New interferons are currently being developed to offer
enhanced activity, improved AE profiles and, hopefully, better
tolerability compared with currently available ones (Table 4.1).
Given the dependence of treatment success on patients
adherence, the development of longer-acting IFN formulations,
with improved pharmacokinetic profiles, is an important focus
of HCV therapy. Their main advantages consist in maintenance
of viral suppression across a longer dosing interval, avoidance of
inter-dose trough, and reduced dosing frequencies (twice or
even once per month compared to once per week for the current
pegylated interferons (PegIFNs). Although studies about
improved formulations of interferons have been focused on HCV
genotype 1, their administration can be also valuable for
genotype 2 or 3 infected patients. In easy-to-treat patients
(infected with genotype 2 or 3), the duration of treatment can be
reduced to 12 weeks if a rapid virologic response (RVR) is
obtained. This can translate into a very convenient therapeutic
regimen of only 3 injections, if longer-acting IFNs, with monthly
dosing, are going to be used.
60 | Hepatitis C Treatment
However, not all patients may benefit from these new types of
IFNs. In particular, it seems unlikely that patients with strong
contraindications to the current IFNs will be eligible for
treatment with newer formulations, even if the AEs profiles of
the new IFNs are milder.
Table 4.1 – New interferons in the treatment of Chronic Hepatitis C*
Interferons/
Manufacturer
Description Clinical
trial phase
Interferon alfacon (consensus
interferon- INFERGEN®)
Three Rivers Pharmaceuticals
www.3riverspharma.com
Bio-engineered IFN, consisting
of the most frequently observed
amino acid in each
corresponding position in the
natural alfa IFN
approved
IFN formulations with improved pharmacokinetic profiles
Albinterferon (Zalbin™)
Human Genome Sciences
www.hgsi.com
Recombinant IFN alfa-2b
fused with human albumin
III
IFN preparations with improved side-effect profiles
Pegylated Interferon lambda
Zymogenetics/Bristol-Myers
Squibb
www.zymogenetics.com
Type III interferon with
restricted receptor distribution
(especially on hepatocytes)
II
Controlled-release recombinant interferon systems
Locteron®
BiolexTherapeutics
www.octoplus.nl
Recombinant IFN alfa-2b in
polyetherester microspheres
II
Interferon alfa-2b XL
Flamel Technologies
www.flamel.com
Recombinant IFN alfa-2b with
Medusa® nanoparticles delivery
system
II
Omega Interferon
Intarcia Therapeutics
www.intarcia.com
Delivered with Omega DUROS®-
continuous micropump infusion
system
II
* According to data from: Hepatitis C new drug pipeline
(http://www.hcvdrugs.com, accessed on 4/29/2011); low dose oral interferon
(Amarillo Bioscience) and oral Belerofon (Nautilus) are not included.
Interferon alfacon or consensus interferon (CIFN) (Infergen®,
Three Rivers Pharmaceuticals) is a recombinant, bio-engineered
interferon, consisting of the most frequently observed amino
acid in each corresponding position in the natural alfa IFN. It
Searching for new antiviral therapies | 61
shares an 89%, 30% and 60% homology with IFN alfa, IFN beta
and IFN omega, respectively. The CIFN molecule binds to the
IFN-alfa receptor with higher affinity than all other known IFN
alfa molecules (including the natural subtypes, the variants or
recombinants). In vitro it appears to be approximately 5 to 20-
fold more active than PegIFN alfa-2a and alfa-2b (Gonzalez 2009).
Data derived from clinical trials support the use of CIFN for
treatment-naive patients, particularly those with high VL or
genotype 1 infection (Sjogren 2005), as well as in the retreatment
of relapsers and nonresponders (Leevy 2008).
Clinical trials suggested a dose-dependent rate of viral
clearance, however the maximum tolerated dose of daily CIFN in
difficult-to-treat patients is up to 15 μg/day (Bacon 2009).
Administration of an induction dose (up to 18μg/day) or of a
higher dose (24μg/day), did not translate to better rates of SVRs
and was associated with more serious AEs and more
discontinuations (Meyer 2010).
CIFN is approved as monotherapy for CHC in adults with
compensated liver disease, and, from 2010, for retreatment of
CHC, in combination with RBV, being especially effective for
interferon-sensitive patients with lower baseline fibrosis scores.
