| |
New therapies for hepatitis C: VX-950 (telaprevir)
|
| |
| |
Hepatology Sept 2007
Apurva A. Modi, M.D., Jay H. Hoofnagle, M.D. *
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
No challenge in clinical hepatology is as great today as the management of patients with chronic hepatitis C who have failed to respond to an adequate course of antiviral therapy. At present, the optimal regimen is a combination of peginterferon and ribavirin.[1] When given for 24 or 48 weeks, this combination results in a sustained eradication of hepatitis C virus (HCV) and a long-term remission of the disease in at least 75% of patients with genotype 2 or 3 HCV infection and in 40%-50% of those with genotype 1.[2][3] Although impressive, these sustained virological response (SVR) rates leave as many as half of patients without benefit and with no means of ameliorating the subsequent course of the disease. Despite the importance of chronic hepatitis C (the leading cause of end-stage liver disease and need for liver transplantation in the Western world) and the intensity of the research on this viral infection, there have been no further improvements in response rates to therapy in many years. When will this change?
In this issue of HEPATOLOGY, two original articles provide exciting new results on a novel orally available antiviral agent that has potent effects against HCV in vitro and in vivo.[4][5] VX-950, now known as telaprevir, is a peptide-mimetic drug that was developed with structure-based drug design.[6] Telaprevir is a specific, reversible inhibitor of the HCV genotype 1 serine protease encoded by the nonstructural 3 and 4A region of the viral genome. This protease is essential for HCV replication,[7] and its inhibition in cell culture systems results in marked suppression of viral replication.[6][7] In humans, telaprevir is orally available and causes a rapid and marked decrease in serum HCV RNA levels.[8] In phase Ia studies using various doses and schedules, a dose of 750 mg of telaprevir given every 8 hours resulted in rapid 3-5 log10 decreases in serum HCV RNA levels in virtually all patients. Stopping therapy at 2 weeks led to a rapid return of HCV RNA to the pretreatment levels. These results suggest that longer term therapy might lead to the eradication of the virus in a high proportion of patients.
However, even before the application of VX-950 to humans, the specter of antiviral drug resistance was raised. In replicon cell culture systems, the application of VX-950 was found to select for HCV variants with drug resistance.[9] Similar kinetics for the development of antiviral resistance were found for other inhibitors of the nonstructural 3 protease, although these variants had different specific mutations and mechanisms of resistance. These findings indicated that the long-term use of HCV protease inhibitors would probably require a combination therapy with other protease inhibitors, HCV polymerase inhibitors, or perhaps peginterferon with or without ribavirin. It was the last combination that was eventually pursued.
In this issue of HEPATOLOGY, Forestier and her coinvestigators[4] from Saarland University Hospital, the University of Amsterdam, and Vertex Pharmaceutics describe the preliminary clinical results of a small phase Ib trial of telaprevir.[4] The report provides information on HCV RNA and alanine aminotransferase levels in 8 patients who received telaprevir alone, 8 who received telaprevir with peginterferon, and 4 who served as controls and received peginterferon alone for 2 weeks. Telaprevir was then stopped, but the patients were offered a continuation of treatment with a combination of peginterferon and ribavirin until 48 weeks and thus were provided the standard of care for chronic hepatitis C, genotype 1. Telaprevir led to a rapid decline in HCV RNA levels within 1-4 days. The combination of peginterferon with telaprevir resulted in a similar early decline in viral levels, but importantly, the combination therapy was associated with an additional, continuing decline after the first 4 days of treatment. At 14 days, the median decrease in HCV RNA was 5.5 log10 with telaprevir and peginterferon, 4.0 log10 with telaprevir alone, and only 1.1 log10 with peginterferon. These results suggest that peginterferon and telaprevir are synergistic (or at least additive) in their antiviral activity against HCV, and this finding is supported by cell culture results.[10]
The basis for the synergy between peginterferon and telaprevir is suggested by the second article in this issue on telaprevir by Kieffer and coworkers[5] from Vertex Pharmaceuticals and the Johann Wolfgang von Goethe University Hospital at Frankfurt, who investigated variations in the nonstructural 3 and 4A sequence of HCV from patients in this same phase Ib trial. HCV sequence variants with lower sensitivity to telaprevir arose in a high proportion of patients within 10-14 days of the initiation of therapy. However, the telaprevir-resistant variants of HCV appeared to be sensitive to interferon, and the subsequent treatment with peginterferon and ribavirin was associated with further decreases in HCV RNA and a lack of further detection of the viral variants. Thus, the apparent synergy of peginterferon and telaprevir may be due to the sensitivity of the low levels of telaprevir-resistant viral variants to interferon. Consequently, a short course of telaprevir followed by peginterferon and ribavirin may be highly effective, the protease inhibitor lowering HCV RNA to levels that are readily susceptible to peginterferon.
