`
`Review article: investigational agents for chronic hepatitis C
`A. J. V. THOMPSON Er J. G. MCHUTCHISON
`
`
`Division 0 f GastroenteroIogy/
`Hepatology. Duke Clinical Research
`Institute, Duke University, Durham,
`NC. USA
`
`Correspondence to:
`Dr J. Cr. Mctlutchison. Department of
`Medicine, Duke Clinical Research
`Institute. 2400 Pratt Street. Room
`0311 , Terrace Level, Durham. NC
`27?]5, USA.
`E-mail: mehurm1©rnedukeedu
`
`Publication dam
`Submitted 27 October 2008
`First decision 10 November 2008
`Resubmitted 19 December 2008
`Accepted 21 December 2008
`Epuh Accepted Article I? 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:waw.
`clinicaltrialsgov). The focus was restricted 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 NSB/tta protease inhibitors
`now entering phase 3 programmes. New interferon—a 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.
`
`Afiment Pharmacol Ther 29. 589—705
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`
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`© 2009 Blackwell Publishing Ltd
`doi:10.111'llj.2365-2036.2009.0392?.x
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`689
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`I-MAK, INC. V GILEAD PHARMASSET LLC
`|PR2018—00120
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`GIL2016
`I-MAK, INC. V GILEAD PHARMASSET LLC
`IPR2018-00120
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`690 A. J. V. THOMPSON and J. G. McHUTCHlSON
`
`INTRODUCTION
`
`Chronic hepatitis C virus [HCV} infection affects 170
`million people worldwide.l
`It is estimated that 20% of
`HCV—infected patients will develop cirrhosis, with the
`associated risks of developing liver failure and/or liver
`cancer.2 Chronic hepatitis C. [CHCl
`is the leading cause
`of death from liver disease and the most common
`
`indication for liver transplantation in the US,3 (UNOS
`database, 1111p:waw.optn.orgl'latestDatalrptDataasp).
`It
`is predicted that the number of patients presenting
`for management of their HCV—related morbidity will
`continue to increase over the next 10-20 years, as the
`infected population agesz' 4 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—or [pegIFNal and ribavirin (REV).
`is expensive. and its efficacy is limited.5’6 Treatment
`of genotype 1
`infection, the most prevalent genotype
`in North America." is successful
`in less than 50% of
`cases.8 This clearly mandates more effective therapies
`that have less toxicity.
`intensive effort over the past
`decade. has been focused on the discovery of anti—viral
`agents that target specific steps in the viral life cycle.
`or specifically targeted anti—viral
`therapy for HCV
`[STAT—Cl {Table l]. 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 and release.
`Aside from the STAY-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
`
`IFN preparations and a liver—targeting prodrug of REV.
`taribavirin {TBV}, have been designed to improve to]—
`erability and efficacy. Existing agents are being inves-
`tigated for previously unrecognized anti—viral effects.
`including the antiprotozoal nitazoxanitie and the statin
`class of 3—hydtoxy—3—rnethylglutaryl CoA lHMGCoA}
`reductasc inhibitors. Finally, preliminary data exist
`concerning direct immune stimulants, both innate and
`adaptive, as well as therapeutic vaccines.
`A particular challenge to overcome in the develop—
`ment of direct anti-Vitals will be antinviral resistance.
`
`As for HIT:r 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 quasispccics consisting of one dominant
`[wild
`
`type, WT] virus and many minor variants. Direct anti—
`viral drug treatment applies a sclcction 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 Flaviuiridae
`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
`dntg targets. The elucidation of the three-dimensional
`structure of HCV proteins through X—ray crystallogra—
`phyg'13 and the development of the subgenomic repli—
`con system,'4'16 have together enabled structure—based
`drug design. allowing screening of candidate l-[CV
`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
`limitedl.” 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 [N33/4a
`and NSBB protein structure, relevant to inhibitor bind“
`ing and drug resistance, have recently been reviewed
`and will not be discussed in detail].18 A common
`theme. in the development of these agents is that coma
`bination therapy with pegIFth and RBV will continue
`to be important.
`to increase anti—viral efficacy and
`limit the selection of drug resistant mutants.
