Alimentary Pharmacology & Therapeutics
`
`Review article: investigational agents for chronic hepatitis C
`A. J. V. THOMPSON & J. G. MCHUTCHISON
`
`
`Division of Gastroenterology/
`Hepatology, Duke Clinical Research
`Institute, Duke University, Durham,
`NC, USA
`
`Correspondence to:
`Dr J. G. MeHutchison, Department of
`Medicine, Duke Clinical Research
`Institute, 2400 Pratt Street, Room
`0311 - Terrace Level, Durham, NC
`27715, USA.
`E-mail: mchut001@me.duke.edu
`
`Publication data
`Submitted 27 October 2008
`First decision 10 November 2008
`Resubmitted 19 December 2008
`Accepted 21 December 2008
`Epub Accepted Article 17 January
`2009
`
`SUMMARY
`
`Background
`The need for effective treatment for chronic hepatitis C infection has
`driven the development of novel antiviral agents that target specific
`steps in the viral replication cycle.
`
`Aim
`
`To evaluate the current literature concerning investigational agents for
`chronic hepatitis C virus infection.
`
`Methods
`
`Resources used included PubMed, conference proceedings from the
`American and European Liver Associations’ meetings 2005-2008 and
`the National
`Institute of Health’s clinical
`trials website (http://www.
`clinicaltrials.gov). The focus wasrestricted to investigational agents that
`have progressed beyond preclinical development.
`
`Results
`
`Over 50 investigational agents for chronic hepatitis C infection are cur-
`rently in clinical development. Specifically targeted anti-viral
`therapy
`for HCV (STAT-C) shows great promise with NS3/4a protease inhibitors
`now entering phase 3 programmes. New interferon-« and ribavirin for-
`mulations aim to optimize anti-viral efficacy yet limit toxicity. Other
`candidates include novel immunomodulators and therapeutic vaccines.
`
`Conclusions
`
`A new era of therapy for chronic hepatitis C beckons, promising
`increased cure rates with shortened duration of therapy. However, the
`era will not be without challenges including viral resistance, drug toxic-
`ity and the need to optimize combination therapy in the face of a rap-
`idly evolving therapeutic arsenal.
`
`Aliment Pharmacol Ther 29, 689-705
`
`©2009 Blackwell Publishing Ltd
`doi:10.1111/).1365-2036.2009.03927.x
`
`689
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`GILEAD08924889
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`GIL2016
`I-MAK, INC. V GILEAD PHARMASSETLLC
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`GIL2016
`I-MAK, INC. V GILEAD PHARMASSET LLC
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`

`

`690 A. J. V. THOMPSON and J. G. McHUTCHISON
`
`INTRODUCTION
`
`infection affects 170
`Chronic hepatitis C virus (HCV)
`million people worldwide.'
`It is estimated that 20%of
`HCV-infected patients will develop cirrhosis, with the
`associated risks of developing liver failure and/or liver
`cancer.” Chronic hepatitis C (CHC) is the leading cause
`of death from liver disease and the most common
`indication for liver transplantation in the US? (UNOS
`database, http://www.optn.org/latestData/rptData.asp).
`It
`is predicted that the number ofpatients presenting
`for management of their HCV-related morbidity will
`continue to increase over the next 10-20 years, as the
`infected population ages.” * HCV infection is curable,
`however, and therefore such complications may be
`prevented by successful anti-viral therapy.
`Unfortunately, the current standard of care therapy,
`pegylated interferon-x (pegIFNaz) and ribavirin (RBV),
`is expensive and its efficacy is limited. ° Treatment
`of genotype |
`infection, the most prevalent genotype
`in North America,’ is successful
`in less than 50% of
`cases." This clearly mandates more effective therapies
`that have less toxicity. Intensive effort over the past
`decade has been focused on the discovery ofanti-viral
`agents that target specific steps in the viral life cycle,
`or specifically targeted anti-viral
`therapy for HCV
`(STAT-C) (Table 1). Inhibitors of the following steps in
`the HCV life-cycle are currently at various stages of
`clinical development - viral entry, HCV RNA transla-
`tion and post-translational processing, HCV replica-
`tion, viral assembly andrelease.
`Aside from the STAT-C agents, there are a number
`of other novel
`therapeutic approaches under clinical
`investigation (Table 2), Refinements to the existing
`armamentarium in the form of modified or alternative
`
`type, WT) virus and many minor variants. Direct anti-
`viral drug treatment applies a selection pressure, pro-
`moting the emergence of resistant mutants as WT
`virus is suppressed.
`This review will highlight the most promising new
`therapies for the treatment of CHC, concentrating on
`agents that have already progressed to the clinical
`development stage.
`
`SPECIFICALLY TARGETED THERAPY FOR
`HEPATITIS C
`
`Hepatitis C virus is a single-stranded RNA (ssRNA)
`virus of positive polarity belonging to the Flaviviridae
`family.
