The consequences of acquiring HCV drug resistance are currently unknown; it may be a transient phenomenon since HCV does not integrate into the host cell's genome. But it is possible that mutations may confer resistance to an agent -- or an entire class of agents. Drug-resistant HCV may be less fit, but a lower replication capacity will be a scant consolation for people who have acquired a treatment-resistant virus (Mo 2005; Zhou 2007). Studies of people who have developed resistance to HCV antivirals should be performed in order to fully understand the clinical implications of HCV drug resistance.
As with HIV, hepatitis C treatment requires a combination of drugs that target different steps in the replication cycle. Sponsors will need to collaborate on multi-agent trials to identify and optimize treatment strategies. Unfortunately, we must wait until there are enough drugs at similar stages of development, while pushing to facilitate these studies through dialogues with industry, researchers, and regulators.
BILN-2061, an HCV protease inhibitor from Boehringer Ingleheim, was the first of its class. Although BILN-2061 was discontinued due to cardiotoxicity in animals, proof of concept was established (Lamarre 2003). Since then, there have been high hopes for HCV protease inhibitors, and several are in clinical development. So far, all have been studied in people with HCV genotype 1. Telaprevir, an HCV protease inhibitor being co-developed by Vertex and Tibotec, is also being studied in people with genotypes 2, 3, and 4 in trials outside of the U.S.
|BI 12202*||Boehringer Ingleheim||Phase I|
|Boceprevir (SCH 503034)||Schering Plough||Phase II|
|ITMN-191 (R7227)||Intermune/Roche||Phase Ib|
|Telaprevir (VX-950)||Vertex||Phase III|
|TMC 435350||Medivir/Tibotec||Phase II|
Boehringer Ingleheim has not released information about their HCV protease inhibitor candidate.
Schering has conducted a pair of phase II studies of boceprevir, their HCV protease inhibitor. Their dose-finding study assessed safety and efficacy of 100, 200, and 400 mg/TID (three times daily), plus pegylated interferon, with or without ribavirin, in non-responders with HCV genotype 1. African Americans were initially excluded from this study, until an additional, higher-dose arm (boceprevir 800 mg/TID) was added. The company permitted 15 African Americans to enroll in the higher-dose arm, due in part to community outrage.
The protocol was subsequently amended, when concerns about lack of response in the low-dose arms led the Data and Safety Monitoring Board (DSMB) to recommend that all virological responders be given the 800 mg dose plus ribavirin.
Schering is also studying safety and efficacy of boceprevir plus pegylated interferon and ribavirin in treatment-naive people with HCV genotype 1 in an ongoing trial. HCV SPRINT-1 (Serine Protease Inhibitor Therapy-1) is a seven-arm study, evaluating 800 mg of boceprevir TID. Notably, participants in two arms of HCV SPRINT-1 are receiving a lower-than-usual dose of ribavirin (400-1,000 mg/day, rather than 800-1,400 mg/day according to weight).
In October 2007, Schering issued a press release announcing the top-line results of their non-responder study, and interim results from HCV SPRINT-1, the treatment-naive trial. More details are expected at the European Association for the Study of the Liver (EASL) meeting in April 2008. Until then, a hodgepodge of regimens, doses, and treatment durations make it difficult to interpret the results, which ranged from 7% to 14% SVR in the boceprevir arms, versus 2% of those in the control arm (who were re-treated with pegylated interferon and ribavirin). Headache, nausea, fatigue, and anemia were the most commonly reported adverse events.
Interim results from HCV SPRINT-1, the treatment-naive study, are promising. The early virological response rates (EVR; see Terms for Response to HCV Treatment, page 34) ranged from 54% to 79% in the boceprevir arms, vs. 34% in the control arm (pegylated interferon plus ribavirin). Adverse events were the same as those in the non-responders study: fatigue, headache, nausea, and anemia. Discontinuation rates were higher in the boceprevir arms, ranging from 8% to 12%, versus 5% in the control arm.
Schering is planning to launch phase III studies in the near future.