`
`NS3/4a protease inhibitors
`
`The HCV N33 protein is a multifunctional protein con—
`sisting of an amino—terminal serine protease and a car—
`boxy—terminal
`helicase/nucleoside
`triphosphatase
`domain.19 The N53 serine protease is necessary for
`post—translational processing of the NS3—NSE region
`of the HCV polyprotein to generate components of the
`viral RNA replication complex.” N54a acts as a cofac—
`tor
`to facilitate the serine protease function. The
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`Table ‘l. STATMC {specifically targeted antiviral therapy for hepatitis C virus)
`
`Life cycle step
`
`Target
`
`Agent
`
`Phase of
`development
`
`Viral entry
`
`HCV RNA translation
`
`l-ICV receptor
`HCV receptor
`HCV RNA 7 ELUTR
`
`Post-translational
`processing
`
`[RES/R40/eIF3 complex
`Liver specific microRNAalzz {mime/219"“
`NS3/4a protease
`
`liCV replication
`
`NSE—N54a interaction
`
`NSSb polymerase
`(i) NI [target catalytic site)
`
`(ii) NNI {target allosteric sites]
`
`Viral assembly/release
`
`NSSA inhibitor
`
`Cyclophilin 3 inhibitors
`Glucosidase inhibitor
`
`[rhino sugar - glucosidase inhibitor
`
`NI, nucleosltlide inhibitor; NNl, non—nucleosfihde inhibitor.
`
`HCV immunoglobulin [polyclonal]
`HCV-AB 65/65 {monoclonal}
`Ami-1065 [antisense]
`151514803 [antisensel
`VGXJHOC {small molecule inhibitor]
`SPC3649
`
`Telaprevir {VX-9 50]
`Bocepreveir [931503034]
`TMC435350
`MKJDGS
`VX-SGO
`R722? {ITMN 191}
`BILN 2061
`ACl-l—BDE [GS—9132)
`R1626
`R7128
`1DX134
`
`Valopieitabine {NM283}
`MK—DEGB
`VCH-7 59
`PE—00868554
`A—837093
`GS 9190
`GSK625433
`ANASBB
`ABT—333
`VCH—916
`HUI—796
`XTL 2125
`A—33t
`Debits-025
`Celgosivir
`[IT-2MB
`
`Phase 2
`Phase 2
`Halted
`Halted
`Halted
`Phase I
`
`Phase 3
`Phase 3
`Phase 2
`Phase 2
`Phase I
`Phase 1
`Halted
`Halted
`Phase 2
`Phase ]
`Phase I
`
`Halted
`Halted
`Phase 2
`Phase 1
`Phase I
`Phase 1
`Phase I
`Phase 1
`Phase 1
`Phase ]
`Halted
`Halted
`Phase 1
`Phase 2
`Phase 2
`Halted
`
`helicase is thought to have a role in viral replication
`by unwinding the viral RNA.'9 The NS3/4a pmtcase is
`therefore required for viral replication.
`In addition, the N53/4a protease has been shown to
`be a key regulator of intracellular type I lFN pathways.
`NS3/4a controls cellular induction of IFN by inhibits
`ing activation of [RF-3. it does this by targeted prote-
`olysis of both the {PM}? promoter stimulator—l
`[lPS—l,
`also known as MAVS, CARDIF or VISA} and Toll—IL—l
`receptor domainecontaining adaptor
`inducing IFNfi
`('l'RlF}, which respectively mediate the ll-‘N/t response
`to ssRNA stimulation of retinoic acid inducible gene—l
`
`{RIGell and Tollelike receptor 3 [111231.20-23 Inhibitors
`of the, NSS/tta protease therefortt act to inhibit directly
`viral replication and,
`in addition, may stimulate the
`innate anti—viral
`immune response by restoring intra—
`cellular IFNesignalIing [Figure 1].
`Bihcrach,
`BILN
`206]
`(Boehringer
`Ingelheim,
`Germany) was the first NS3/4a protease inhibitor to
`enter clinical trials. Treatment of patients with genotype
`1 (HQ for 2 days resulted in a rapid decline of the viral
`load, exceeding a 2 logic reduction in all subjects
`administered the higher dOSLfS.24' 25 Unfortunately, clin-
`ical development of BlLN 2061 was halted following the
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`Class
`
`Agent
`
`Phase of
`development
`
`Table 2. Other novel therapeu—
`tic approaches
`
`Slow—release type I
`interferon
`
`Oral interferon at
`
`Lambda~intetferon [IL-29)
`Modified ribavirin
`Immune stimulants
`
`TI.R ligand
`
`Therapeutic vaccine
`
`Albuferon
`Locteron
`Belerofon
`Omega Duros device [IFNH delivered
`by implantable infusion pump)
`Belerofon
`
`Pegylated interferon 2.1
`Taribavirin
`Nitazoxanide
`Bavituximab
`
`Uglufanide [IMBEZ]
`SCV-O?