Although this is a promising approach, only limited information has been provided on its success. Forestier et al.[4] report 12-week follow-up results and Kieffer et al.[5] report 24-week follow-up results for the subsequent course of the 15 telaprevir-treated patients who were then treated with peginterferon and ribavirin. HCV RNA was undetectable (<10 IU/mL) in all patients at 12 weeks and in all but 1 at 24 weeks. No information is given on the results at 48 week or on the SVR results at 72 weeks, which, in view of the time of initiation of the study, should now be available.
In the meantime, a phase II trial of telaprevir in chronic hepatitis C, genotype 1, has been initiated, and early but still incomplete results were presented as a late-breaking abstract at the annual meeting of the European Association for the Study of the Liver.[11] In this second trial, telaprevir was given for 12 weeks in combination with peginterferon and ribavirin and compared with therapy with peginterferon and ribavirin alone. Patients who received triple therapy for 12 weeks stopped telaprevir and were then randomized to (1) stop all therapy at 12 weeks, (2) continue peginterferon and ribavirin for another 12 weeks (total duration = 24 weeks), or (3) continue peginterferon and ribavirin for another 36 weeks (total duration = 48 weeks). The 3 telaprevir-combination arms were compared to the standard of care: a 48-week course of peginterferon and ribavirin alone. Preliminary results indicated that 70% of the patients given triple therapy had no detectable HCV RNA (<10 IU/mL) at 12 weeks versus only 39% of the patients given the conventional combination therapy. When all therapy was stopped at 12 weeks in 1 arm of the study, relapses occurred, but there was inadequate follow-up to provide a reliable rate of SVR. The remaining categories of telaprevir-treated patients are still receiving peginterferon and ribavirin or are in active follow-up. These findings suggest that a 12-week course of triple therapy may not be adequate.
We now await studies in which triple therapy is given for a full 24 or 48 weeks, but until then, issues of safety and the success of abbreviated therapy will need to be addressed. Early results of the preliminary trials of telaprevir indicate a possible problem of tolerability. In the 2-week phase Ib trial, 25% of the patients developed a mild or moderate rash, but none required early discontinuation of treatment.[4] In the 12-week phase II trial, a higher proportion of patients receiving telaprevir developed a rash that led to early discontinuation for some.[11] The cause of the rash has not been elucidated.
Thus, telaprevir is a promising agent but still must pass the critical tests of ultimate efficacy and safety. If all goes well, phase III trials should begin within the next 1-2 years, and this means that new therapies for hepatitis C are at least 3 years away (2010 or beyond) from general availability. What else is available or might become available sooner?