IFN lambda (IFN-λ) is a type III interferon (comprising of
IL28A, IL28B and IL29), which has previously demonstrated
strong antiviral activity and good tolerability. IFN-λ mediates
antiviral activity through a different signaling pathway than
type I interferons (such as IFN alfa), having a complex binding
mainly through the IL28 receptor, which is present only on
plasmacytoid dendritic cells, peripheral B cell, hepatocytes and
epithelial cells. This restricted distribution compared to that of
IFN-alfa receptor offers the potential for more targeted hepatic
delivery, as well as for a better tolerability and safety profile
than the conventional interferons in terms of bone marrow
suppression (Sommereyns 2008). IFN-λ can enhance the subsaturating
levels of IFN-ɑ and increase its antiviral efficacy. As a
result, the combination of IFNλ and IFN-ɑ may provide additive
62 | Hepatitis C Treatment
therapeutic effects through the complementary roles of the two
types of cytokines (Pagliaccetti 2008). IFN-λ may be used to
target specific cell responses and to avoid the AEs of IFN-ɑs.
Interferon lambda has been pegylated (Zymogenetics/Bristol-
Myers Squibb); its administration in treatment-naive patients
chronically infected with HCV genotypes 1/2/3/4 resulted in
higher rates of RVR and EVR, which extended across all IL28B
host genotypes, and was associated with fewer hematologic
toxicities, flu-like and musculoskeletal symptoms compared with
PegIFNɑ-2a (Zeuzem 2011). IFN lambda might prove to be
increasingly important for the treatment of CHC, due to the
recent findings (see chapter 1) on the impact of host genetics in
the response to therapy (Tanaka 2010).
Albinterferon (Zalbin™, Human Genome Sciences) is a longeracting
IFN, allowing for once or twice/month dosing schedule. It
consists of IFN alfa-2b genetically fused to recombinant human
albumin. Several unique features of albumin make it an ideal
candidate for integration into a drug-design platform, including
its unusually long half-life (~19 days), wide distribution,
negligible potential for confounding enzymatic or
immunological function and its physiological role as a carrier of
blood substances. The pharmacodynamic attributes of
albinterferon, which include the maintenance of viral
suppression across a longer dosing interval, might reduce viral
rebounds, while also improving patient’s compliance.
In phase III trials, in patients with genotype 1 CHC,
albinterferon (900 μg every 2 weeks) achieved noninferiority
compared with PegIFN alfa-2a, indicating that the two drugs are
equivalent (Nelson 2009). Albinterferon was also administered
with good results in combination with RBV in non-responders to
prior IFN therapy and is evaluated for the treatment of HIV/HCV
coinfected patients. However, the preliminary FDA evaluation
indicates that the licensing of this dosing regimen is unlikely,
due to the unfavorable risk-benefit profile, mainly caused by
slightly increased rates of serious pulmonary AEs, coughing and
Searching for new antiviral therapies | 63
alopecia compared to PegIFN. Development and testing of once
per month dosage is undergoing.
Controlled-release recombinant interferon alfa-2b
formulations were designed to improve the pharmacokinetic
parameters, in order to maintain continuous drug levels and
consequently minimize side effects as compared to current IFNs.
Locteron® (Biolex Therapeutics/OctoPlus) is a recombinant
nonglycosylate IFN alfa-2b produced in polyether-ester
microspheres. This steady controlled-release formulation avoids
fluctuation in IFN levels. A pilot study reported that after
injection of 320 μg Locteron®, the concentration of serum IFN
remained elevated through 14 days (De Leede 2008). Locteron®
can be administered twice monthly, with its trough
concentration between doses maintaining adequate antiviral
activity. Preliminary results of phase IIb studies, showed that in
treatment-naive patients, Locteron®, in combination with RBV,
produced similar viral suppression to that of PegIFN/RBV, with
fewer flu-like side effects and substantially lower rates of
depression.
IFN XL (Flamel Technologies) is an extra-long controlledrelease
formulation of recombinant IFN alfa-2b, based on the
nanoparticles Medusa delivery system, designed for the
tailored delivery of fully-active proteins. Basically this is a
nanoparticle polymer with embedded IFN, which has a slow,
sustained release with increased efficacy. In a phase I study, IFN
XL induced greater reduction in VL after two weeks with fewer
AEs compared to PegIFN (Soriano 2009). A phase IIa study
designed to evaluate IFN XL in combination with RBV in naive
and previous G1 HCV non-responders to SoC is ongoing.
Omega interferon (Intarcia Therapeutics, Inc.) is a type 1
interferon delivered with an osmotic mini-pump implanted
subcutaneously. Omega DUROS® is a drug delivery system that
stabilizes therapeutic proteins, delivering a continuous dose of
omega interferon at a constant rate for 3 months.
enhanced activity, improved AE profiles and, hopefully, better
tolerability compared with currently available ones (Table 4.1).