Intermune and Roche are co-developing ITMN-191 (also referred to as R7227), an HCV protease inhibitor. Their ongoing phase Ib study is evaluating safety, pharmacokinetics, and activity of ITMN-191 in people with HCV genotype 1. The drug will be studied in treatment-naive people initially, then in the treatment-experienced. A 14-day trial, combining ITMN-191 with pegylated interferon and ribavirin, is planned for the second quarter of 2008.
Merck is conducting a safety and efficacy study with a range of doses of MK-7009 in 145 people with HCV genotype 1, both treatment-naive and treatment-experienced. Study completion is expected by November 2008.
Vertex has studied different durations of treatment with their HCV protease inhibitor, telaprevir, plus pegylated interferon, with or without ribavirin. Given the nasty side-effects profile of the background regimen, Vertex is hoping that adding telaprevir will shorten the course of treatment and increase efficacy, to counterbalance additional toxicity. The cornerstone of their development program has been to use telaprevir as briefly as possible, and to eliminate or abbreviate the subsequent course of pegylated interferon and ribavirin.
There have been disturbing reports of a telaprevir-associated rash, severe enough in some cases to warrant hospitalization and/or discontinuation of treatment. Hopefully, the company will issue guidance on rash management as they roll out their phase III program, which is slated to begin in March 2008.
PROVE 1, 2, and 3, Vertex's phase II trials, are fully enrolled. PROVE 1 and 2 are studying different durations of telaprevir-based treatment vs. the standard of care in treatment-naive persons with HCV genotype 1. PROVE 3 is studying 24 to 48 weeks of telaprevir-based regimens vs. the standard of care in treatment-experienced persons with HCV genotype 1.
Interim results from PROVE 1 and PROVE 2 were announced in November 2007 at the meeting of the American Association for the Study of Liver Diseases (AASLD).
Figure 2. PROVE 1 Study Design (United States)
In PROVE 1, the rapid virological response (RVR; see Terms for Response to HCV Treatment, page 34) guided duration of treatment; therapy was stopped at week 12 or week 24 only for those participants with an RVR. Overall, 18% of study participants in the telaprevir arms discontinued treatment, 13% for adverse events (telaprevir-associated rash was the most common reason) versus an overall rate of 3% in the control arm (2% for adverse events). Itchy skin, rash, gastrointestinal problems, and anemia occurred more frequently among participants who received telaprevir (Jacobson 2007).
Table 3. PROVE 1: Interim Results by Intent-To-Treat Analysis
|Regimen and N||RVR undetectable* HCV RNA at week 4; data pooled from all TPV arms||Interim results|
|Arm A (N=17) TVR + PEG-IFN + RBV for 12 weeks|
|Arm B (N=79) TVR + PEG-IFN + RBV 12 weeks, followed by PEG-IFN + RBV for 12 weeks|
|Arm C (N=79) TVR + PEG-IFN + RBV for 12 weeks, followed by PEG-IFN + RBV for 36 weeks|
|65% undetectable at end of treatment; SVR not yet available|
|Arm D -- Control (N=75)|
PEG-IFN + RBV + TVR placebo for 48 weeks
|45% undetectable at end of treatment; SVR not yet available|
Jacobson IM, Everson GT, Gordon SG, et al. (abstract 177) Interim analysis results from a phase II study of telaprevir with peginterferon alfa-2a and ribavirin in treatment-naive subjects with hepatitis C. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
Figure 3. PROVE 2 Study Design (Europe)
Interim results from PROVE 2 (see Table 4. PROVE 2: Interim Results by Intent-to-Treat Analysis, page 19) emphasize the importance of ribavirin for preventing viral breakthrough. Only 1% to 2% of people who received ribavirin had a breakthrough during treatment (defined as either a >1-log increase in HCV RNA from the nadir, or an HCV RNA of >100 after becoming undetectable), whereas viral breakthrough occurred in 24% of the no-ribavirin arm.
