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					     H C V treatment
any new hope in the horizon

       Prof. Ali Gaballa, MD
   Professor of internal medicine
         Cairo University
                               New HCV Treatment




New Interferons   Alternative Ribavirin       New HCV Inhibitors           Other Drugs




                                  NS3/4A protease          Inhibitors of HCV
                                     Inhibitors                replication
   Type of drug                       Drug               Manufacturer
New lnterferons         Albinterferon-o2b             Human Genome Sciences &
                        Controlled-release IFN-o2b    Novartjs
                        (LocteronrM)                  Biolex Therapeutics•
                        IFN-a2bXL                     Flamel Technologies
                        1TCA638 (Omega DUROS IFN)     Intarcia Therapeutics
                        Pegylated lFN- (PEG-rlL-29)   Zymogenetics


Alternative Ribavirin   Taribavirin                   Valeant Pharmaceuticals
HCV inhibitors                    PR0206                       Progenix Pharmaceuticals
Entry inhibitors                  Telaprevir (VX-950)          Vertex Pharmaceuticals &Tibotec
NS3I4A protease inhibitors        Boceprevir (SCH 503034)      Schering-Plough
Nucleos(t)ide analogs             TMC43S                       Tibotec
Non-nucleoside RdRp inhibitors    R7227 (ITMN-191)             InterMune & Roche
NS5A inhibitors                   MK-7009                      Merck
Cyclophilin inhibitors            B1201 335                    Boehringer-lngelheim
HCV assembly/release inhibitors   SCH 900518                   Schering-Ploug h
                                  R7128                        Pharmasset & Roche
                                  IDX1 84                      Idenix Pharmaceuticals
                                  GS-91 90                     Gilead Sciences
                                  ANA598                       Anadys Pharmaceuticals
                                  Bl2071 27                    Boehringer-lngelheim
                                  VCH-91 6                     Vertex Pharmaceuticals
                                  Filibuvir (PF-00868554)      Pfizer
                                  BMS-790052                   Bristol-Myers Squibb
                                  DEBIO-025                    DebioPharm
                                  SCY-635                      Scynexis
                                  NIM81 1                      Novartis
                                  Celgosivir                   Migenix


Other drugs                       Nitozoxanide (Alinia) .      Romark Laboratories
                                  Silibinin    (Legalon SIL)   Madaus Rottapharm
           I-New Interferons
•   Albinterferon-α2b
•   Controlled-release INF-α2b (Locteron™)
•   INF-α2bXL
•   ITCA638 (Omega DUROS INF)
•   Pegylated INF-λ (PEG-rlL-29)
II-Alternative Ribavirin


        Taribavirin
       III-New HCV Inhibitors
• NS3/4A protease     •   PRO207
                      •   Telaprevir(VX-950)
  inhibitors          •   Boceprevir(SCH-503034)
• Inhibitors of HCV   •   TMC435
  replication         •   R7128
                      •   IDX184
                      •   GS-9190
                      •   ANA598
                      •   BI207127
                      •   VCH-916
                      •   Filibuvir(PF-00868554)
                      •   BMS-790052
                      •   DEBIO-025
                      •   SCY-635
                      •   NIM811
                      •   Celgosivir
            IV-Other Drugs
• Nitozoxanide (Alinia)
• Silibinin (Legalon SIL)
             I- New Interferons
• Albinterferon-α2b Is an INF-α2b molecule
 attached to a human albumin moeity which has a
 prolonged half-life that allows dosing at intervals of
 2 to 4 weeks.
• Controlled-release INF-α2b (Locteron™)
 which combines a recombinant non-pegylated INF-
 α2b molecule with poly-esther-ester microspheres.
• INF-α2bXL is an INF-α2b molecule linked to the
 Medusa polymer, a self-assembeled poly-aminoacid
 nanoparticles system that can be used as a protein
 carrier for longer acting drug.
• INF Omega (Omega DUROS INF) is a
 glycosylated form of INF omega delivered by
 implantable DUROS device without the need for
 repeated injections.
• Pegylated INF-λ (PEG-rlL-29) is a member
 of novel family of cytokines that are distantly
 related to the type 1 INFs which exhibits dose and
 time dependant inhibition of HCV.
       II-Alternative Ribavirin
• Taribavirin is the only alternative to ribavirin
  -still in development.
• In a recent phase IIb trial a combination
  pegylated INF-α2b with taribavirin dose of 20
  mg/kg, 25mg/kg and 30mg/kg yielded slightly
  higher SVR rates than weight-based dosed
  ribavirin, but the incidence of severe anemia
  was significantly lower.
• However, taribavirin administration was
  associated with higher rates of diarrhea than
  ribavirin.
      III- New HCV Inhibitors
• Advances in virology have led to the
  development of novel therapeutics specifically
  targeting HCV.

