Hepatitis C therapies

Published: 19/05/2011

Hepatitis C therapies

The term hepatitis C, coined in 1989, refers to an infectious viral disease, which affects more than 180 million people worldwide. Hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure and liver cancer, and is the major cause of liver transplantation in Europe and the US. Diagnosis is often complicated as most patients with a chronic infection are asymptomatic or exhibit only mild symptoms. Disease management is also an issue as hepatitis C manifests as one of six genotypes and more than 50 subtypes, which dictates the duration of therapy and response to treatment.

Interferons

The primary goals of therapy are to prevent complications and death from hepatitis C, while reducing adverse events and maintaining quality of life. The first treatment to be approved for hepatitis C was interferon a-2b (Intron A). However, treatment efficacy was limited due to rapid absorption in subcutaneous tissue, a large volume of distribution, rapid renal elimination, short half-life and variable peak-trough concentrations. The addition of a polyethylene glycol moiety led to the resolution of several of these issues. Currently, the standard treatment for hepatitis C is pegylated interferon in combination with ribavirin (Copegus). Ribavirin is an oral synthetic nucleoside analogue that acts synergistically with pegylated interferon.

Two pegylated interferon products have been approved by the US Food and Drug Administration (FDA), peginterferon a-2a (Pegasys) and a-2b (Cylatron). The IDEAL trial was the first head-to-head comparison of the two therapies, demonstrating that both peginterferon a-2a and a-2b were equally effective and had similar safety profiles as first-line therapy in patients with genotype 1 infection. However, these combinations are simply the best of the suboptimal therapies that are available at present. Furthermore, both peginterferons and ribavirin are associated with a multitude of adverse effects. All interferon products have the potential to cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischaemic and infectious disorders, while ribavirin has the potential to cause birth defects, foetal death and haemolytic anaemia.

Although peginterferon and ribavirin combinations are the recommended treatment for hepatitis C, there are other products on the market. Interferon alfacon-1 (Infergen) is a non-naturally occurring recombinant type I interferon. In 2006, Astellas Pharma voluntarily withdrew the marketing authorisation for the product in the European Union for commercial reasons. However, last year the FDA approved expanded labelling of interferon alfacon-1 to include its daily use in combination with ribavirin for retreatment of chronic hepatitis C. The approval was based on data from the DIRECT trial showing that the combination was safe and provided an effective retreatment option for patients failing initial therapy with standard therapeutics.

Thymalfasin (Zadaxin), a synthetic version of thymosin a-1, has been launched as a monotherapy in Asia, Middle East, Russia and South America. However, the drug has not received the FDA seal of approval. Phase III trials evaluating thymalfasin in combination with peginterferon a in the US and Europe have consistently shown no further benefit with the addition of the thymalfasin over peginterferon a alone. However, the drug has successfully completed phase II trials in Japan and Schering-Plough is working to begin a clinical programme to study its use in combination with interferon a-2b.

New entrants
Two new competitors, telaprevir and boceprevir, have stepped forward. Both are NS3 protease inhibitors being developed as add-ons to standard therapy. NS3 protease is an enzyme essential for viral replication, thus making it an attractive target for therapeutic intervention. Additionally, both treatments have shown promising potency and the potential to reduce treatment duration. These new players are likely to be on the market by late 2011 or early 2012, adding a new dimension to hepatitis C therapeutics.

Telaprevir is being developed by Vertex for treatment of patients with genotype 1 infection. The drug was granted fast track designation by the FDA in December 2005. Since then, telaprevir has been evaluated in three pivotal phase III trials that included more than 2,200 patients in the US and Europe. Two of these trials (ADVANCE and ILLUMINATE) were in treatment-naïve patients, while the third (REALIZE) was conducted in patients who experienced treatment failure. In the ADVANCE trial, telaprevir in combination with standard therapy showed a cure rate of approximately 70 per cent in comparison to 45 per cent with standard therapy alone, highlighting an immense potency. Additionally, the ILLUMINATE trial showed that the duration of treatment can be halved with the addition of telaprevir (from 48 to 24 weeks). Telaprevir also demonstrated compelling efficacy in patients who failed prior therapy in the REALIZE trial.

Although telaprevir was the first protease inhibitor to enter phase III development, Merck's boceprevir has been close behind. Boceprevir was granted fast track designation by the FDA in late January 2006, shortly after telaprevir. Phase III trials for boceprevir have shown promising results. In the SPRINT-2 trial, boceprevir showed a cure rate of 66 per cent for a longer duration, and 63 per cent for a shorter duration of treatment, among treatment-naïve patients with genotype 1 infection. In addition, the response-guided design of the trial confirmed that many patients could be treated successfully with a three-month reduction in treatment duration relative to standard therapy. The RESPOND-2 trial, in patients who did not respond or relapsed after standard therapy, also demonstrated higher sustained virological response with the addition of boceprevir.