Table 4. PROVE 2: Interim Results by Intent-To-Treat Analysis
|Regimen and N||Undetectable* at week 4||Undetectable* at week 12||Discontinued Tx by week 12||Interim results|
|Arm A (N=82)|
TVR + PEG-IFN + RBV for 12 weeks
|Arm B (N=78)|
TVR + PEG-IFN (no RBV) for 12 weeks
|Arm C (N=81)|
TVR + PEG-IFN + RBV for 12 weeks, followed by PEG-IFN + RBV for 12 weeks
|SVR 12: 65% (undetectable 12 weeks after Tx completion)|
|Arm D -- Control (N=82)|
PEG-IFN + RBV + TVR placebo for 48 weeks
Hezode C, Ferenci P, Dusheiko G, et al. (abstract 80) Prove-2: Phase II study of VX-950 (telaprevir) in combination with peginterferon with or without ribavirin in subjects with chronic hepatitis C, first interim analysis. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
There was a greater incidence of rash, both overall and grade 3, in the telaprevir arms. Although the rash resolved when the drug was stopped, it was severe enough that 3% of the no-ribavirin arm and 7% of the people in the 12- and 24-week arms discontinued treatment. There was a greater incidence of decreased hemoglobin and anemia in the telaprevir arms, especially when combined with ribavirin (Grade 1, 35%; Grade 2, 18%, Grade 3/4, 3%). Gastrointestinal side effects occurred more frequently in the telaprevir arms (Hezode 2007).
Although these results are impressive, given the abbreviated treatment duration, it is important to note that a majority (65.74%) of study volunteers had minimal liver fibrosis (METAVIR of <F2), which may have contributed to the high response rates. Other favorable characteristics may have boosted response rates, such as a low median body mass index (BMI), ranging from 68 to 73 across treatment arms, a high proportion (~40%) of female participants, and an almost exclusively White population (93.99%).
Figure 4. PROVE 3 Study Design
Re-treatment options for people who did not respond to pegylated interferon and ribavirin are currently limited to torturous strategies, such as extending treatment with the current standard of care, and doubling doses (see Table 2. Re-treatment Trials in Non-Responders to PEG-IFN and Ribavirin: Strategies and SVR).
Unfortunately, PROVE 3 will add a single new drug to a previously unsuccessful regimen. At best, this strategy will yield a higher rate of SVR in people who did not respond to re-treatment with pegylated interferon-based regimens. Hopefully, study participants will not be left with drug resistance that limits their future treatment options. If SVR from a telaprevir-based re-treatment regimen surpasses 16% (the highest response to re-treatment of non-responders to pegylated interferon and ribavirin; see Table 2. Re-treatment Trials in Non-Responders to at Least 12 Weeks of PEG-IFN and Ribavirin: Strategies and SVR), Vertex may seek an indication for use in this population. Unless the results are truly impressive, treatment-experienced people should consider waiting -- if possible -- until telaprevir can be paired with at least one additional new drug to increase the chance of SVR.
Interim data from PROVE 3 are expected in May 2008; final data will follow a year later.
Meanwhile, Tibotec, Vertex's European development partner, is also conducting a portfolio of phase II studies of telaprevir in people with genotypes 2, 3, and 4, and different dosing schedules of telaprevir (every 8 hours, versus every 12 hours) in treatment-naive people with HCV genotype 1.
In January of 2008, Vertex announced the phase III development plan for telaprevir. In the first quarter of 2008, they will begin enrolling 1,050 treatment-naive people who have HCV genotype 1 in ADVANCE, an international, three-arm trial (see Figure 5. Telaprevir Phase III Trial Design). An additional study will be looking at SVR after 48 weeks of treatment in approximately 400 to 500 people. Final data are expected in 2010, and the company is hoping for FDA approval, for an indication in treatment-naive people, by 2011.
Tibotec and Medivir are co-developing TMC 435350, which has entered phase II. In Europe, TMC 435350 is being studied in both treatment-naive and treatment-experienced people with hepatitis C genotype 1. This trial is evaluating a seven-day lead-in with different doses of TMC 435350 or placebo, with or without pegylated interferon and ribavirin. The lead-in is followed by 21 days of triple-therapy with TMC 455350 plus pegylated interferon and ribavirin. Participants will subsequently receive 24 or 48 weeks of standard-of-care treatment, according to early treatment response (see Terms for Response to Treatment).