Given the dependence of treatment success on patients
adherence, the development of longer-acting IFN formulations,
with improved pharmacokinetic profiles, is an important focus
of HCV therapy. Their main advantages consist in maintenance
of viral suppression across a longer dosing interval, avoidance of
inter-dose trough, and reduced dosing frequencies (twice or
even once per month compared to once per week for the current
pegylated interferons (PegIFNs). Although studies about
improved formulations of interferons have been focused on HCV
genotype 1, their administration can be also valuable for
genotype 2 or 3 infected patients. In easy-to-treat patients
(infected with genotype 2 or 3), the duration of treatment can be
reduced to 12 weeks if a rapid virologic response (RVR) is
obtained. This can translate into a very convenient therapeutic
regimen of only 3 injections, if longer-acting IFNs, with monthly
dosing, are going to be used.
60 | Hepatitis C Treatment
However, not all patients may benefit from these new types of
IFNs. In particular, it seems unlikely that patients with strong
contraindications to the current IFNs will be eligible for
treatment with newer formulations, even if the AEs profiles of
the new IFNs are milder.
Table 4.1 – New interferons in the treatment of Chronic Hepatitis C*
Interferons/
Manufacturer
Description Clinical
trial phase
Interferon alfacon (consensus
interferon- INFERGEN®)
Three Rivers Pharmaceuticals
www.3riverspharma.com
Bio-engineered IFN, consisting
of the most frequently observed
amino acid in each
corresponding position in the
natural alfa IFN
approved
IFN formulations with improved pharmacokinetic profiles
Albinterferon (Zalbin™)
Human Genome Sciences
www.hgsi.com
Recombinant IFN alfa-2b
fused with human albumin
III
IFN preparations with improved side-effect profiles
Pegylated Interferon lambda
Zymogenetics/Bristol-Myers
Squibb
www.zymogenetics.com
Type III interferon with
restricted receptor distribution
(especially on hepatocytes)
II
Controlled-release recombinant interferon systems
Locteron®
BiolexTherapeutics
www.octoplus.nl
Recombinant IFN alfa-2b in
polyetherester microspheres
II
Interferon alfa-2b XL
Flamel Technologies
www.flamel.com
Recombinant IFN alfa-2b with
Medusa® nanoparticles delivery
system
II
Omega Interferon
Intarcia Therapeutics
www.intarcia.com
Delivered with Omega DUROS®-
continuous micropump infusion
system
II
* According to data from: Hepatitis C new drug pipeline
(http://www.hcvdrugs.com, accessed on 4/29/2011); low dose oral interferon
(Amarillo Bioscience) and oral Belerofon (Nautilus) are not included.
Interferon alfacon or consensus interferon (CIFN) (Infergen®,
Three Rivers Pharmaceuticals) is a recombinant, bio-engineered
interferon, consisting of the most frequently observed amino
acid in each corresponding position in the natural alfa IFN. It
Searching for new antiviral therapies | 61
shares an 89%, 30% and 60% homology with IFN alfa, IFN beta
and IFN omega, respectively. The CIFN molecule binds to the
IFN-alfa receptor with higher affinity than all other known IFN
alfa molecules (including the natural subtypes, the variants or
recombinants). In vitro it appears to be approximately 5 to 20-
fold more active than PegIFN alfa-2a and alfa-2b (Gonzalez 2009).
Data derived from clinical trials support the use of CIFN for
treatment-naive patients, particularly those with high VL or
genotype 1 infection (Sjogren 2005), as well as in the retreatment
of relapsers and nonresponders (Leevy 2008).
Clinical trials suggested a dose-dependent rate of viral
clearance, however the maximum tolerated dose of daily CIFN in
difficult-to-treat patients is up to 15 μg/day (Bacon 2009).
Administration of an induction dose (up to 18μg/day) or of a
higher dose (24μg/day), did not translate to better rates of SVRs
and was associated with more serious AEs and more
discontinuations (Meyer 2010).
CIFN is approved as monotherapy for CHC in adults with
compensated liver disease, and, from 2010, for retreatment of
CHC, in combination with RBV, being especially effective for
interferon-sensitive patients with lower baseline fibrosis scores.