`It consists of a 9.6-kB open-reading frame,
`encoding a polyprotein of approximately 3000 amino
`acids length, which is co- and post-translationally pro-
`cessed into 10 mature proteins, both structural and
`nonstructural. Many of these proteins are potential
`drug targets. The elucidation of the three-dimensional
`structure of HCV proteins through X-ray crystallogra-
`phy?
`and the development of the subgenomic repli-
`con system,'* '® have together enabled structure-based
`drug design, allowing screening of candidate HCV
`inhibitors for high in vitro anti-viral activity (it should
`be noted that until recently, only genotype 1 replicon
`systems were available and therefore the efficacy of
`these agents for other genotypes may be theoretically
`limited).'” Inhibitors of the HCV NS3/4a serine prote-
`ase and the NSSb RNA-dependent RNA polymerase
`(RdRp) show great promise and have progressed to the
`more advanced stages of clinical development (NS3/4a
`and NS5B protein structure, relevant to inhibitor bind-
`ing and drug resistance, have recently been reviewed
`and will not be discussed in detail)!" A common
`theme in the developmentof these agents is that com-
`bination therapy with pegIFNz and RBV will continue
`to be important
`to increase anti-viral efficacy and
`limit the selection of drug resistant mutants,
`
`IFN preparations and a liver-targeting prodrug of RBV,
`taribavirin (TBV), have been designed to improve tol-
`erability and efficacy. Existing agents are being inves-
`tigated for previously unrecognized anti-viral effects,
`including the antiprotozoal nitazoxanide and thestatin
`class of 3-hydroxy-3-methylglutary] CoA (HMGCoA)
`reductase inhibitors. Finally, preliminary data exist
`concerning direct immune stimulants, both innate and
`The HCV NS3 protein is a multifunctional protein con-
`sisting of an amino-terminal serine protease and a car-
`adaptive, as well as therapeutic vaccines.
`
`A particular challenge to overcome in the develop- _helicase/nucleoside—_triphosphataseboxy-terminal
`
`ment of direct anti-virals will be anti-viral resistance.
`domain.’ The NS3 serine protease is necessary for
`post-translational processing of the NS3-NS5 region
`of the HCV polyprotein to generate components of the
`viral RNA replication complex.'” NS4a acts as a cofac-
`tor
`to facilitate the serine protease function. The
`
`NS3/4a protease inhibitors
`
`As for HIV and HBV, HCV has a high replication rate
`and an error-prone polymerase, but does not have a
`proof-reading mechanism. HCV therefore exists as a
`viral quasispecies consisting of one dominant
`(wild
`
`Aliment Pharmacol Ther 29, 689-705
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`REVIEW: INVESTIGATIONAL AGENTS FOR CHRONIC HEPATITIS C 691
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`
`
`Table 1. STAT-C (specifically targeted anti-viral therapy for hepatitis C virus)
`
`Life cycle step
`
`Target
`
`Agent
`
`Phase of
`development
`
`Viral entry
`
`HCV RNAtranslation
`
`HCV receptor
`HCV receptor
`HCV RNA - 5’-UTR
`
`Post-translational
`processing
`
`IRES/R40/elF3 complex
`Liver specific microRNA-122 (miR122)7'~°*
`NS3/4a protease
`
`HCV replication
`
`NS3-NS4ainteraction
`
`NS5Sb polymerase
`(i) NI (target catalytic site)
`
`{ii) NNI {target allosteric sites)
`
`Viral assembly/release
`
`NS5Ainhibitor
`
`Cyclophilin B inhibitors
`Glucosidase inhibitor
`
`Imino sugar - glucosidase inhibitor
`
`NI, nucleos({tjide inhibitor; NNI, non-nucleos(t)ide mhibitor.
`
`HCV immunoglobulin (polyclonal)
`HCV-AB 68/65 (monoclonal)
`AVI-4065 (antisense)
`ISIS 14803 (antisense)
`VGX-410C {small molecule inhibitor)
`SPC3649
`
`Telaprevir (VX-950)
`Bocepreveir (SCH503034)
`TMC435350
`MK-7009
`VX-500
`R7227 {ITMN 191)
`BILN 2061
`ACH-806 (GS-9132)
`R1626
`R7128
`IDX 184
`
`Valopicitabine (NM283)
`MK-0608
`VCH-759
`PF-00868554
`A-837093
`GS 9190
`GSK625433
`ANA598
`ABT-333
`VCH-916
`HCV-796
`XTL 2125
`A-831
`Debio-025
`Celgosivir
`UT-231B
`
`Phase 2
`Phase 2
`Halted
`Halted
`Halted
`Phase 1
`
`Phase 3
`Phase 3
`Phase 2
`Phase 2
`Phase 1
`Phase 1
`Halted
`Halted
`Phase 2
`Phase 1
`Phase 1
`
`Halted
`Halted
`Phase 2
`Phase 1
`Phase 1
`Phase 1
`Phase 1
`Phase 1
`Phase 1
`Phase 1
`Halted
`Halted
`Phase 1
`Phase 2
`Phase 2
`Halted
`
`helicase is thought to have a role in viral replication
`by unwinding theviral RNA.'” The NS3/4a proteaseis
`therefore required for viral replication.