Other approaches to the therapy of chronic hepatitis C include modifications of the dose and duration of combination therapy. The use of modified or improved interferons (such as consensus interferon, albumin-labeled interferon,[12] or omega interferon[13]) may be helpful, but they are unlikely to improve SVR rates to a great extent. Modified or improved forms of ribavirin include a prodrug, viramidine, which is now known as taribavirin.[14] Taribavirin has promise as a better tolerated form of ribavirin, but recent results indicate that it is less effective in increasing SVR rates.[15] Higher doses of ribavirin (1400-2400 rather than 800-1200 mg daily) have been studied in small clinical trials and appear to yield higher rates of SVR, but at the expense of much more toxicity (anemia requiring growth factor support and blood transfusions).[16]
Perhaps more promising are the many other small-molecule inhibitors of HCV that are currently in human trials, which include polymerase inhibitors (NM283, HCV-796 [RECENTLY DISCONTINUED STUDY DUE TO TOXICITY], and R1626) and protease inhibitors (BILN-2061, SCH503034, and SL196).[17-19] BILN-2061 was the first HCV-specific protease inhibitor to be assessed in humans, and preliminary studies showed great promise with marked activity against HCV genotype 1.[19] Unfortunately, toxicities were identified in laboratory animals receiving BILN-2061, and further development was abandoned. Another promising agent is NM283 (RECENTLY DISCONTINUED DUE TO TOXICITY), now known as valopicitabine, which is a cytidine analogue and RNA chain terminator.[20] Preliminary studies showed that valopicitabine had variable activity against HCV, but a high rate of gastrointestinal intolerance was found at the most potent doses. Unfortunately, in phase II studies of valopicitabine in combination with peginterferon, this regimen was less effective than the standard combination therapy and was ineffective in peginterferon/ribavirin nonresponders.[21][22] Finally, there are multiple innovative and molecular approaches to therapy, including the use of alpha-glucosidase inhibitors, modified cyclophilins, viral entry inhibitors, antisense molecules, ribozymes, and small interfering RNAs.[17] These approaches need major refinements and further assessments for safety before efficacy trials can be initiated.
The vicissitudes of the development of new agents for the therapy of hepatitis C are distressing but typical for new drug development. For every 10 new therapeutic agents that enter human trials, only 1 or 2 are likely to survive the careful scrutiny for efficacy and lack of toxicity. The 2 publications on telaprevir provide hope for the future. For the next 3-5 years, however, the combination of peginterferon and ribavirin is likely to remain the recommended regimen for the treatment of hepatitis C, and future optimal therapies of hepatitis C may employ 3 or 4 agents together rather than a simple regimen of 1 or 2.
References
1 Hoofnagle JH, Seeff LB. Peginterferon and ribavirin therapy of hepatitis C. N Engl J Med 2006; 355: 2444-2451. Links
2 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982. Links
3 Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet 2001; 358: 958-965. Links
4 Forestier N, Reesink H, Weeink C, McNair L, Kieffer T, Chu H-M, et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. HEPATOLOGY 2007; 46.doi: 10.1002/hep.21774. Links
5 Kieffer T, Sarrazin C, Miller J, Welker M, Forestier NJ, Kwong A, et al. Telaprevir and pegylated interferon-alfa-2a inhibit wild-type and resistant genotype 1 HCV replication in patients. HEPATOLOGY 2007; 46.doi: 10.1002/hep.21781. Links
6 Lin C, Kwong AD, Perni RB. Discovery and development of VX-950, a novel, covalent, and reversible inhibitor of hepatitis C virus NS3.4A serine protease. Infect Disord Drug Targets 2006; 6: 3-16. Links
7 Bartenschlager R, Ahlborn-Laake L, Mous J, Jacobsen H. Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for the cleavage at the NS3/4 and NS4/5 junctions. J Virol 1993; 67: 3835-3844. Links
8 Reesink HW, Zeuzem S, Weegink CJ, Forestier N, Van Vliet A, Van de Wetering de Rooij J, et al. Rapid decline in viral RNA in hepatitis C patients treated with VX-950: a phase 1b, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997-1002. Links
9 Lin C, Lin K, Luong YP, Rao BG, Wei YY, Brennan DL, et al. In vitro resistance studies of hepatitis C virus serine protease inhibitors, VX-950 and BILN 2061: structural analysis indicates different resistance mechanisms. J Biol Chem 2004; 279: 17508-17514. Links
10 Lin K, Kwong AD, Lin C. Combination of a hepatitis C virus NS3-NS4A protease inhibitor and alpha interferon synergistically inhibits viral RNA replication and facilitates viral RNA clearance in replicon cells. Antimicrob Agents Chemother 2004; 48: 4784-4792. Links
11 McHutchison JG, Everson GT, Gordon S, Jacobson I, Kauffman R, McNair L, et al. Results of an interim analysis of a phase 2 study of telaprevir (VX-950) with peginterferon alfa-2a and ribavirin in previously untreated subjects with hepatitis C [Abstract]. Available at: http://www.easl.ch/easl2007/Program/search.asp.