IFN lambda (IFN-λ) is a type III interferon (comprising of
IL28A, IL28B and IL29), which has previously demonstrated
strong antiviral activity and good tolerability. IFN-λ mediates
antiviral activity through a different signaling pathway than
type I interferons (such as IFN alfa), having a complex binding
mainly through the IL28 receptor, which is present only on
plasmacytoid dendritic cells, peripheral B cell, hepatocytes and
epithelial cells. This restricted distribution compared to that of
IFN-alfa receptor offers the potential for more targeted hepatic
delivery, as well as for a better tolerability and safety profile
than the conventional interferons in terms of bone marrow
suppression (Sommereyns 2008). IFN-λ can enhance the subsaturating
levels of IFN-ɑ and increase its antiviral efficacy. As a
result, the combination of IFNλ and IFN-ɑ may provide additive
62 | Hepatitis C Treatment
therapeutic effects through the complementary roles of the two
types of cytokines (Pagliaccetti 2008). IFN-λ may be used to
target specific cell responses and to avoid the AEs of IFN-ɑs.
Interferon lambda has been pegylated (Zymogenetics/Bristol-
Myers Squibb); its administration in treatment-naive patients
chronically infected with HCV genotypes 1/2/3/4 resulted in
higher rates of RVR and EVR, which extended across all IL28B
host genotypes, and was associated with fewer hematologic
toxicities, flu-like and musculoskeletal symptoms compared with
PegIFNɑ-2a (Zeuzem 2011). IFN lambda might prove to be
increasingly important for the treatment of CHC, due to the
recent findings (see chapter 1) on the impact of host genetics in
the response to therapy (Tanaka 2010).
Albinterferon (Zalbin™, Human Genome Sciences) is a longeracting
IFN, allowing for once or twice/month dosing schedule. It
consists of IFN alfa-2b genetically fused to recombinant human
albumin. Several unique features of albumin make it an ideal
candidate for integration into a drug-design platform, including
its unusually long half-life (~19 days), wide distribution,
negligible potential for confounding enzymatic or
immunological function and its physiological role as a carrier of
blood substances. The pharmacodynamic attributes of
albinterferon, which include the maintenance of viral
suppression across a longer dosing interval, might reduce viral
rebounds, while also improving patient’s compliance.
In phase III trials, in patients with genotype 1 CHC,
albinterferon (900 μg every 2 weeks) achieved noninferiority
compared with PegIFN alfa-2a, indicating that the two drugs are
equivalent (Nelson 2009). Albinterferon was also administered
with good results in combination with RBV in non-responders to
prior IFN therapy and is evaluated for the treatment of HIV/HCV
coinfected patients. However, the preliminary FDA evaluation
indicates that the licensing of this dosing regimen is unlikely,
due to the unfavorable risk-benefit profile, mainly caused by
slightly increased rates of serious pulmonary AEs, coughing and
Searching for new antiviral therapies | 63
alopecia compared to PegIFN. Development and testing of once
per month dosage is undergoing.
Controlled-release recombinant interferon alfa-2b
formulations were designed to improve the pharmacokinetic
parameters, in order to maintain continuous drug levels and
consequently minimize side effects as compared to current IFNs.
Locteron® (Biolex Therapeutics/OctoPlus) is a recombinant
nonglycosylate IFN alfa-2b produced in polyether-ester
microspheres. This steady controlled-release formulation avoids
fluctuation in IFN levels. A pilot study reported that after
injection of 320 μg Locteron®, the concentration of serum IFN
remained elevated through 14 days (De Leede 2008). Locteron®
can be administered twice monthly, with its trough
concentration between doses maintaining adequate antiviral
activity. Preliminary results of phase IIb studies, showed that in
treatment-naive patients, Locteron®, in combination with RBV,
produced similar viral suppression to that of PegIFN/RBV, with
fewer flu-like side effects and substantially lower rates of
depression.
IFN XL (Flamel Technologies) is an extra-long controlledrelease
formulation of recombinant IFN alfa-2b, based on the
nanoparticles Medusa delivery system, designed for the
tailored delivery of fully-active proteins. Basically this is a
nanoparticle polymer with embedded IFN, which has a slow,
sustained release with increased efficacy. In a phase I study, IFN
XL induced greater reduction in VL after two weeks with fewer
AEs compared to PegIFN (Soriano 2009). A phase IIa study
designed to evaluate IFN XL in combination with RBV in naive
and previous G1 HCV non-responders to SoC is ongoing.
Omega interferon (Intarcia Therapeutics, Inc.) is a type 1
interferon delivered with an osmotic mini-pump implanted
subcutaneously. Omega DUROS® is a drug delivery system that
stabilizes therapeutic proteins, delivering a continuous dose of
omega interferon at a constant rate for 3 months.
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