`
`IMO-2125 = TIRE agonist
`CPGIOIDI = TLR9 agonist
`ANA245 : TLR7 agonist
`GI 5005
`1011
`T023040
`PeviPRGTM
`I-ICV/MF'SB
`
`HMGCOA reductase
`inhibitors
`
`CbronVac-C [DNA-based therapeutic
`Va cci ne]
`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 I
`Phase 2
`Phase 1
`Halted
`Halted
`Phase 2
`Phase 2
`Phase 1
`Phase 1
`Phase 1
`Phase 1
`
`Phase 1
`
`observation of cardiac toxicity in laboratory animals.26
`The BILN 2061 experience was also notable for limited
`efficacy in genotype 2/3 infection and the rapid emer—
`gence of drug resistance in uttm, conferred by a single
`amino acid [aa] mutationfl'za Prootlot‘econcept 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 VXaQSO; Vertex Pharmaceuticals,
`Cambridge. MA, USA} and boceprevir (formerly SCI-I
`503034; Schering—Plough, Kenilworth, NJ. USA].
`
`a potent pcptidomimetic
`is
`'l‘elaprevir
`Tetoprevtr.
`inhibitor of the HCV NS3/4a protease.
`In a phase 1!)
`study examining telaprevir monotherapy in patients
`with genotype 1 CHC, 14 days of closing with 450 mg
`every 8 h, 750 mg every 8 h or [250 mg every 12 it
`reduced l-ICV viral
`load by at least 2 logm IU/mL in
`all patients.” The T50 mg treatment group was associ—
`ated with the highest trough plasma drug concentra—
`tion and maximal median viral
`load reduction of
`
`4.4 loglo lU/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 doubie 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, R155K/T] or highrlevel
`resistance
`(Amer/v, V36M + RISBK, V36M + Ararat)?" 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.30 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 antievira] therapy or disease
`progression.
`Combination therapy has been shown to be syner—
`gistic in terms of anti-viral effect and reduce the
`
`Aliment Pharmacot titer 29. 689—705
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` Egress
`NSSMa
`
`" LRR domain
`
`TIH domain
`iii
`
`
`
`
`W+
`\ +
`
`‘9 \A
`HOVpolyprotein
`
`
`
`
`
`&a wvw”
`
`
`
`
`\NVW ,
`wvm /\/
`eplication
`
`l
`wvm+ HCV ssFiNA
`
`Figure I. in addition to a necessary,r role in HCV replication, the N53/4a protease targets the cellular dsRNA — type-l IFN
`pathways, by cleaving both TRIP and LPSAI. NSJ/ita protease inhibitors have been shown to restore TLR3 and RIG~I
`signalling in vitra {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-interleukinal receptor domain {effector
`domain); TRIP, TIR-domain-containing- adaptor producing IFNIJ’; 'I'BK—l, TRAF-farnily—mernber-associated NFKB activator —
`binding lcinase 1', IKK, inhibitor of NFKB {IKE} kinase; IRE-3, interferon regulatory factor 3;'RIG-l, refinoic acid inducible
`gene-1; CARD. caspase activation and recruitment domain; [PS-1, 11-?fo promoter stimulator-1: IRAFB, tumour necrosis
`factor {TNF} receptor associated factor 3: N'FKB, nuclear factor KB.