12 Bain VG, Kaita KD, Yoshida EM, Swain MG, Heathcote EJ, Neumann AU, et al. A phase 2 study to evaluate the antiviral activity, safety, and pharmacokinetics of recombinant human albumin-interferon alfa fusion protein in genotype 1 chronic hepatitis C patients. J Hepatol 2006; 44: 671-678. Links
13 Novozhenov V, Zakharova N, Vinogradova E, Nikitin I, Gorbakov V, Yakovlev A, et al. Phase 2 study of omega interferon alone or in combination with ribavirin in interferon-naive subjects with genotype-1 chronic hepatitis C [Abstract]. Gastroenterology 2007; 132(Suppl 2): A778. Links
14 Aora S, Xu C, Teng A, Peterson J, Yeh LT, Gish R, et al. Ascending multiple-dose pharmacokinetics of viramidine, a prodrug of ribavirin, in adult subjects with compensated hepatitis C infection. J Clin Pharmacol 2005; 45: 275-285. Links
15 Marcellin P, Lurie Y, Rodrigues-Torres M, Chasen R, Xu Y, Murphy B. The safety and efficacy of taribavirin plus pegylated interferon alfa-2a versus ribavirin plus pegylated interferon alfa-2a in therapy-naive patients infected with HCV: phase 3 results [Abstract]. J Hepatol 2007; 46(Suppl 1): S7. Links
16 Lindahl K, Stahle L, Bruchfeld A, Schvarcz R. High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. HEPATOLOGY 2005; 41: 275-279. Links
17 McHutchison JG, Bartenschlager R, Patel K, Pawlotsky J-M. The face of future hepatitis C antiviral drug development: recent biological and virologic advances and their translation to drug development and clinical practice. J Hepatol 2006; 44: 411-421. Links
18 Sarrazin C, Rouzier R, Wagner F, Forestier N, Larrey D, Gupta SK, et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon -2b for genotype 1 nonresponders. Gastroenterology 2007; 132: 1270-1278. Links
19 Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 2003; 426: 186-189. Links
20 Pierra C, Amador A, Benzaria S, Cretton-Scott E, D'Amours M, Mao J, et al. Synthesis and pharmacokinetics of valopicitabine (NM283), an efficient prodrug of the potent anti-HCV agent 2C-methylcytidine. J Med Chem 2006; 49: 6614-6620. Links
21 Lawitz E, Nguyen T, Younes Z, Santoro J, Gitlin N, McEniry D, et al. Clearance of HCV RNA with valopicitabine (NM283) plus peginterferon in treatment-naive patients with HCV-1 infection: results at 24 and 48 weeks [Abstract]. J Hepatol 2007; 46(Suppl 1): S9. Links
22 Afdhal N, O'Brien C, Godofsky E, Rodriguez-Torres M, Pappas S, Lawitz E, et al. Valopicitabine (NM283), alone or with peginterferon, compared to peginterferon/ribavirin retreatment in patients with HCV-1 infection and prior non-response to peginterferon/ribavirin: final results [Abstract]. J Hepatol 2007; 46(Suppl 1): S5. Links
|
|
| |
| |
|
|
|