`In addition, the NS3/4a protease has been shown to
`be a key regulator ofintracellular type I IFN pathways.
`NS3/4a controls cellular induction of IFN by inhibit-
`ing activation of IRF-3. It does this by targeted prote-
`olysis of both the IFNf promoter stimulator-1 (IPS-1,
`also known as MAVS, CARDIF or VISA) and Toll-IL-1
`receptor domain-containing adaptor
`inducing IFNf
`(TRIF), which respectively mediate the IFNf response
`to ssRNA stimulation of retinoic acid inducible gene-l
`
`(RIG-I) and Toll-like receptor 3 (TLR3).°°? Inhibitors
`of the NS3/4a protease therefore act to inhibit directly
`viral replication and,
`in addition, may stimulate the
`innate anti-viral
`immune response by restoring intra-
`cellular IFN-signalling (Figure 1).
`Biberach,
`BILN
`2061
`(Boehringer
`Ingelheim,
`Germany) was the first NS3/4a protease inhibitor to
`enterclinical trials. Treatment of patients with genotype
`| CHC for 2 days resulted in a rapid decline of the viral
`load, exceeding a 2 log;g reduction in all subjects
`administered the higher doses.’ 7° Unfortunately, clin-
`ical development of BILN 2061 was halted following the
`
`Aliment Pharmacol Ther 29, 689-705
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`692 A.J. V. THOMPSON and J. G. McHUTCHISON
`
`Class
`
`Agent
`
`Phase of
`development
`
`Table 2. Other novel therapeu-
`tic approaches
`
`Slow-release type 1
`interferon
`
`Oral interferon «
`
`Lambda-interferon (IL-29)
`Modified ribavirin
`Immune stimulants
`
`TLR ligand
`
`Therapeutic vaccine
`
`Albuferon
`Locteron
`Belerofon
`Omega Duros device (IFN? delivered
`by implantable infusion pump)
`Belerofon
`
`Pegylated interferon 4,
`Taribavirin
`Nitazoxanide
`Bavituximab
`
`Oglufanide (IM862)
`SCV-07
`
`IMO-2125 = TLR9 agonist
`CPG10101 = TLR9 agonist
`ANA245 = TLR7 agonist
`GI 5005
`Ic41
`TG4040
`PeviPROTM
`HCV/MF59
`
`HMGCoA reductase
`inhibitors
`
`ChronVac-C (DNA-based therapeutic
`vaccine)
`Class effect
`
`TLR,Toll-like receptor;HMGCoA, 3-hydroxy-3-methylglutaryl CoA.
`
`Phase 3
`Phase 2
`Phase 1
`Phase 2
`
`Phase 1
`
`Phase 1
`Phase 3
`Phase 2
`Phase 1
`
`Phase 1
`Phase 2
`
`Phase |
`Halted
`Halted
`Phase 2
`Phase 2
`Phase 1
`Phase 1
`Phase 1
`
`Phase 1
`
`Phase 1
`
`observation of cardiac toxicity in laboratory animals.”°
`The BILN 2061 experience was also notable for limited
`efficacy in genotype 2/3 infection and the rapid emer-
`gence of drug resistance in vitro, conferred by a single
`amino acid (aa) mutation.*” ** Proof-of-concept had
`been established, however, and there are now at least
`six protease inhibitors that have entered clinical trials.
`Two agents are currently in phase 3 programmes -
`telaprevir (formerly VX-950; Vertex Pharmaceuticals,
`Cambridge, MA, USA) and boceprevir (formerly SCH
`503034; Schering-Plough, Kenilworth, NJ, USA).
`
`a potent peptidomimetic
`is
`Telaprevir
`Telaprevir.
`inhibitor of the HCV NS3/4a protease.
`In a phase 1b
`study examining telaprevir monotherapy in patients
`with genotype 1 CHC, 14 days of dosing with 450 mg
`every 8h, 750 mg every 8h or 1250 mg every 12h
`reduced HCV viral
`load by at least 2 log; g IU/mL in
`all patients.” The 750 mg treatment group was associ-
`ated with the highest trough plasma drug concentra-
`tion and maximal median viral
`load reduction of
`
`4.4 log;g U/mL. However, viral breakthrough was
`noted in a significant number of patients during the
`second week of treatment. Viral breakthrough during
`telaprevir therapy has been associated with a number
`of single or double point mutations in the catalytic
`region of the enzyme.*°
`Telaprevir-resistance mutations have been classified
`by in vitro phenotypic analysis as associated with low
`(T54A, V36A/M, RI55K/T) or high-level
`resistance
`(A156T/V, V36M+RI55K, V36M+A1561).° All
`appear to have reduced fitness compared to WT virus
`in vitro, with the most resistant viruses bearing the
`A156V/T mutations also being the least fit.?° On with-
`drawal of telaprevir therapy, WT virus again becomes
`dominant, although resistant mutants may remain
`detectable for months. It is not known whether these
`
`variants are archived in the liver or what implication
`they may have for future anti-viral therapy or disease
`progression.