`
`emergence of telaprcvir resistance. Telap revir plus peg—
`lFNor therapy was investigated in a small randomized
`trial of treatment naive, genotype I patients. The anti—
`viral effect was greater with 14 days of combination
`therapy compared with either telaprevir or pegIFNo
`monotherapy, with median HCV RNA reductions of
`5.5, 4.0 and 1.0 IU/mL.3| 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 I
`phase [I study that examined the efficacy of telaprevir
`plus peglFNa and REV in 260 treatment—naive, geno—
`type 1, noncirrhotic patients. Patients were randomized
`to one of four arms, comparing standard of care [peg-
`lFNor 180 pg/weclr and RBV 1000/1200 mg/day for
`48 weeks)
`to triple therapy with telaprevir, 750 mg
`every B 11, plus pegIFNor and RBV for i2 weeks,
`fol—
`lowed by an additional
`treatment period of pcglFNor
`and RBV for 36, 12 or 0 weeks. The final results have
`recently been presented in abstract form {Table 3a]I.32
`Patients who received triple therapy achieved a signifi—
`
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`- Table 3. Results from recent phase 2 studies investigating telaprevir [3,131, boceprevi: [c], R1626 [d] and albnnn'nu
`interferon—ac {e132, 3:. 45. 73. 95. 96
`
`{a} PROVE—l {32)
`
`n
`
`RVR [0111)
`
`cEVR {0111]
`
`SVR [0111]
`
`Relapse [We]
`
`Discontinuation {010}
`
`PR, 48 weeks
`TPR, 12 weeks + PR, 36 weeks
`TPR, 12 weeks + PR, 12 weeks
`TPR. 12 weeks
`
`7'5
`79
`79
`17
`
`11
`61
`BI
`59
`
`45
`60
`68
`T1
`
`I11
`6?“
`61T
`35
`
`23
`6
`2
`33
`
`4
`IB
`
`[h] PROVE-2 [33)
`
`n
`
`RVR ['16)
`
`cEVR [0.6]
`
`SVR [We] Relapse (0/0]
`
`Discontinuation {We}
`
`PR, 48 weeks
`TPR. 12 weeks + PR. 12 weeks
`T1311, 12 weeks
`TP [110 ribavirin], 12 weeks
`
`[c] SPRINTrl {35]
`
`82
`81
`82
`73
`
`13
`69
`BO
`50
`
`13
`3'3
`80
`62
`
`RVR"
`
`cEVR“
`
`n
`
`{0111)
`
`104
`
`103
`[03
`
`8
`
`64
`64
`
`[016]
`
`36
`
`33
`83
`
`45
`691
`605
`36“
`
`SV'R
`
`[“111]
`
`38
`
`56
`7411
`
`22
`14
`30
`48
`
`Viral
`
`10
`16
`[2
`10
`
`breakthroughT’f [‘16] Discontinuation {011}
`
`0
`
`4
`'5
`
`7
`11
`
`15
`
`2.6
`26
`
`28
`3B
`
`PR, 48 weeks
`Lead-in (PR, 4 weeks)
`BPR. 24 weeks
`BPR. 44 weeks
`No leadrin
`BPR, 28 weeks
`BPR. 48 weeks
`
`{11} R1626 [44. 45]
`
`PR. 48 weeks
`R1626 [1500 mg) + P, 4 weeks
`PR, 44 weeks
`R1626 [3000 mg) + P. 4 weeks
`PR, ‘1‘] weeks
`R1626 [1500 mg) + PR, 4 weeks
`PR, 44 weeks
`
`10?
`103
`
`40
`37
`
`RVR
`{011)
`
`11
`
`20
`
`21
`
`32
`
`31
`
`5
`
`29
`
`69
`
`374
`
`79
`79
`
`ETR
`{011]
`
`60
`
`52
`
`66
`
`31
`
`55
`6611
`
`SVR§§
`1%)
`
`Relapse
`[I111]
`
`Gr IV
`neutropenia 1%)
`
`50
`
`2’1
`
`53
`
`58
`
`[7
`
`55
`
`19
`
`23
`
`10
`
`52
`
`78
`
`42
`
`[e] Alb-IFNo: {73]
`
`n
`
`RVR 1%)
`
`cEVR [Ufa]
`
`EDT {0.11)
`
`SVRW 1%)
`
`PR. 48 weeks
`Alb—IFNoc [900 11g, qzwk) + R. 48 weeks
`Alb-IFer [1200 pg, q2wk) + R, 48 weeks
`Alb—IFNoc (1200 pg q4wk] + R. 43 weeks
`
`114
`113
`110
`115
`
`2.6
`25
`34
`18
`
`66
`59
`3'5
`53
`
`75
`57
`74
`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-111; R, ciliavin'n: TPR. telaprevir/pegylaterl interferonwn/rihafirin
`combination therapy; B, boceprevir; BPR, hoceprevir/peallated interferon—a/fihavirin combination therapy; 'leatl—in'. 4 weeks
`of SOC; alb—lFNac, albumin—interference
`“ P = 0.001 vs. control (PR, 48 weeks]; 1‘ P = 0.02 vs. control; i P = 0.004 vs. control [PK 48 weeks]; 5 P = 0.12 vs. control;
`1| P : 0.20 vs. control; “' RVR and cEVR defined as undetectable HCV RNA after 4 and 12 weeks of boceprevir therapy respec—
`tively; TT HCV RNA: persistent 22 log“) increase from nadir and 250 000 IU/mL; ii SW12 = SVR at 12 weeks of follow—up;
`§§ P :2 0.05 for all comparisons: 1l1| P = 0.64 for comparison of alb—IFNx to peglFNa.