• Every step of the HCV lifecycle constitutes a
  potential target for one or several classes of
  inhibitor molecules with one or several target
  sites.
• Target sites includes:
  - Viral attachment, entry and fusion.
  - HCV RNA translation
  - Post translational processing.
  - HCV replication.
  - HCV assembly and release.
• The most promising HCV inhibitors in the
  near term are highly selective NS3/4A
  protease inhibitor and HCV replication
  inhibitor.
             III-HCV Inhibitors
          1-NS3/4A protease inhibitors
• A number of potent NS3/4A protease inhibitors have
  reached phase I, II or III clinicaI development,
  including:
  – Telaprevir (VX-950, Vertex Pharmaceuticals, Cambridge,
    Massachusetts).
  – Boceprevir (SCH 503034, Schering-Plough Corporation,
    Kenilworth, New Jersey).
  – TMC 435 (Tibotec, Mechelen, Belgium).
  – ITMN-191/R7227 (InterMune, Brisbane, California, and
    Roche, Basel, Switzerland).
  – MK-7009 (Merck, Whitehouse Station, New Jersey).
  – BI 201335 (Boehringer-lngelheim, Ingelheim, Germany).
  – SCH 900518 (Schering-Plough).
• All of them are able to reduce HCV RNA
  levels by 3 log or more were administered
  alone over a few days.

• However, selection of HCV variants that are
  resistant to their antiviral action is frequent on
  monotherapy.

• The most advanced molecules are telaprevir
  and boceprevir, both are in phase III
  evaluation.
• Prove 1and Prove 2 are Phase II trials
  assessing the efficacy and safety of telaprevir
  + pegylated INF  2a ± ribavirin in naïve HCV
  genotype 1 in USA and Europe respectively.

• Prove 3 assessed the efficacy and safety of
  telaprevir + pegylated INF  2a ± ribavirin in
  HCV genotype 1 who failed on previous
  treatment with pegylated INF  2a and
  ribavirin.
            Patient
                                                Treatment Arm                              SVRn(5)
            population
                                       pegylated IFN-α2a+ Ribavirin 48 weeks                (41%)


                            Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 24 weeks    (61%)

         Treatment-Naïve,
PROVE1
              Genotype 1                                                                    (67%)
                            Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 48 weeks


                            Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 12 weeks    (35%)
            Patient
                                               Treatment Arm                               SVRn(5)
            population

                                      pegylated IFN-α2a + Ribavirin 48 weeks                (46%)

         Treatment-Naïve,   Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 24 weeks    (69%)
PROV 2
              Genotype 1
                            Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 12 weeks    (60%)

                                 Telaprevir 12 weeks + pegylated IFN-α2a 12 weeks           (36%)
              Patient
                                                   Treatment Arm                               SVRn(5)
              population
                                          pegylated IFN-α2a + Ribavirin 48 weeks                (14%)
         Pegylated IFN-a and
                 ribavirin     Telaprevir 12 weeks + pegylated IFN-α2a + Ribavirin 24 weeks     (51%)
PROVE3
          treatment failure,
                genotype 1     Telaprevir1 24 weeks + pegylated IFN-α2a + Ribavirin 48 weeks    (52%)

                               Telaprevir 24 weeks + pegylated IFN-α2a + Ribavirin 24 weeks     (23%)
• Sustained virological response rates in the
  SPRINT-1 trial.
• A phase II trial testing the combination of
  boceprevir with pegylated IFN-α2b and
  ribavinin, with or without a lead-in phase with
  pegylated IFN-α2b and ribavirin without
  boceprevir, in treatment-naive patients infected
  with HCV genotype 1.
                    SPRINT-1



           Treatment Arm               SVRn(5)



        pegylated IFN-o2b+
                                        (54%)
     Ribavirin+boceprevir, 28 weeks




pegylated IFN-o2b+ Ribavirin 4 weeks
       → pegylated IFN-o2b+             (56%)
     Ribavirin+boceprevir, 24 weeks
            SPRINT-1 (Cont.)