`Combination therapy has been shown to be syner-
`gistic in terms of anti-viral effect and reduce the
`
`Aliment Pharmacol Ther 29, 689-705
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`REVIEW: INVESTIGATIONAL AGENTS FOR CHRONIC HEPATITIS C 693
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`
`
`WW
`WW"
`
`~ LRR domain
`Helicase
`
`™ domain
`
`
`
`
`Egress
`
`CARD
`domain
`
`m\
`
`
`R
`
`ER :
`
`WA ON
`VW
`eplication
`
`+
`
`HCV polyprotein
`
`vw"
`
`complex
`
`“
`WWVV\"sOHCV ssRNA
`
`
`IPS-1
`CO
`
`
`
`Mitochondrion
`
`[ix
`
`|
`
`Nucleus
`
`aN
`
`
`
`Entry
`
`Figure 1. In addition to a necessary role in HCV replication, the NS3/4a protease targets the cellular dsRNA - type-1 IFN
`pathways, by cleaving both TRIF and IPS-1. NS3/4a protease inhibitors have been shown to restore TLR3 and RIG-I
`signalling in vitro (see text). ssRNA, single-stranded RNA; dsRNA, double-stranded RNA; ER, endoplasmic reticulum; LRR
`domain, leucine-rich repeat domain (involved in ligand recognition); TIR, Toll-interleukin-1 receptor domain (effector
`domain); TRIF, TIR-domain-containing adaptor producing IFN; TBK-1, TRAF-family-member-associated NF«B activator -
`binding kinase 1; IKK, inhibitor of NFB {IxB) kinase; IRF-3, interferon regulatory factor 3; RIG-I, retinoic acid inducible
`gene-I; CARD, caspase activation and recruitment domain; IPS-1, IFN/} promoter stimulator-1; TRAF3, tumour necrosis
`factor (TNF) receptor associated factor 3; NF«B, nuclear factor xB.
`
`emergence of telaprevir resistance. Telaprevir plus peg-
`IFN therapy was investigated in a small randomized
`trial of treatment naive, genotype | patients. The anti-
`viral effect was greater with 14 days of combination
`therapy compared with either telaprevir or pegIFNe
`monotherapy, with median HCV RNA reductions of
`5.5, 4.0 and 1.0 IU/mL.' Viral sequence analysis iden-
`tified resistant mutations in 2/7 in the combination
`
`arm compared to 7/8 receiving telaprevir monothera-
`py; despite this, no patient in the combination arm
`experienced virological
`rebound on treatment com-
`pared to 50% in the telaprevir monotherapy arm.
`
`study, conducted in the US, was a
`The PROVE 1
`phase II study that examined the efficacy of telaprevir
`plus pegIFNx and RBV in 260 treatment-naive, geno-
`type 1, noncirrhotic patients. Patients were randomized
`to one of four arms, comparing standard of care (peg-
`IFNa 180 wg/week and RBV 1000/1200 mg/day for
`48 weeks)
`to triple therapy with telaprevir, 750 mg
`every 8h, plus pegIFNx and RBV for 12 weeks, fol-
`lowed by an additional
`treatment period of pegiFNa
`and RBV for 36, 12 or 0 weeks. The final results have
`recently been presented in abstract form (Table 3a).””
`Patients who received triple therapy achieved a signif-
`
`Aliment Pharmacol Ther 29, 689-705
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`694 A. J.V. THOMPSON and J. G. McHUTCHISON
`
`Table 3. Results from recent phase 2 studies investigating telaprevir (a,b), boceprevir {c), R1626 (d) and albumin-
`interferon-w (e)?? 7% *% 7 9% %
`
`{a) PROVE-1 (32)
`
`n
`
`RVR (%)
`
`cEVR (%)
`
`SVR (%)
`
`Relapse (9%)
`
`Discontinuation {%)
`
`PR, 48 weeks
`TPR, 12 weeks + PR, 36 weeks
`TPR, 12 weeks + PR, 12 weeks
`TPR, 12 weeks
`
`75
`79
`79
`17)
`
`11
`«#81
`«81
`59
`
`45
`80
`68
`EL
`
`41
`67*
`61T
`35
`
`23
`6
`2
`33
`
`4
`18
`
`{b) PROVE-2 (33)
`
`n
`
`RVR (%)
`
`cEVR (%)
`
`SVR (%) Relapse (%)
`
`Discontinuation {%)
`
`PR, 48 weeks
`TPR, 12 weeks + PR, 12 weeks
`TPR, 12 weeks
`TP (no ribavirin), 12 weeks
`
`{c) SPRINT-1 (35)
`
`82
`81
`82
`78
`
`13
`69
`80
`50
`
`43
`73
`80
`62
`
`RVR™
`
`cEVR*™*
`
`n
`
`(9%)
`
`104
`
`103
`103.
