on these approaches are in later stages of development,
and clinical trials of these agents often focus on non-responders to
current interferon-based therapy.HCV protease and polymerase inhibitors offer the most promise for radically transforming the nature and success of hepatitis C treatment. However, as with HIV, these agents will inevitably face the challenge of drug resistance, and they will only be successful when used in combination. Ideally, a combination of HCV protease and polymerase inhibitors could eventually replace interferon and ribavirin, improving SVR rates while reducing side effects and shortening the duration of treatment. In turn, such a paradigm shift would likely result in a dramatic increase in the number of people with hepatitis C seeking treatment and expand the pool of HCV-treating physicians beyond a relatively small number of liver specialists. However, these developments are still several years off and would not occur until the next decade. In the meantime, projected rises in HCV-related deaths by 2010 lend increasing urgency to the search for new drugs. The following review describes agents currently in clinical trials, focusing on the drugs that show the most promise or those furthest along in development. HCV PROTEASE INHIBITORS HCV protease inhibitors have generated the most attention in the hepatitis C community, in part because of the success of HIV protease inhibitors. As with HIV, inhibition of the HCV protease interrupts the viral replication cycle by blocking cleavage of HCV proteins. Early trial results from Boehringer Ingelheim's protease inhibitor BILN 2061, presented in late 2002, heightened enthusiasm for this class of agents. Over a 2-day dosing period, people with hepatitis C experienced dramatic reductions in their HCV viral load. People with genotype 1 (the least responsive to standard treatment) showed a 2- to 3-log drop in HCV RNA. People with genotype 2 or 3 showed a lesser decline in HCV viral load, as BILN 2061 was specifically designed to target the genotype 1 HCV protease. Unfortunately, further development of BILN 2061 was halted after the discovery of cardiac toxicity in monkeys treated at high doses, though Boehringer Ingelheim is pursuing the development of follow-up protease inhibitors. It remains unclear whether the cardiac toxicity (not seen in humans treated fin. 2 days) was specific to BILN 2061 or is a potential side effect of all HCV protease inhibitors. The HCV protease enzyme is a challenging target because the binding site is extremely shallow. Indeed, many companies that initially pursued development of HCV protease inhibitors have subsequently abandoned their programs or shifted focus to other targets. However, new agents are entering clinical development, including Vertex Pharmaceuticals' VX-950, which has completed initial Phase la testing in healthy volunteers and moved into a placebo-controlled Phase 1b trial in 60 healthy volunteers and people with hepatitis C, who will be treated for up to 14 days. Schering-Plough has also begun clinical testing of its HCV protease inhibitor, and InterMune is expected to begin human trials of its lead candidate in 2005. HCV POLYMERASE INHIBITORS A number of companies are developing HCV polymerase inhibitors, which prevent replication of HCV RNA through one of 2 ways: blocking the elongation of new viral RNA strands (nucleoside nucleoside /nu·cleo·side/ (noo´kle-o-sid?) one of the compounds into which a nucleotide is split by the action of nucleotidase or by chemical means; it consists of a sugar (a pentose) with a purine or pyrimidine base. nu·cle·o·side (n analogs) or inhibiting the HCV polymerase enzyme itself (non-nucleoside inhibitors). Ribavirin itself is a nucleoside analog, though its precise mechanism of action remains unclear, and ribavirin used as monotherapy has no durable antiviral efficacy. Idenix is developing a nucleoside analog, dubbed NM-283. At its highest dose (800 mg once daily), people with HCV genotype 1 experienced about a l-log drop in viral load during 15 days of treatment in a Phase 1 study; lower doses were less effective. Initial results of a Phase 2a, 28-day study of NM-283 in combination with pegylated interferon showed an average drop of 2.7 logs in HCV RNA levels. Nausea and vomiting were the most common side effects in people treated with NM-283; these side effects appeared early after starting the drug and were generally transient. In 2005, Idenix will conduct a 6-month Phase 2b trial of NM-283 and pegylated interferon, compared to pegylated interferon and ribavirin or NM-283 alone, in 165 people with HCV genotype 1 who did not respond to prior treatment. Several other