The HCV pipeline efficacy and side effect of compounds in Phase 3 studies
Simon Collins, HIV i-Base
Christoph Sarrazin from Goethe Hospital, Frankfurt presented an update on recent research relating to HCV treatment. 
The context for the importance of new HCV treatment for use in coinfection, is the urgent need for more effective therapies; less than 50% of currently treated patients achieve a sustained virological response (SVR), with up to 25% being non-responders and another 25% relapsing. Many more patients are excluded from treatment because of co-morbidities, contraindications to treatment or an individual choice to defer treatment based on the side effect profile of pegylated interferon plus ribavirin. These factors all underline the need for better treatment for HCV.
As with HIV, a broad understanding of the HCV life cyle has provided several targets for treatment, outlined in Table 1. Most antiviral pipeline compounds are either protease (NS3/4A), polymerase (NS5B nucleosides and non-nucleoside) or NS5A inhibitors, or they interact with host proteins or work via unknown mechanisms (silibinin, nitazoxanide etc). However, the development of many compounds have been stopped due to poor efficacy or tolerability, and most of those remaining are only in Phase 1 or 2 studies. Only two HCV antivirals are currently in Phase III studies, both of them protease inhibitors: telaprevir
(VX-950) and boceprevir (SCH-503034).
Table 1: HCV life cycle and target for drugs in pipeline
|Life cycle stage||Potential compound types||Compounds in development||Development stopped or
|Cell entry||Interaction with receptors via immunoglobulins or specific HCV antibodies||–||–|
|Protein synthesis||Inhibited by IRES inhibitors and
inhibitors interfering with translation factors
|Cleavage||NS2 and NS3 protease inhibitors and NS4A
|Phase 1: TMC435350; BMS-650032; PHX1766. Phase 2: ITMN 191/R7227; TMC-435350; BI201335; SCH900518 (narlaprevir); MK7009. Phase 3:
telaprevir (VX-950); boceprevir (SCH-503034).
|BILN 2061 (cardiac in monkeys); ACH-806 (Nephrotoxicity).|
|RNA replication||Helicase inhibitors, NS5A inhibitors, NS5B polymerase inhibitors, cyclophylin inhibitors, silibinin||NS5B inhibitors: Phase 1: VCH222; Phase
2: R7128; GS9190; ANA598; PF-00868554 (filibuvir); VCH916; ABT-333. Host protein/unknown: Phase 2: nitazoxanide; silibinin; Debio-025; NIM811;
|NS5B inhibitors: NM283 (GI toxicity); R1626 (GI toxicity included grade 4 and deaths); BILB1941 (GI toxicity); HCV796 (hepatic
toxicity); VCH759; VCH916. NS5A inhibitor: Phase 1: BMI700052.
Telaprevir and boceprevir were both highly active in early studies in HCV monoinfected, treatment-naive patients with HCV genotype-1, producing rapid viral load drops (approximately 4 logs and 2 logs,respectively) after 3 days of monotherapy. [2, 3]
However, only a minority of patients had continued declines over 14 days. As with HIV monotherapy, a single hepatitis C antiviral is not sufficiently potent to eliminate the virus or even maintain viral suppression. The rapid emergence of resistance around the active binding site (at codons V36, T54, R155 and A156) leads to reduced antiviral activity. The long-term clinical implications of HCV antiviral drug resistance are unknown.
When telaprevir was combined with PEG-IFN as dual therapy in a Phase 1 study, reductions of up to 7 logs were maintained for all patients at day 14, but the PROVE-2 Phase 2 trial showed that ribavirin also need to be included for sustained and durable responses. Notably, the triple combination reduced both duration of treatment (from 48 down to 12 weeks) and the risk of viral breakthrough to 3%. See Table 2. 
Table 2: Percentages of pts with undetectable HCV PCR (<10 IU/mL) in the PROVE study
|Wk 4||Wk 12||SVR (24 wk f/u)||% VL breakthrough|
|PEG-IFN + ribavirin (48wks)||13||43||46||–|
|telaprevir + PEG (12
|telaprevir + PEG + ribavirin (12 wks)||80||80||60||3%|
Roches INFORM-1 study provided an indication of the potential to combine new HCV drugs without the PEG-IFN plus ribavirin. INFORM-1 is a proof-of-principle study using a dual protease/polymerase inhibitor combination of R7227 plus R7128, presented at EASL in 2009 (5).
Treatment-naive patients in the higher dose arms had HCV viral load declines of -5 logs, with up to 30% achieving undetectable levels, and with no evidence of early viral breakthrough. At the 2009 AASLD meeting, INFORM-1 data from treatment experienced patients (relapsers, non-responders and null responders) were presented; the median HCV RNA drop was >4 log. 