`
`8
`
`64
`64
`
`(9%)
`
`36
`
`83
`83
`
`46
`69t
`608
`36%)
`
`SVR
`
`(%)
`
`38
`
`56
`7Att
`
`22
`14
`30
`48
`
`Viral
`
`10
`16
`12
`10
`
`breakthrough?? (%) Discontinuation (%o)
`
`0
`
`4
`5
`
`7
`11
`
`15
`
`26
`26
`
`28
`38
`
`PR, 48 weeks
`Lead-in (PR, 4 weeks)
`BPR, 24 weeks
`BPR, 44 weeks
`No lead-in
`BPR, 28 weeks
`BPR, 48 weeks
`
`{d) R1626 (44, 45)
`
`PR, 48 weeks
`R1626 (1500 mg) + P, 4 weeks
`PR, 44 weeks
`R1626 (3000 mg) + P, 4 weeks
`PR, 44 weeks
`R1626 (1500 mg) + PR, 4 weeks
`PR, 44 weeks
`
`107.
`103
`
`40
`37
`
`RVR
`(%)
`
`n
`
`20
`
`21
`
`32
`
`31
`
`5
`
`(29
`
`69
`
`74
`
`79
`79
`
`ETR
`(%)
`
`60
`
`52
`
`66
`
`81
`
`55
`66tt
`
`SVRS§
`(%)
`
`Relapse
`{%)
`
`GrIV
`neutropenia {%)
`
`50
`
`24
`
`53
`
`58
`
`L¥
`
`55
`
`19
`
`28
`
`10
`
`52
`
`78
`
`42
`
`{e) Alb-IEN« (73)
`
`n
`
`RVR (%)
`
`cEVR (%)
`
`EOT (%)
`
`SVR(9)
`
`PR, 48 weeks
`Alb-IFNa (900 yg, q2wk) +R, 48 weeks
`Alb-IFNe (1200 jg, q2wk) + R, 48 weeks
`Alb-IFN(1200 ug q4wk) +R, 48 weeks
`
`114
`118
`110
`116
`
`26
`25
`34
`18
`
`66
`69
`75
`53
`
`75
`67
`7A
`66
`
`58
`59
`56
`51
`
`RVR, rapid virological response; cEVR, complete early virological response; ETR, end-of-treatment response; SVR, sustained
`virological response; T, telaprevir; P, pegylated interferon-a; R, ribavirin; TPR, telaprevir/pegylated interferon-a/ribavirin
`combination therapy; B, boceprevir; BPR, boceprevir/pegylated interferon-«/ribavirin combination therapy; ‘lead-in’, 4 weeks
`of SOC; alb-IFNx, albumin-interferon-«.
`* P= 0.001 vs. control (PR, 48 weeks); + P = 0.02 vs. control; { P = 0.004 vs. control (PR, 48 weeks); § P = 0.12 vs. control;
`§| P = 0.20 vs. control; ** RVR and cEVR defined as undetectable HCV RNA after 4 and 12 weeks of boceprevir therapy respec-
`tively; tf HCV RNA:persistent >2 logjo increase from nadir and >50 000 IU/mL; 7} SVR12 = SVR at 12 weeks of follow-up;
`§§ P > 0.05 for all comparisons; 4\{| P = 0.64 for comparison of alb-IFNa to peglFN«.
`
`Aliment Pharmacol Ther 29, 689-705
`© 2009 Blackwell Publishing Ltd
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`

`REVIEW: INVESTIGATIONAL AGENTS FOR CHRONIC HEPATITIS C 695
`
`phase 2 trial of telaprevir triple therapy is currently
`cantly higher sustained virological response (SVR) rate
`underway in this patient population (PROVE3). Interim
`compared with those who received the standard of
`
`results were released—(http://investors.recently
`
`care
`(67% and
`61% vs. 41% standard therapy,
`vrtx.com/releasedetail.cfm?ReleaselD=3 14874). Patients
`P=0.001
`and
`0.02
`respectively), The
`improved
`were categorized according to previous nonresponse
`efficacy of triple therapy was associated with very
`high rates of week 4 rapid virological response (RVR;
`(including null responders (<1 logy, IU/mL decline by
`81% vs. 11% standard of care, P < 0.001) and low
`week 4, <2 logy9 IU/mL decline in HCV RNA by week
`12) and partial responders (2 logjo [U/mL decline but
`rates of both virological breakthrough and relapse. The
`data suggested that a period of pegIFNa/RBV consoli-
`HCV RNA positive at week 12, HCV RNA undetectable
`by week 24), breakthrough or relapse, to pegIFN&/RBV.
`dation is required following triple therapy, but that a
`total
`treatment duration of 24 weeks might be suffi-
`In patients treated with telaprevir, 750 mg every 8h
`cient for the majority of patients.