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`cantly higher sustained virological response [SVR] rate
`compared with those who received the standard of
`care
`[67% and
`61% vs. 41% standard therapy,
`P = 0.001
`and
`0.02
`respectively]. The
`improved
`efficacy of triple therapy was associated with very
`high rates of week 4 rapid virological response. [RVR;
`81% vs. 11% standard of care, P-e 0.001] and low
`rates of both virological breakthrough and relapse. The
`data suggested that a period of peglFNot/RBV consoli—
`dation is required following triple therapy, but that a
`total
`treatment duration of 24 weeks might be suffi-
`cient for the majority of patients.
`The results from a second phase 2 study conducted
`in Europe support these conclusions [Table 3b}.33 The
`PROVE 2 study had a design similar to that of PROVE
`1, but with a number of
`important differences.
`Although the control patients received 48 weeks of
`standard therapy, none of the three telaprevir—contain—
`ing arms
`received
`48 weeks of
`therapy. Rather,
`patients were randomized to telaprevir/peglFNot/RBV
`triple therapy for 12 weeks followed by peglFNa/RBV
`for 12 weeks [the '12 + 12’ arm) or triple therapy for
`12 weeks only. The. fourth arm of the study random—
`ized
`patients
`to
`combination
`telaprevir/pegll-‘Not
`[without RBV]
`for
`12 weeks. The SVR rate in the
`‘12 + 12' arm was greater than that
`in the control
`group, 69% vs. 46% [P = 0.004}. There was a trend for
`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 come
`mon in the telaprevir—containing treatment arms. Gas—
`trointestinal events, skin events (rash, pruritus) and
`anaemia were more common compared with peg—
`IFNot/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 [EN-based thera—
`pies is not known. The concern in true null responders
`to [FN 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
`
`Atiment Pharmoeol Titer 29, 689—?05
`CL?! 2009 Blackwell Publishing Ltd
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`phase 2 trial of telaprevir triple therapy is currently
`underway in this patient population [PROVE 3]. Interim
`results were
`recently
`released
`[http:flinvestors.
`vmeeomfreleasedetail.cfm?ReleaselD=314824}. Patients
`were categorized according to previous nonresponse
`[including null responders [<1 logm [ll/mL decline by
`week 4, <2 logm lU/nlL decline in HCV RNA by week
`12} and partial responders [22 logm IU/mL decline but
`HCV RNA positive at week 12, HCV RNA undetectable
`by week 24], breakthrough or relapse, to peglFer/RBV.
`In patients treated with telaprevir, 750 mg every 8 h
`for 12 weeks plus 24 weeks of pegiFNot/RBV, rates of
`SVR12 were 41%, 44% anti 72% respectively.
`The. development of telaprevir has therefore been
`instructive. Despite. potent anti-viral efficacy, the rapid
`emergence of drug resistance limits monotherapy. It is
`clear that in the. short- to medium-term, combination
`with pegIFNa/RBV will be required. The PROVE] and
`2 studies suggest
`that
`triple therapy regimens will
`increase SVR rates with shorter treatment duration, a
`significant step forward. These triple combination regi—
`mens carry some additional cost in terms of increased
`toxicity; it is hoped that with greater experience, these
`could be better managed. 0n the basis of this promis-
`ing phase 2 data.
`telaprevir has now progressed to
`phase 3 programmes in treatment~naive and treat—
`meat—experienced patients.
`
`Boceprevir. Boceprevir [formerly SCH 503034} is a
`second peptidomimetic HCV NS3/4a protease inhibi-
`tor. In a dose finding study of genotype ] nonrespond—
`ers, patients were treated with 14 days of boeeprevir 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
`
`in combination
`2.0610g.,~_.lU/mL.34 Anti—viral effect
`with pcglFNot was subsequently found to be additive,
`achieving a mean maximal reduction of viral
`load of
`2.88 :l: 0.22 logI0 lU/mL at 14 days.