These were exciting 14 day results, but results from longer-term results on efficacy, resistance and tolerability are now awaited. BMS has initiated a Phase 2 study combining 790052, an NS5a inhibitor plus BMS-650032,an HCV protease inhibitor, in null responders. These newest compounds are important for their activity against HCV genotype-1, currently the least responsive to PEG-IFN plus ribavirin. Both boceprevir and telapravir, however, have reduced activity against HCV genotpye-2 and virtually no activity against genotypes 3 and 4.
Adding boceprevir to the current standard of care in treatment-naive patients with genotpye-1 increased SVR response rates from approximately 40% to 56% at week 28 and to 75% at week 48 for the triple combination. 
Similar results were seen for telaprevir in the PROVE-1/2 studies, with SVR rates of 60-70% using only 12 weeks of triple therapy. [8, 4] In PROVE 3, SVR rates of approximately 70% and 40% were seen at 12 weeks in previous relapsers and non responders respectively, using telaprevir triple therapy, and this compared to SVR rates of 20% and 9% using PEG-IFN plus ribavirin. Rates in relapsers, but not non-responders, increased slightly when treated to 24-weeks, but relapse rates in both groups decreased with longer duration of treatment.
The preliminary nature of these studies – none of which are in people with HIV coinfection – has only provided limited tolerability data. However, discontinuation rates were 18% in first 12 weeks in the Phase 3 telaprevir studies, compared to around 4% using PEG-IFN plus ribavirin, indicating that poor tolerability remains an important limitation. Other common side effects occurred in 20-30% more patients, including nausea (~50% vs 30%), pruritis (~45% vs 23%), diahhroea (~40% vs 28%), rash (~60% vs 40%), moderate-severe rash (~25% vs 9%), vomiting (~24% vs 12%) and haemorrhoids (~ 15% vs 1%). [4, 8]
Many of the discontinuations were within the first four weeks, precluding the likelihood of a successful outcome from treatment, but later discontinuations were reported too, and as a result, future telaprevir studies will limit treatment to 8-12 weeks.
Boceprevir had a similar doubling of discontinuation rates in triple therapy compared to standard treatment arms: 15% vs 7% in patients using epoetin-alpha (EPO), and 38% vs 15% when EPO was not used. However, boceprevir had a comparable longer-term toxicity profile to dual PEG-IFN plus ribavirin therapy from week 24 to 48, allowing longer duration of treatment. Anaemia rates were higher (approximately 60% vs 34%), neutropenia (17-30% vs 12%; especially grade-2), vomiting (17-44% vs 5%) and taste changes (20-44% vs 9%) in the boceprevir groups. 
Very limited data on protease inhibitors in Phase 1-2 studies suggests specific side effects from these drugs; gastrointestinal complications and, for BI201335, jaundice relating to increased unconjugated bilirubin (16%) and severe rash (2.5%). Polymerase inhibitors include heterogeneous reports of nausea, neutropenia, headache, diarrhoea, dizzyness (for nukes) and generalised erythema, mild rash, headache and fatigue (for non-nukes).
Both boceprevir and telaprevir require dosing three times a day (every eight hours with food). However, SCH900518 (narlaprevir) which is also dosed TID has been studied twice-daily with QD 100mg ritonavir boosting, suggesting a similar potential for boosting HCV protease inhibitors, as with some PIs used to treat HIV. Preliminary response rates look similar to boceprevir and telaprevir, perhaps with reduced discontinuations. Studies of the Roche compound R7227 are also planned using ritonavir boosting.
These preliminary results in HCV monoinfection, especially for relapsers and non-responders with genotype-1, are exciting and encouraging.
They also highlight the importance of studying promising new HCV compounds in HIV/HCV coinfected patients.
- Sarrazin C. New antiviral drugs against HCV adverse event profiles and pharmacokinetic interactions. 11th Intl Workshop on Adverse Drug Reactions. 26-28 October 2009, Philadelphia. Session 1 plenary. Webcast available online.
- Reesink HW et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomised study. Gastroenterology 2006;131:997-1002.
- Zeusem et al. Hepatology, 2005.
- Hezode et al. Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection. NEJM, Volume 360 (18):1839-1850. 30 April 2009.
- Gane et al. First-in-man demonstration of potent antiviral activity with a nucleoside polymerase (R7128) and protease (R7227/ITMN-191) inhibitor combination in HCV: safety, pharmacokinetics, and virologic results from INFORM-1. 44th Annual Meeting of the European Association for the Study of the Liver (EASL). 23-26 April 2009, Copenhagen. Late-breaker abstract 1046.
- Gane et al. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, Massachusetts. 30 October 3 November 2009. Abstract 193.
- Kwo P et al. HCV SPRINT-1 final results: SVR 24 from a Phase 2 study of boceprevir plus pegIntron (Peginterferon alfa-2b)/ribavirin in treatment-naive subjects with genotype 1 chronic hepatitis C. 44th European Association for the Study of the Liver (EASL). 23-26 April 2009, Copenhagen. Oral abstract 4.
- McHutchinson et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. NEJM, Volume 360 (18):1827-1838. 30 April 2009