companies, including Japan Tobacco, ViroPharma, Roche, and Rigel, have also conducted clinical trials of HCV nucleoside analogs, though none has reached Phase 3 testing. Other companies, notably Abbott, also have HCV polymerase inhibitor programs and are expected to bring additional drug candidates into human trials in 2005 and 2006. As of yet, no non-nucleoside HCV RdRp inhibitors have moved into Phase 1 studies. NON-SPECIFIC ANTIVIRALS AND IMMUNE MODULATORS Phase 3 studies InterMune's Infergen (consensus interferon) is an alternate form of interferon approved as monotherapy for hepatitis C treatment in the 1990s, but seldom used. Side effects are similar to those of the pegylated interferons, but some clinicians report that their patients find Intiergen much harder to tolerate. In addition, InterMune has not developed a pegylated version of Infergen, which needs to be taken 3 times a week by injection. InterMune is conducting 2 large Phase 3 studies of high-dose Infergen in combination with ribavirin in non-responders to standard treatment (patients who typically will not respond to retreatment with pegylated interteron and ribavirin). Preliminary results of uncontrolled studies show that over a third of prior non-responders may achieve an SVR using Infergen and ribavirin; as with pegylated interferons, African-Americans do not respond as well to Infergen. The first Phase 3 study, the DIRECT trial, will study the efficacy of this regimen (evaluating 2 different doses of Infergen). Valeant's Viramidine is a prodrug of ribavirin that targets the liver. The prodrug formulation should reduce the major drawback of ribavirin, hemolytic anemia, resulting from ribavirin's uptake into red blood cells. Indeed, initial data indicate that Viramidine is equally effective as ribavirin when used in combination with pegylated interferon, but with a substantially lower incidence of anemia: 27% in people taking ribavirin, compared with 0% to 11% at various doses of Viramidine. Valeant is conducting further testing of Viramidine in comparison with ribavirin in 2 Phase 3 studies, both with pegylated interferon, and each study will enroll approximately 1,000 people. Valeant expects to market Viramidine in 2007. SciClone's Zadaxin (Thymosin alfa-1; thymalfasin) is a synthetic peptide, derived from human thymus gland extracts, that modulates immune responses. Zadaxin requires twice-weekly injections. In the US, SciClone has launched 2 Phase 3 studies of pegylated interferon, given with or without Zadaxin, in patients who did not respond to prior treatment. Results from these studies are expected in 2006. A European study, conducted by SciClone's partner Sigma Tau, is evaluating 550 non-responders who will receive pegylated interferon and ribavirin, with or without Zadaxin. Phase 2 studies Maxim's Ceplene (histamine dihydrochloride) is an immune modulator that prevents oxidative stress, thereby protecting immune cells and possibly liver tissue. Ceplene is given by injection. Maxim has conducted a Phase 2 study in more than 300 patients who did not respond to prior treatment; they will be given pegylated interferon and ribavirin, with or without Ceplene. Maxim has indicated that it will focus further clinical developmerit efforts on an oral version of Ceplene, which completed Phase la testing in 2004. InterMune's Actimmune (interferon gamma-1b) is a synthetic version of gamma interferon, a human protein with antiviral and immune-modulating effects that overlap with those of alpha interferon (the basis for the pegylated interferons). Actimmune is administered by injection 3 times per week and has side erects similar to those of pegylated interferon. InterMune is conducting a Phase 2 study of Actimmune with Infergen (consensus interferon) in non-responders to standard treatment. Human Genome Sciences' Albuferon is a form of synthetic alpha interferon fused to albumin, giving the drug a longer half-life and potentially enabling a dose schedule of every 2 to 4 weeks. Side effects are comparable to those of pegylated interferon. In late 2004, Human Genome Sciences launched a 48-week Phase 2 study in patients who did not respond to prior treatment, comparing different doses of Albuferon given with ribavirin. Vertex Pharmaceuticals' Merimepodib is an IMPDH (inosine-5'-monophosphate mon·o·phos·phate (m n![]() -f s dehydrogenase) inhibitor, thought to
boost the antiviral activity of ribavirin. Vertex recently launched the
METRO study, a Phase 2b trial examining the efficacy of pegylated
interferon and ribavirin, with or without Merimepodib, in patients who
did not respond to prior treatment.ADDITIONAL INVESTIGATIONAL AGENTS * Imino im·i·no ( m![]() -n sugar derivatives: These compounds may work by targeting