`Boceprevir subsequently progressed to a phase 2
`programme using a higher dose of 800 mg t.d.s.,
`in
`both treatment na't've patients with genotype 1
`infec-
`tion and previous nonresponders. The SPRINT-1 [HCV
`Serine Protease inhibitor Therapy] trial enrolled treat—
`meat—naive patients?5 Patients were randomized to
`one of six treatment arms: 4 weeks of pegll—‘Na-
`Zb/RBV [lead—in phase] followed by the addition of
`boceprevir, BOO mg t.d.s., to the combination for 24 or
`44 weeks
`[totalling 28 or 48 weeks of treatment];
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`boceprevir in combination with peglFNa—Zb/RBV for
`28 or 43 weeks
`[no lead—in phase}; boceprevir
`in
`combination with pegli-‘Na-Zb and low-dose RBV
`{400-1000 mg
`daily]
`for
`48 weeks
`and
`finally,
`pegIFNo—Zb/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 pegIFNot—Zb and RBV prior to the
`introduction of boceprevir. The results of a planned
`interim analysis were recently presented in abstract
`form.35 Virologieal response rates were higher in the
`active treatment arms vs. control (55, 55% {SW} and
`66, 74% (SVRIZ) for 28- and 48-week boceprevir arms
`compared to 38% [SVR [2” [Table 3c}. A role for lead—
`in therapy was not clear; numerically superior interim
`response rates were observed, although the differences
`were not. significant.
`In a second phase 2 study, dose—finding study, boce—
`previr combination therapy was used to treat previous
`nonresponders to peglFNd/RBV. Although the regi-
`mens containing boceprevir yielded higher SVR rates
`compared with control,
`they were
`disappointing
`[?—14% vs. 2%].36 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/peglFNoc
`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 viva
`occurs rapidly in the setting of boeeprevir monothera—
`py.” Common mutations include the VBEM,
`'1‘54S/A,
`R155K, V36L and V170A.“ in vitro studies also indi—
`cate that boccprevir is cross—resistant with tclaprevir.38
`Combination with both pegIFNtt and RBV is necessary
`lnerea sed
`to reduce the emergence of resistancedfi
`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 (2572M; vs.
`14%}. Boccprevir has also
`progressed to phase 3 programmes in naive and prior
`nonresponder patient populations.
`
`Other HCV N53/4o protease inhibitors. Other prote—
`ase inhibitors recently entering phase 1—2 clinical pro—
`grammes
`inelude
`'l‘MC435350
`fl‘ibotee, Meeheien,
`Belgium and Medivir, Huddinge, Swedenln‘m and
`MJK~7009 (Merck, NJ, USA}. On the basis of encour~
`aging preclinical data, R722? [formerly lTMN—lgi;
`
`Intermune, CA, USA and Roche Pharmaceuticals,
`
`Basel, Switzerland] has entered a phase i programme.
`
`(Achillion Pharma-
`ACH—SOS. ACH-806 (GS-9132]
`ceuticals, CT, USA and Gilead Sciences, CA, USA] was
`an agent that inhibited binding of NS4A to the N53
`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
`N53/4a protease complex, without cross—resistance to
`the petidomimetie inhibitors.
`
`NS5B polymerase inhibitors
`
`The HCV NSEB RNA-dependent RNA polymerase is a
`key enzyme involved in HCV replication, eatalysing
`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 nucleosltlide
`and non—nucleosItfide polymerase inhibitors [NI/NNI]
`are currently in development. in addition, the replica—
`tive activity of the dep has recently been reported to
`be. augmented by direct binding to cyclophilin B, a host
`cell isomerase.42 A cyclophilin B inhibitor has also pro-
`gressed to a phase 2 clinical development programme.
`
`N558 Nils. R1626: R1626 [Roche Pharmaceuticals} is
`the. only Ni currently in phase 2 development. R1626
`is the prodrug of R1479, a cytidine nucleoside ana—
`logue. In a phase 1b study, 14 days of treatment with
`1500, 3000 and 4500 mg, b.d., achieved viral
`load
`reductions of
`l.2, 2.6 and 3.? logLOIU/mL respetb
`tively.“ Dose-limiting gastro-intestinal AEs were
`noted in the 4500—mg arm. Mild—to—moderate revers—
`ible. leucopcnia was also noted.
