New treatments on the horizon for hepatitis C

by Geoffrey Dusheiko
- Royal Free Hospital and University College London Medical School

The current standard of care for hepatitis C is pegylated interferon (PEG IFN) used in combination with ribavirin (RBV). Each genotype responds differently to treatment. The ideal outcome of treatment is a sustained virological response, (SVR), ie. undetectable HCV RNA by real time PCR six months after completing response. There are several well known limitations in the effectiveness of IFN alpha and RBV, and side effects. Patients with compensated cirrhosis are candidates for treatment; successful clearance of HCV alters the natural history of the disease, and reduces the risk of complications of cirrhosis. Alpha IFN is difficult to apply in decompensated cirrhosis and liver transplant recipients, and may precipitate deterioration. Abbreviated courses in rapid responders however assist some patients, however.

A large number of patients have failed prior IFN treatment. The overall SVR rates in retreated non responders are in the region of 20%. Generally, prior relapsers respond better than non responders. Although the primary goal of treatment remains eradiction of the virus, this goal may require the advent of new direct antivirals rather than re-treatment with PEG IFN and RBV
Genetic variation in the immune response may contribute to the ability to clear the virus. Recent data from genome wide association studies have tested the association of hundreds of thousands of single nucleotide polymorphisms (SNPs) in the human genome and response to PEG IFN and RBV. Genetic responsiveness to IFN may be determined by a region upstream of the IL28b gene. A single nucleotide polymorphism upstream of the IL28B gene, which encodes the type III IFN, IFN lambda-3, associates strongly with response to IFN treatment. SVR rates have been found to be highest in patients with the cc allele (for example 69% of naive Caucasians with genotype 1 infection and the IL28B cc allele had SVR compared to 27% of those with the tt allele).

New treatments on the horizon

The limitations of IFN and RBV treatment have necessitated a continuing search for improved therapies. Important progress is being made in the development of new treatments, in particular new specific inhibitors or direct antiviral agents active against hepatitis C. There is an urgent need to develop improved therapies for patients and to improve the outcomes in prior non-responders to treatment. A diverse range of targets are being exploited for anti-HCV drug development. Two protease inhibitors are at the most advanced stage of development. Several new NS3 protease inhibitors, NS5b nucleoside polymerase inhibitors, non-nucleoside polymerase inhibitors are being assessed in phase 2 or 3 studies. Numerous other compounds are being tested in phase 1 and 2.

Protease inhibitors in advanced study:

VX-950, (telaprevir) is a peptidomimetic protease inhibitor of the hepatitis C NS3/4A protease. Encouraging results in phase 2 studies have been reported. Large phase 3 studies have been completed but not yet analysed. The combination of telaprevir, PEG IFN and RBV improves SVR rates compared to PEG IFN and RBV (69% vs 46 %) in IFN naïve genotype 1 patients. Telaprevir, RBV and PEG IFN alpha will likely be dosed for 12 weeks, followed by a combination of PEG IFN alpha and RBV for a further 12 weeks in naive patients. In phase 2 studies telaprevir has been dosed at 750 mg 8 hourly and 1125 mg 12 hourly, with both PEG IFN alpha2a and 2b. Equal efficacy has been noted. A high percentage of patients (approximately 80%) achieve a rapid viral response (RVR) i.e. have undetectable HCV RNA at 4 weeks with a triple combination of telaprevir, PEG IFN and RBV; more than 90% of IFN naive genotype 1 patients with undetectable HCV RNA at week 4 are cured after 6 months of therapy. RBV remains an essential component of treatment. Flu-like syndrome, nausea, diarrhea, pruritus, rash, headache, insomnia, and anaemia have been observed in telaprevir treated patients. Antiviral resistance remains a limitation of the drug.

Dose modifications of RBV, are required. Severe rash has been noted in 5-7% of telaprevir recipients, and although some patients may respond to measures such as topical corticosteroids, severe generalised rash usually necessitates discontinuation of telaprevir. The pathogenesis of the rash is unknown, but eosinophilia has been noted. The median time to onset of moderately severe rash has been of the order of 7 weeks.

Phase 2 studies have been completed in prior non responders, or relapsers. These groups require precise definition, but the results are encouraging. The PROVE 3 trial is a phase 2 study of telaprevir; 453 previous nonresponders infected with genotype 1 HCV were randomised to one of 4 treatment arms: 48 weeks of PEG IFN AND RBV (control), 24 weeks of PEG IFN plus telaprevir (no RBV), 24 weeks of PEG IFN plus RBV plus telaprevir followed by 24 weeks of PEG IFN OR RBV or 12 weeks of PEG IFN plus RBV plus telaprevir followed by 12 weeks of PEG IFN and RBV. 51% of patients treated for 12 weeks and 53% of patients treated with 24 weeks of triple therapy achieved SVR. 69 % of relapsed patients show an SVR. Patients who received PEG IFN plus telaprevir without RBV achieved a relatively poor 24% SVR rate, further establishing the importance of RBV. The SVR rate among patients in the control arm of PEG IFN and RBV was only 14%. (McHutchison JG, et al. AASLD 2009. Abstract 66).