`for 12 weeks plus 24 weeks of peglFN«/RBV, rates of
`The results from a second phase 2 study conducted
`SVR12 were 41%, 44% and 72%respectively.
`in Europe support these conclusions (Table 3b).?? The
`The development of telaprevir has therefore been
`PROVE 2 study had a design similar to that of PROVE
`instructive. Despite potent anti-viral efficacy, the rapid
`1, but with a number of
`important differences.
`emergence of drug resistance limits monotherapy.It is
`clear that in the short- to medium-term, combination
`Although the contro] patients received 48 weeks of
`standard therapy, none of the three telaprevir-contain-
`with pegIFNe/RBV will be required. The PROVE and
`ing arms
`received
`48 weeks of
`therapy. Rather,
`2 studies suggest
`that
`triple therapy regimens will
`increase SVR rates with shorter treatment duration, a
`patients were randomized to telaprevir/peglFNe/RBV
`triple therapy for 12 weeks followed by pegIFN«/RBV
`significant step forward. These triple combination regi-
`mens carry some additional cost in terms of increased
`for 12 weeks (the "12 + 12’ arm) or triple therapy for
`12 weeks only. The fourth arm of the study random-
`toxicity; it is hoped that with greater experience, these
`ized
`patients
`to
`combination
`telaprevir/peglFNe
`could be better managed. On the basis of this promis-
`(without RBV)
`for
`12 weeks. The SVR rate in the
`ing phase 2 data,
`telaprevir has now progressed to
`“12+ 12’ arm was greater than that
`in the control
`phase 3 programmes in treatment-naive and treat-
`group, 69% vs. 46% (P = 0.004). There was a trend for
`ment-experienced patients.
`the SVR rate in the ‘12 + 12’ arm to be higher than
`that of the 12-week triple therapy arm and the relapse
`rate lower, supporting the importance of a period of
`consolidation therapy. Virological breakthrough was
`responsible for the disappointing results in the telapre-
`vir/pegIFN group [26% compared to 2% in the triple
`therapy arms (pooled data)], and therefore RBV will be
`indispensable in future triple combination regimens.
`In both trials, adverse events (AEs) were more com-
`mon in the telaprevir-containing treatment arms. Gas-
`trointestinal events, skin events (rash, pruritus) and
`anaemia were more common compared with peg-
`IFNe/RBV alone. The discontinuation rate was 18%
`
`compared to 4% in the control arm in PROVE], during
`the first 12 weeks of therapy (the period of telaprevir
`therapy).
`The utility of telaprevir combination therapy in
`patients who have previously failed IFN-based thera-
`pies is not known. The concern in true null responders
`to IFN is that triple therapy might equate to functional
`monotherapy, with the inherent
`risk of virological
`breakthrough. However, preliminary data indicate that
`virological responses are encouraging. A randomized
`
`Aliment Pharmacol Ther 29, 689-705
`© 2009 Blackwell Publishing Ltd
`
`is a
`Boceprevir. Boceprevir (formerly SCH 503034)
`second peptidomimetic HCV NS3/4a protease inhibi-
`tor. In a dose finding study of genotype 1 nonrespond-
`ers, patients were treated with 14 days of boceprevir at
`100, 200, 400 mg twice daily (b.d.), or 400 mg three
`times daily (t.d.s.). The dose of 400 mg t.d.s. produced
`a maximal mean
`reduction
`in HCV RNA of
`2.06 logy IU/mL.** Anti-viral effect
`in combination
`with pegIFNx was subsequently found to be additive,
`achieving a mean maximal reduction of viral
`load of
`2.88 + 0.22 logig IU/mL at 14 days.
`Boceprevir subsequently progressed to a phase 2
`programmeusing a higher dose of 800 mg t.d.s.,
`in
`both treatment naive patients with genotype 1
`infec-
`tion and previous nonresponders. The SPRINT-1 (HCV
`Serine Protease Inhibitor Therapy) trial enrolled treat-
`ment-naive patients.’? Patients were randomized to
`one of six treatment arms: 4 weeks of peglFNe-
`2b/RBV (lead-in phase) followed by the addition of
`boceprevir, 800 mg t.d.s., to the combination for 24 or
`44 weeks
`(totalling 28 or 48 weeks of treatment);
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`696 A.J. V. THOMPSON and J. G. McHUTCHISON
`
`boceprevir in combination with pegIFNz-2b/RBV for
`28 or 48 weeks
`(no lead-in phase); boceprevir
`in
`combination with peglFNe-2b and low-dose RBV
`(400-1000 mg
`daily)
`for
`48 weeks
`and
`finally,
`peglFNe¢-2b/RBV alone for 48 weeks
`(control). The
`induction dose was intended to minimize the develop-
`ment of drug resistance by achieving steady state con-
`centrations of both pegIFNx-2b and RBV prior to the
`introduction of boceprevir. The results of a planned
`interim analysis were recently presented in abstract
`form.** Virological response rates were higher in the
`active treatment arms vs. control (55, 56% (SVR) and
`66, 74% (SVR12) for 28- and 48-week boceprevir arms
`compared to 38%(SVR12)) (Table 3c). A role for lead-
`in therapy was not clear; numerically superior interim
`response rates were observed, although the differences
`were notsignificant.