`synergy was
`study,
`in
`a
`subsequent phase
`23
`observed between R1626 and pegll-‘Not :i: RBV when
`used in combination.44 Maximal mean viral load reduc—
`
`tion of 5.2 loglo IUme from baseline was observed in
`the triple treatment arm (R 1626 1500 mg b.d., pegIFNo
`130 gig weekiy and RBV 1000—1200 mg daily], which
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`translated into a rate of RVR of 74%” and an end—of—
`
`trcatment [E'l'Rl response of 81% compared to 5% and
`60% respectively for standard of care.45 Despite this
`finding, high relapse rates were observed at week 72 in
`patients treated with R1626, such that SVR rates were
`equivalent to that achieved in the control group [Table
`3:13.45 This high relapse rate was attributed to cyto-
`penia—related R1626 dose interruptions.
`a high
`Published data suggest
`that R1626 has
`genetic barrier to drug resistance. Although the resis—
`tance mutations 396T and S.‘3‘6’1‘/N1421"“3 have been
`
`identified in vitro, they are yet to be identified in viva.
`using the HCV NSSB phenotypic assay.” as More
`recently, clonal analysis of serum from patients expe—
`riencing virological
`rebound also failed to identify
`resistant nutations.‘la Serum was tested pre— and post—
`treatment, but not during treatment. The.
`low in Ultra
`replication capacity (or fitness} of these resistant repli—
`cons (4—5% of W145} and the relatively low level of
`resistance of these variants to R1626 [four- to fivefold
`decreased susceptibility to R1626“) might account for
`this observation.
`
`Unfortunately, profound haematological toxicity was
`observed when R1626 was combined with peglFNor.‘19
`The rate of grade 4 neutropenia [neutrophil count
`<05 x 10'3 cells/L) was 78% when R1626 was admirtis~
`tcred at a dose of 3000 mg ltd. 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 [RifiZfi/peglFNot/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 ofR1626, despite ongoing peglFNar. Gas~
`trointestinal AEs [vomiting and diarrhoea, particularly
`in the 3000—mg arm) and rash were also more common
`than in controls.
`
`triple therapy with R1626 and peg—
`Therefore,
`IFch/RBV is associated with potent anti—viral effect
`and an encouraging resistance profile. Unfortunately.
`toxicity is an issue. As R1626 moves forwards, it will
`be important to determine whether lower doses of this
`agent with full-dose peglFNa/RBV or lower doses of
`peglFNor with full doses of R1626 are able to minimize
`AEs whilst maintaining efficacy.
`R7128: R7128 lPharrnasset, 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
`
`Aliment Phormocol lher 29, 689—705
`@I 2009 Blackwell Publishing Ltd
`
`observed in genotype 1 previous nonresponders. After
`14 days of treatment,
`a maximum mean decline of
`2.7210ginlU/ml. occurred at
`the highest dose of
`1500 mg b.d.5" No virological rebound was observed.
`The drug was well
`tolerated as monotherapy and no
`serious AEs were reported in any study arm.
`In treatment naive genotype 1 patients,
`the combi-
`nation of R7128 {1500 mg, MI.) in combination with
`pegIFNcr and RBV achieved a reduction in HCV RNA
`of approximately 5 log“I lU/mL at 4 weeks translat—
`ing into an RVR rate of 85% (vs. —2 logm lU/mL and
`10% in the standard of care control atoll."I No viro—
`logical rebound was observed during R7128 treatment
`to 4weeks.
`Importantly, R7128 was generally well—
`tolerated in combination with pcglFNo: and RBV;
`grade 3/4 haematological
`toxicity was rare and not
`different to the control arm (5% vs. 10%]. Headache
`{65% vs. 40%), fatigue (40% vs. 20) and chills (35%
`vs. 20%} were. all more common than control; all
`were classed as mild AEs. Preliminary resistance test—
`ing failed to identify any variants to week 4. This
`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;
`Valopicitabiae: Valopicitabine
`ldenix Pharmaceuticals, MD, USA and Novartis
`international, Basel, Switzerland] was a promising Nl.
`Unfortunately, the FDA placed its clinical development
`on hold in mid-2001’ 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
`N15:
`lDX184
`[ldenix
`Pharmaceuticals,
`
`Cambridge,