There are two distinct classes of hepatitis C polymerase inhibitors -- nucleosides and non-nucleosides. Each inhibits HCV replication by a different mechanism; nucleosides are chain terminators, while non-nucleosides cause conformational change. Polymerase inhibitors may have activity across HCV genotypes; they hold great promise, but their Achilles heel is toxicity, which has led to the discontinuation of more than one candidate.
|GS 9190||Gilead||Phase I|
|VCH-759||Virochem||Phase II completed|
Gilead has conducted a phase I study of their non-nucleoside polymerase inhibitor, GS 9190, in people with HCV genotype 1. They reported that HCV RNA decreased by more than one log after a single dose, and by almost 2 logs after 8 days of the 120 mg dose (Bavisotto 2007); however, a safety issue emerged: QT prolongation (an abnormality in the heart's rhythm), which may cause fainting, and -- in rare cases -- sudden death from cardiac arrhythmia. After expert consultation and a separate dose-ranging study in healthy volunteers, the company said that QT prolongation at a lower dose of the drug was "... clinically manageable." Gilead plans to resume development of GS 9190.
An ongoing phase I study is evaluating safety, pharmacokinetics, activity, and tolerability of GSK625433 in healthy volunteers and people with hepatitis C.
Pfizer is conducting a phase I study of safety, tolerability, pharmacokinetics, and pharmacodynamics of different doses (100, 300, or 450 mg/BID [twice daily] and 300 mg/ TID [three times daily] of PF-00868554) in people with HCV genotype 1.
Roche's HCV nucleoside polymerase inhibitor, R1626, is currently being studied in people with HCV genotype 1. No resistance was detected in study volunteers who received the drug for two weeks by itself, or after four weeks of combination treatment with pegylated interferon and ribavirin (Le Pogam 2007). Although the drug is effective (see Table 5. Week 4 Results from a Phase IIa Study of R1626 plus Pegylated Interferon, With or Without Ribavirin, vs. Standard of Care), a serious safety issue emerged: grade 4 (severe or life-threatening) neutropenia, which occurred more often in the R1626 arms (Pokros 2007 b). Roche is conducting a phase IIb study with R1626 (500, 1,000, or 1,500 mg/day), and 90 or 180µg of pegylated interferon plus weight-based ribavirin, hoping to identify a safe and effective regimen.
|Study Arm and N||RVR|
HCV RNA undetectable at week 4
|Incidence of grade 4 neutropenia|
|Dual Low (N=21)|
R1626 1500mg/day + 180µg PEG-IFN
|Dual High (N=32)|
R1626 3000mg/day + 180µg PEG-IFN
|Triple Low (N=31)|
R1626 1500mg/day + 180µg PEG-IFN & RBV
|Standard of Care (N=20)|
180µg PEG-IFN & RBV
Pokros P, Nelson D, Godofsky E, et al. (abstract 67) Robust synergistic antiviral effect of R1626 in combination with peginterferon alfa-2a (40KD), with or without ribavirin.interim analysis Results of Phase 2a study. 58th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA. November 2-6, 2007.
R7128 is a nucleoside polymerase inhibitor being co-developed by Roche and Pharmasset. They have initiated a phase I trial in healthy volunteers, moving on to dosing in treatment-experienced people with HCV genotype 1. After 14 days of monotherapy with 1,500 mg of R7128, there were reductions in HCV RNA ranging from 1.2 log to 4.2 log (mean of 2.7 log). So far, no serious adverse events have been reported. The most commonly reported side effects were headache and dry mouth (McHutchison 2007). Hopefully, there will be no emergent toxicities as development of R7128 moves forward.
Safety, tolerability, pharmacokinetics, and activity of VCH-759 were evaluated in 32 treatment-naive people with HCV genotype 1. HCV RNA decreased by more than 1 log regardless of dose, and by more than 2 logs in people who received 800 mg twice or three times per day. There were no serious adverse events or discontinuations during this ten-day study; the most commonly reported side effects were gastrointestinal in nature (Cooper 2007). VCH-759 is currently in phase IIa.