`In a second phase 2 study, dose-finding study, boce-
`previr combination therapy was used to treat previous
`nonresponders to peglFNe#/RBV. Although the regi-
`mens containing boceprevir yielded higher SVR rates
`compared with control,
`they were
`disappointing
`(7-14% vs. 2%).°° However, multiple protocol changes
`during the course of the trial, including increasing all
`patients to a boceprevir dose of 800 mg t.d.s. and add-
`ing in RBV to patients started on boceprevir/pegIFNe
`dual therapy,
`limited the interpretation of this dataset
`and further
`trials
`in this hard-to-treat group are
`underway.
`The emergence of drug-resistant mutations in vivo
`occurs rapidly in the setting of boceprevir monothera-
`py.’ Common mutations include the V36M, T54S/A,
`R155K, V36L and V170A.”° In vitro studies also indi-
`cate that boceprevir is cross-resistant with telaprevir.””
`Combination with both pegIFN« and RBV is necessary
`Increased
`to reduce the emergence of resistance.’®
`rates of anaemia and dysgeusia were noted compared
`to standard therapy in both of these phase 2 trials.
`Discontinuation rates were also higher compared with
`pegIFN/RBV (26-28%vs. 14%). Boceprevir has also
`progressed to phase 3 programmes in naive andprior
`nonresponder patient populations.
`
`Other HCV NS3/4a protease inhibitors. Other prote-
`ase inhibitors recently entering phase 1-2 clinical pro-
`grammes
`include TMC435350
`(Tibotec, Mechelen,
`Belgium and Medivir, Huddinge, Sweden)?” *° and
`MK-7009 (Merck, NJ, USA). On the basis of encour-
`aging preclinical data, R7227 (formerly [TMN-191;
`
`Intermune, CA, USA and Roche Pharmaceuticals,
`Basel, Switzerland) has entered a phase | programme.
`
`(Achillion Pharma-
`ACH-806. ACH-806 (GS-9132)
`ceuticals, CT, USA and Gilead Sciences, CA, USA) was
`an agent that inhibited binding of NS4A to the NS3
`protease. It therefore inhibited polyprotein processing
`by preventing the formation of the active proteinase
`complex. In phase 1 studies, 5 days of treatment led to
`a 0.9 log, reduction in HCV RNA.*' Although clinical
`development was subsequently halted because of con-
`cerns regarding possible proximal renal tubular toxic-
`ity,
`this
`study provided proof of concept
`for an
`alternative molecular
`target
`for
`inhibition of
`the
`NS3/4a protease complex, without cross-resistance to
`the petidomimetic inhibitors.
`
`NS5B polymerase inhibitors
`
`The HCV NS5SB RNA-dependent RNA polymerase is a
`key enzyme involved in HCV replication, catalysing
`the synthesis of the complementary minus-strand RNA
`and subsequent genomic plus-strand RNA from the
`Mammalian
`cells
`do not
`minus-strand template.
`express an equivalent enzyme, allowing highly selec-
`tive targeting of HCV replication. Both nucleos(tjide
`and non-nucleos(t)ide polymerase inhibitors (NI/NNI)
`are currently in development. In addition, the replica-
`tive activity of the RdRp has recently been reported to
`be augmented by direct binding to cyclophilin B, a host
`cell isomerase.*” A cyclophilin B inhibitor has also pro-
`gressed to a phase 2 clinical development programme.
`
`NS5B Nis. R1626: R1626 (Roche Pharmaccuticals) is
`the only NI currently in phase 2 development. R1626
`is the prodrug of R1479, a cytidine nucleoside ana-
`logue. In a phase lb study, 14 days of treatment with
`1500, 3000 and 4500 mg, b.d., achieved viral
`load
`reductions of 1.2, 2.6 and 3.7 logig [U/mL respec-
`tively."* Dose-limiting gastro-intestinal AEs were
`noted in the 4500-mg arm. Mild-to-moderate revers-
`ible leucopenia was also noted.
`synergy was
`study,
`In
`a
`subsequent phase
`2a
`observed between R1626 and peglFNx + RBV when
`used in combination.** Maximal mean viral load reduc-
`tion of 5.2 log,9 IU/mL from baseline was observed in
`the triple treatment arm (R1626 1500 mg b.d., pegIFNx
`180 wg weekly and RBV 1000-1200 mg daily), which
`
`Aliment Pharmacol Ther 29, 689-705
`© 2009 Blackwell Publishing Ltd
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`REVIEW: INVESTIGATIONAL AGENTS FOR CHRONIC HEPATITIS C 697
`
`translated into a rate of RVR of 74%"? and an end-of-
`observed in genotype 1 previous nonresponders. After
`treatment (ETR) response of 81% compared to 5% and
`14days of treatment,
`a maximum mean decline of
`60% respectively for standard of care.” Despite this
`2.72 log;g [U/mL occurred at
`the highest dose of
`1500 mg b.d.”° No virological rebound was observed.