           Treatment Arm               SVRn(5)



        pegylated IFN-o2b+
                                        (67%)
     Ribavirin+boceprevir, 48 weeks



pegylated IFN-o2b+ Ribavirin 4 weeks
       → pegylated IFN-o2b+             (75%)
     Ribavirin+boceprevir, 44 weeks




    pegylated IFN-o2b low dose
                                        (36%)
    Ribavirin+boceprevir, 48 weeks
                 III-HCV Inhibitors
             2-Inhibitors of HCV replication

• The HCV replication process is complex and
  therefore offers a large variety of targets for antiviral
  intervention.
• Direct inhibitors of the HCV RNA-dependent RNA
  polymerase belong to two categories, namely
  nucleoside/nucleotide analogs and non-nucleoside
  inhibitors.

• Other inhibitors of HCV replication include so-called
  NS5A inhibitors and cyclophilin inhibitors.
• Nucleoside/nucleotide inhibitors
  - Target the catalytic site of the viral enzyme.
  - A prodrug of a cytidine analog, R7128 (Pharmasset,
  Princeton, New Jersey, and Roche), is in clinical development.
  - R7128 potently inhibits viral replication, resulting in a 2.7
  log HCV RNA level reduction after 14 days of monotherapy in
  patients infected with HCV genotype 1.
  - R7128 has at least additive antiviral effects to pegylated IFN-
  o2a and ribavirin in patients infected with both HCV genotype
  1 and genotypes 2 and 3.
- The S282T substitution has been reported to confer a 3- to 6
fold loss of sensitivity in vitro to the active derivative of
R7128.
- No resistance-associated substitutions have been selected in
reported studies where R7128 was administered up to 4 weeks.
Longer administration is under study.
- Preliminary results from the INFORM-I trial, which
assessed the efficacy and safety of a combination of R7227
and R7128, showed that the combination has strong antiviral
potency with acceptable safety and tolerability over 14 days of
administration.
• Non-nucleoside inhibitors (NNIs):
 - Target allosteric sites of the RNAdependent
 RNA polymerase.
 - Five such sites, designated A to E, have been
 identified within the polymerase structure, and a
 number of molecules are in preclinical or early
 clinical development.
 - In the replicon system in vitro, NNIs have been
 shown to select numerous resistance-associated
 substitutions at positions generally close to their
 target sites.
 -Rapid selection of highly replicative resistant
 variants by NNIs has been observed.
- Results have been presented for several
molecules in clinical development, including:

   - GS-9190
   (Gilead Sciences, Foster City, California).
   - ANA598
   (Anadys Pharmaceuticals, San Diego, California).
   - B12071 27
   (Boehringer-lngelheim).
   - VCH-916
   (Vertex Pharmaceuticals).
   - Filibuvir
   (PF-008685S4, Pfizer, New York, New York).
• NS5A inhibitors:
  - Have been tested in various models in vitro.
  - The function of NS5A in the HCV lifecycle
  is still unknown, the three-dimensional
  structure of the entire protein has not been
  determined, and no functional assay is
  available.
  - As a result, the supposed action of these
  drugs on NS5A is based on their inhibitory
  effect in replicon assays and on the selection of
  amino acid substitutions in the NS5A protein
  sequence.
- BMS-790052 (Bristol- Myers Squibb, New York, New
York) was recently shown to potently inhibit HCV
replication both in vitro and in patients infected by HCV
genotype 1.
• Cyclophilins:

 - These are host cell proteins that seem to play a
 critical role in HCV replication.

 - Synthetic non-immunosuppressive inhibitors of
 cyclophilins are being tested in patients with
 chronic HCV infection. The actual mode of action
 of these compounds is unclear.
- Cyclophilin inhibitors in development
include:

   - DEBIO-025
   (DebloPharm, Lausanne, Switzerland).
   - SCY-635
   (Scynexis, Research Triangle Park, North Carolina).
   - NIM 811
   (Novartis, Basel, Switzerland).
           IV- OTHER DRUGS
      Other drugs with so far unknown mechanisms of
  anti-HCV action are also in clinical development.
• Nitozoxanide (Alinia).
   – (Romark Laboratories, Tampa, Florida)
   – An approved antiparasitic agent that appears to enhance
     IFN-o responses in HCVinfected patients.
• Silibinin
   – (Madaus Rottapharm) A flavonolignan extracted from the
     milk thistle (Silybum marianum), that induces a significant,
     dose-dependent reduction of HCV RNA levels upon
     intravenous administration.
Thank You

				
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posted:8/31/2012
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