the formation and proper folding of HCV envelope proteins, or through
inhibiting ion channel formation and possibly preventing the release of
new virus from infected cells. Migenix's Celgosivir (MX-3253) is
currently under evaluation as monotherapy in a 12-week, 60-person Phase
2 study. United Therapeutics' UT-231B failed to demonstrate
efficacy in non-responders in a Phase 2 study, but the company is
planning another trial in partial responders to standard treatment
(people whose viral load declined but who did not achieve an SVR) to
assess whether UT-231B can prevent virologic relapse.* Anadys' ANA975 is an oral prodrug of Isatoribine (ANA245), a nucleoside analog that functions as a toll-like receptor agonist, increasing the production of alpha interferon and stimulating immune responses. Based on promising results showing that high doses of Isatoribine produced on average a 0.76-log drop in HCV RNA over a 7-day dosing period, Anadys plans to begin Phase 1 testing of ANA975. Side effects will likely resemble those of pegylated interferon. Coley Pharmaceuticals also has a toll-like receptor agonist, Actilon, currently in Phase 1-2 testing in people with hepatitis C. * Isis Pharmaceuticals' ISIS 14803 is an anti-sense oligonucleotide, a short synthetic strand of RNA designed to bind to HCV RNA and block replication. The drug requires injection. In 2003, the company launched a Phase 2 study of ISIS 14803 in combination with pegylated interferon and ribavirin in patients who did not respond to prior treatment. Unfortunately, the company recently announced that it was dropping further development of this compound. * Idun Pharmaceuticals' IDN-6556 is a liver-targeting caspase inhibitor that prevents apoptosis (cell death). IDN-6556 is being evaluated in a 3-month, placebo-controlled Phase 2 trial in people with hepatitis C to determine its potential to decrease liver damage. * Innogenetics and Intercell have conducted Phase 2 studies of therapeutic vaccines for hepatitis C. Innogenetics has reported that its therapeutic vaccine, designed to stimulate immune responses to one of HCV's envelope proteins, showed improvements in liver histology (reducing inflammation and/or fibrosis) in over a third of treated subjects with hepatitis C, despite having no effect on viral load. Intercell has reported that its vaccine, based on 5 HCV epitopes, successfully stimulated or strengthened anti-HCV immune responses, though without substantial effects on viral load. Further studies of these vaccines are planned. CONCLUSIONS The encouraging range of activity in HCV drug development bodes well for future treatment options, though dramatic short-term improvements in treatment safety and efficacy are unlikely. While several agents offer some hope for people who cannot tolerate or did not respond to current treatments, interferon will remain a mainstay of HCV treatment for the foreseeable future, and the most promising drugs--HCV protease and polymerase inhibitors--are still several years away from approval. Advocates following the HCV pipeline should press for clinical trial designs relevant to "real-world" people with HCV--particularly those who respond poorly to current therapy, including people co-infected with HIV.
Table. HCV therapeutics in development
Company Drug Class
Vertex VX-950 protease inhibitor
Schering-Plough (unnamed) protease inhibitor
Idenix NM-283 polymerase inhibitor
Japan Tobacco JTK-003 polymerase inhibitor
ViroPharma HCV-086 polymerase inhibitor
Viropharma/Wyeth HCV-796 polymerase inhibitor
InterMune Infergen alpha interferon
Valeant Viramidine ribavirin prodrug
SciClone Zadaxin immune modulator
Maxim Ceplene immune modulator
Maxim HD-O Ceplene prodrug
InterMune Actimmune gamma interferon
Human Genome Sciences Albuferon alpha interferon
Vertex Merimepodib IMPDH inhibitor
Migenix Celgosivir imino sugar derivative
United Therapeutics UT=231B imino sugar derivative
Anadys ANA975 toll-like receptor agonist
Coley Actilon toll-like receptor agonist
Idun IDN-6556 apoptosis inhibitor
Innogenetics INNO 101 therapeutic vaccine
Intercell IC41 therapeutic vaccine
Company Status
Vertex Phase 1b
Schering-Plough Phase 1
Idenix Phase 2b
Japan Tobacco Phase 2
ViroPharma Phase 1
Viropharma/Wyeth Phase 1
InterMune approved; Phase 3
with ribavirin
Valeant Phase 3
SciClone Phase 3
Maxim Phase 2b
Maxim Phase 1
InterMune Phase 2 with Infergen
Human Genome Sciences Phase 2
Vertex Phase 2b
Migenix Phase 2
United Therapeutics Phase 2
Anadys Phase 1
Coley Phase 1-2
Idun Phase 2
Innogenetics Phase 2
Intercell Phase 2
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