`finding, high relapse rates were observed at week 72 in
`The drug was well
`tolerated as monotherapy and no
`patients treated with R1626, such that SVR rates were
`serious AEs were reported in any study arm.
`equivalent to that achieved in the control group (Table
`3d)."° This high relapse rate was attributed to cyto-
`In treatment naive genotype 1 patients,
`the combi-
`nation of R7128 (1500 mg, b.d.) in combination with
`penia-related R1626 dose interruptions.
`pegIFNa and RBV achieved a reduction in HCV RNA
`a high
`Published data suggest
`that R1626 has
`
`genetic barrier to drug resistance. Although theresis- of approximately 5 log;gIU/mL at 4 weeks translat-
`tance mutations S96T and S96T/N142T*® have been
`ing into an RVR rate of 85% (vs. —2 log; ) [U/mL and
`10% in the standard of care control arm).°' No viro-
`identified in vitro, they are yet to be identified in vivo,
`using the HCV NSS5B phenotypic assay.2” ** More
`logical rebound was observed during R7128 treatment
`recently, clonal analysis of serum from patients expe-
`to 4 weeks.
`Importantly, R7128 was generally well-
`riencing virological
`rebound also failed to identify
`tolerated in combination with pegIFN« and RBV;
`resistant nutations.*® Serum was tested pre- and post-
`grade 3/4 haematological
`toxicity was rare and not
`different to the contro] arm (5% vs. 10%). Headache
`treatment, but not during treatment. The low in vitro
`replication capacity (or fitness) of these resistant repli-
`(65% vs. 40%), fatigue (40% vs. 20) and chills (35%
`cons (4-5% of WI*®) and the relatively low level of
`vs. 20%) were all more common than control; all
`resistance of these variants to R1626 (four- to fivefold
`were classed as mild AEs. Preliminary resistance test-
`decreased susceptibility to R1626°°) might account for
`ing failed to identify any variants to week 4. This
`this observation.
`trial is ongoing.
`The combination of a potent anti-viral effect and
`satisfactory toxicity profile makes R7128 an attractive
`agent.
`In addition,
`it will be the first polymerase
`inhibitor to be tested for anti-viral activity against
`genotypes 2 and 3 HCV.
`(formerly NM283;
`Valopicitabine: Valopicitabine
`Idenix Pharmaceuticals, MD, USA and Novartis
`International, Basel, Switzerland) was a promising NI.
`Unfortunately, the FDA placed its clinical development
`on hold in mid-2007 after a risk-benefit analysis of
`data from their phase 2 trial concluded that the bene-
`fits of valopicitabine did not outweigh the gastrointes-
`tinal toxicities (nausea, vomiting and diarrhoea).
`Other Nis:
`IDX184
` (Idenix
`Pharmaceuticals,
`Cambridge, MA, USA)
`is a nucleotide analogue that
`Therefore, triple therapy with R1626 and_peg-
`
`IFNa/RBV is associated with potent anti-viral effect
`has recently entered phase 1 development on the basis
`of promising preclinical data.°* The development
`and an encouraging resistance profile. Unfortunately,
`of another NI, MK-0608 (Merck) has recently been
`toxicity is an issue. As R1626 moves forwards,
`it will
`abandonedfor undisclosed reasons.”
`be important to determine whether lower doses of this
`agent with full-dose peglFNa/RBV or lower doses of
`pegIFN« with full doses of R1626 are able to minimize
`AEs whilst maintaining efficacy.
`R7128: R7128 (Pharmasset, NJ, USA and Roche
`Pharmaceuticals)
`is
`the oral prodrug of PSI-6130,
`a second cytidine nucleoside analogue under clinical
`development.
`In a dose-escalating phase
`1b
`trial,
`HCV RNA was
`a
`dose-dependent
`decrease
`in
`
`Unfortunately, profound haematological toxicity was
`observed when R1626 was combined with pegIFN«.”°
`The rate of grade 4 neutropenia (neutrophil count
`<0.5 x 10° cells/L) was 78% when R1626 was adminis-
`tered at a dose of 3000 mg b.d. Even at lower doses,
`the rates of grade 4 neutropenia were relatively high -
`42-52%. Thirty-nine per cent of patients treated with
`triple therapy (R1626/pegIFNa/RBV) also experienced
`grade 3 or 4 anaemia (HB <10.0 and <8.5 g/dL respec-
`tively). Most of the haematological toxicities reversed
`upon removal of R1626, despite ongoing pegIFNz. Gas-
`trointestinal AEs (vomiting and diarrhoea, particularly
`in the 3000-mg arm) and rash were also more common
`than in controls.
`
`the
`NS5