Boceprevir is a small molecule inhibitor of the NS3/4a protease. Phase 2 studies in combination with PEG alpha 2b IFN and RBV in naive and non responder patients showed SVR rates of 74% vs 38% with 48 weeks of PEG IFN and RBV therapy. Shorter treatment courses were less effective: SVR rates were 56%. In studies of prior non responder genotype 1 HCV patients, only 7-14% achieved SVR. Anaemia was common in boceprevir treated patients.
Several other protease inhibitors are in development for the treatment of IFN naive and experienced patients but the data is less mature at this time. (table)

A compendium of other studies is in progress including large phase 3 studies in genotype 1 IFN naïve and non responder patients with genotype 1. The benefit or otherwise of a lead in or delayed start comprised of 4 weeks of treatment with PEG IFN and RBV followed by the protease inhibitor will require assessment. The ideal duration of treatment for different groups remains to be determined. Response guided therapy, i.e. lengthening therapy for patients with slower responses may be the guiding principle particularly for prior non responders. Unfortunately peptidometic protease inhibitors do not appear to be active against genotype 3 infections and have variable activity against the remaining genotypes. Initial data indicates that RBV will remain an essential constituent of treatment with protease inhibitors for the time being.

Resistant variants are present before treatment, as HCV exists as a mixed population of viruses, but most resistant viruses are relatively unfit compared to wild type virus. All antiviral drugs can select resistant variants; the nucleotide changes and amino acid changes that confer resistance to these drugs will require careful assessment. Patients with genotype 1a are more likely to develop resistance to protease inhibitors. Cross resistance among protease inhibitors is likely to remain an important issue, making testing of these new agents in phase 1 somewhat problematical because of the risk of jeopardising future therapy.

Replication inhibitors:

NS5b RNA dependent RNA polymerase inhibitors.
The RNA-dependent RNA polymerase (NS5B) of HCV (HCV) is an attractive target for drug antagonism , as the HCV NS5b polymerase is a key enzyme involved in HCV replication. Two types of HCV polymerase inhibitors are in development: nucleoside and non nucleoside. HCV nucleoside analogues block HCV replication by acting as chain terminators and thus stopping further elongation of the nascent RNA strand. Non nucleosides interact with the polymerase outside the catalytic site- producing allosteric changes that compromise its function.

At least 5 different sites (named A, B, C, D, and E) have been shown to be targeted by non-nucleoside inhibitors. Mutations that confer resistance to individual drug’s binding sites do not cause cross-resistance to other drugs. As non nucleoside inhibitors are allosteric blockers different resistance patterns are observed. Polymerase inhibitors tend to work across genotypes; nucleoside inhibitors lead to slower resistance.

Interestingly, silibinin A and silibinin B, (constituents of milk thistle) both as water-soluble forms, and as commercially available intravenous preparation of silibinins have been shown to inhibit the HCV RNA-dependent RNA polymerase function; intravenous silibinin may interfere with the NS5B-RNA interaction to inhibit HCV replication.

Cyclophilin inhibitors including DEBIO-25 may possess additive antiviral efficacy and unique resistance profiles. New long acting interferons,(albuferon) have been tested and may be licenced shortly, and studies with lambda IFN have begun. Pilot studies of nitazoxanide plus PEG IFN and RBV have been completed but further controlled studies are required to evaluated efficacy.

Summary

Many of the direct antiviral agents show early promise, but it is not clear how treatment with these agents can be optimised. It is also not clear whether a lead-in strategy is important for telaprevir. Optimal dosing schedules also require further investigation. There may be subtype differences in responsiveness and differing activity across genotypes 1 to 6 for new protease inhibitors. A new array of side-effects is being observed with these new agents, which will require appropriate management. These have included rash, severe drug eruptions, gastrointestinal side effects, anaemia and bone marrow suppression, renal impairment and increase in serum aminotransferases. Unfortunately both IFN and RBV are required to reduce resistance and increase efficacy. It is not clear with IL28b polymorphisms influence the response to direct antiviral agents.

There may be an opportunity in the not too distant future for the use of a combination of NS3/4a protease and NS5b polymerase inhibitors in the treatment of hepatitis C. It is to be hoped that such agents will prove synergistic and will reduce the potential for drug resistance thus providing a viable therapeutic option without IFN. Meaningful trials of oral agents will commence shortly, including for example R7128 plus R7227 (ITMN-191) or BMS-650032 plus BMS-790052. Oral treatments and agents with lower toxicity will improve treatment of HCV in the community and have a major societal impact on the existing burden of disease.

There is nonetheless hope that protease inhibitors that are about to be licenced in 2011 will provide important changes to therapy and will be rapidly approved as cost effective in the UK.

Table: Direct antiviral agents and novel agents in development