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Winners and losers
Though the future of protease inhibitors as hepatitis C therapeutics looks bright, not all will be successful. Ciluprevir showed promising results in a phase II proof-of-concept trial but hit a major problem when concurrent testing of supratherapeutic levels in animals resulted in cardiac toxicity. It appears that Boehringer Ingelheim has ceased further development of this product. Telaprevir and boceprevir both have acceptable safety profiles relative to standard therapy, but safety concerns have been highlighted during development. In the ADVANCE trial, telaprevir was associated with a greater incidence of anaemia, rash, pruritus and nausea. Boceprevir was commonly associated with fatigue, nausea, anaemia and dysgeusia in the RESPOND-2 trial. The defining factors in the toxicity profile of these two treatments is the high incidence of rashes for telaprevir versus boceprevirs' notoriety for anaemia.

Competition between telaprevir and boceprevir is fierce with the FDA and the European Medicines Agency (EMA) granting Priority Review status to both therapies. The FDA target review date for telaprevir is due this month (May 2011), barely a few weeks ahead of boceprevir. Although there has not been a head-to-head comparison of the two therapies, telaprevir appears to be a little more efficacious than boceprevir. Physicians favour telaprevir over boceprevir for safety and convenience, but inThought Research panellists predict that managed care is likely to view both drugs as functionally equivalent. The shorter treatment duration (24 versus 36 weeks) is likely to be the swaying factor in favour of telaprevir as patient compliance to the standard two-drug regimen is already a major concern. Though telaprevir appears to have a slight upper hand, the panellists propose that Merck, which manufactures both peginterferon a-2b and ribavirin in addition to boceprevir, may promote the sale of all three agents as a bundle, in an attempt to level the playing field.

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The list of upcoming protease inhibitors also includes TMC 435, which is being jointly developed by Medivir and Johnson & Johnson. The PILLAR trial has shown TMC 435 to be both efficacious and well tolerated when administered in combination with standard therapy in treatment-naïve patients with genotype 1 infections. The drug is all set for evaluation with several phase III trials currently recruiting both treatment-naïve patients and those who have failed prior therapy. Johnson & Johnson expects to file a New Drug Application with the FDA for TMC 435 between 2011 and 2013. Roche is also stepping in with danoprevir, which is currently in phase II development and has shown potency against mutant hepatitis C strains.
An upcoming interferon product is albinterferon a-2b which was created by fusing the genes of interferon a and albumin, enabling a more convenient dosing schedule. The ACHIEVE trial demonstrated non-inferiority of albinterferon a-2b to peginterferon a-2a in treatment-naïve patients with genotype 2 or 3 infection. Though Novartis withdrew its Marketing Authorisation Application to the EMA in April 2010 due to time constraints in obtaining additional new data to support the application, albinterferon a-2b could be a major contender for peginterferon in the near future.

A contender for ribavirin is taribavirin, a guanosine nucleoside analogue. Although the VISER trials showed that taribavirin was inferior to ribavirin, the failure was attributed to suboptimal dosing. Results of a subsequent phase II trial have leant substance to this theory, indicating that taribavirin could replace ribavirin as a cornerstone in the treatment of hepatitis C, but with the advantage of less anaemia.
The next big advance in hepatitis C may be RNA polymerase inhibitors. The NS5B RNA polymerase is required for viral replication, presenting another strong target for therapeutic intervention. The FDA has granted fast track designation to two NS5B RNA polymerase inhibitors, RG 7128 and ANA 598. Both drugs are currently in phase II development. Data from the PROPEL trial, evaluating the addition of RG 7128 to standard therapy, has shown potent antiretroviral activity in patients with genotype 1 or 4 infections. Interim results from evaluation of ANA 598 in treatment-naïve patients with genotype 1 infections have also been positive, although differences from standard therapy alone were not significant.

Another drug of interest is miravirsen, the first of a new class of microRNA inhibitors. Currently in phase II development, it works by binding to its complementary sequence on a targeted microRNA to form a stable duplex that can then no longer bind to or regulate its functional target. The unique mechanism of action of miravirsen, its tolerability profile and its possible barrier to the generation of viral resistance means that it has the potential to replace interferon as a treatment for disease progression, or to be combined with current treatments.

Since the discovery of hepatitis C an immense amount of effort has been put into finding therapies. With the two peginterferon products standing at an impasse, it will be interesting to see which wins the race for approval between telaprevir and boceprevir. Though there are mixed opinions regarding the uptake of these drugs, there is little doubt that with such potency and shortened treatment duration, these drugs are well on the way to becoming the new standard of therapy.

The Author
R&D Pipeline was written by Kajal Naidu of Adis International (Wolters Kluwer Health Pharma Solutions), using data derived from Adis R&D Insight, Clinical Trials Insight and inThought. For information on Adis services, contact Kuljeet Sohanpal on +44 (0) 207 981 0714 or email: Kuljeet.Sohanpal@wolterskluwer.com
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