Pipeline Innovations in Hepatitis C Treatments

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PEER REVIEW PROVIDED BY
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF MEDICINE
OFFICE OF CME
Pipeline Innovations in Hepatitis C Treatments
Dear Colleague:
For most patients infected with hepatitis C virus (HCV), the current
pharmacologic standard of care is peginterferon in combination with ribavirin.
With this therapeutic approach, HCV is a highly treatable disease for patients
with acute hepatitis C or chronic hepatitis C genotype 2 or 3 infection.
However, approximately 50% of patients infected with HCV genotype 1
do not achieve a sustained virologic response (SVR) with initial interferonbased therapy, and retreatment has yielded poor results. For patients who
have failed interferon-based therapy or for those with contraindications to
interferon, current curative treatment options are limited. As the population of
nonresponders grows larger, the need for novel approaches to HCV care grows
more urgent.
As our understanding of HCV infection evolves, many novel HCV therapies
are being developed. Encouraging data are emerging from a range of treatment
strategies, from entirely novel anti-HCV drug classes to modifications of
current therapies. Initial clinical findings of many of these new agents were
presented at The Liver Meeting 2004, which was held October 28 through
November 2 in Boston, Mass. Although these agents are in the early stages
of clinical development, they preview an exciting future of new therapeutic
options for patients with intractable HCV infection.
In this newsletter, we highlight the latest findings on selected novel HCV
therapies reported at The Liver Meeting 2004. In addition, we invite you
to listen to expert commentary on these promising future HCV therapies,
exclusively at www.projectsinknowledge.com/HCVPipeline. This discussion
is not meant to be all-inclusive, but rather encompasses some of the more
promising approaches currently being evaluated for the treatment of HCV.
Sincerely,
Chair
Target Audience
This activity is designed for gastroenterologists and
other physicians who treat patients with hepatitis C.
Activity Goal
The goal of Pipeline Innovations in Hepatitis C
Treatments is to provide physicians with the latest
clinical information and insights on novel treatments
of HCV as reported from The Liver Meeting 2004.
Learning Objectives
After participating in this activity, the participant should
be able to:
• Identify the mechanisms of action and pharmacokinetics of novel agents being evaluated for the
treatment of HCV infection and relate how these may
be associated with improved antiviral efficacy or
improved tolerability compared with current standard
anti-HCV therapy.
• Incorporate an understanding of the timeline for drug
development into a rationale for current treatment
decisions.
John G. McHutchison,
MD, FRACP
Faculty
• Counsel HCV-infected patients regarding current and
future therapeutic approaches to the nonresponder
population.
Contract for Mutual
Responsibility in CME/CE
Michael P. Manns, MD
Professor of Medicine
Director of the Department of Gastroenterology,
Hepatology, and Endocrinology
Medical School of Hannover
Hannover, Germany
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Nucleoside Analog . . . . . . . . . . . . . . . . . . . . . . . . 2
Viramidine
Immune System Modulators . . . . . . . . . . . . . . . . 2
IC41 Vaccine
CPG 10101
Isatoribine
Inhibitors of Viral Replication . . . . . . . . . . . . . . . . 4
Merimepodib
NM283
Alternative Interferon. . . . . . . . . . . . . . . . . . . . . . 4
Albumin-interferon alfa
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
• Evaluate the emerging safety and efficacy data of new
immune modulators, antiviral agents, and alternative
interferon therapies.
John G. McHutchison, MD, FRACP
Associate Professor of Medicine
Duke University Medical Center
Director, Gastroenterology/Hepatology Research
Duke Clinical Research Institute
Durham, North Carolina
Inside This
Projects In Knowledge has developed the Contract for
Mutual Responsibility in CME/CE to demonstrate
our commitment to providing the highest quality professional education to clinicians, and to help clinicians
set educational goals to challenge and enhance their
learning experience.
Michael P. Manns,
MD
Want to listen to what the experts have to say about the promising future
HCV therapies discussed in this Tx Reporter?
Visit www.projectsinknowledge.com/HCVPipeline, and look for the microphone
icons within the online (HTML) version to access the audio commentary.
For more information on the Contract for
Mutual Responsibility in CME/CE, please go to
www.projectsinknowledge.com.
This independent CME activity is supported by an educational grant
from Valeant Pharmaceuticals International.
Copyright © 2005, Projects In Knowledge, Inc.
Little Falls, NJ 07424. All rights reserved.
R E P O R T E RSM : Pipeline Innovations in Hepatitis C Treatments
CME Information
Statement of Accreditation
Projects In Knowledge is accredited by the Accreditation Council
for Continuing Medical Education to provide continuing medical
education for physicians.
Credit Designation
Projects In Knowledge designates this educational activity for a
maximum of 1.0 Category 1 credit toward the AMA Physician’s
Recognition Award. Each physician should claim only those
credits that he/she actually spent in the activity.
This CME newsletter is planned and implemented as an
independent CME activity in accordance with the ACCME
Essential Areas and Policies.
Successful completion for up to 1.0 hour of CME credit requires a
passing score of 70% or higher on the CME posttest. Full instructions for submission are included on the posttest for this newsletter.
CME Instructions
To receive CME credit for your participation in this CME activity:
1. Read this Tx Reporter newsletter carefully.
2. Complete and submit the CME posttest and evaluation
accompanying this Tx Reporter newsletter.
3. Score 70% or higher on the CME posttest.
Disclosure Information
The Disclosure Policy of Projects In Knowledge requires that faculty
participating in a CME activity disclose to the audience: any significant
relationship they may have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of
their presentation; any relationship with the commercial supporter of
this activity; if discussion includes 1) therapies that are unapproved for
use or are investigational; 2) ongoing research; or 3) preliminary data.
Faculty will disclose such discussion.
For complete prescribing information on the products discussed
during this CME activity, please see your current Physicians’ Desk
Reference (PDR).
Michael P. Manns, MD, has received grant/research support from
Bristol-Myers Squibb Company, Gilead Sciences, Inc, GlaxoSmithKline,
Idenix Pharmaceuticals Inc, Intercell AG, Novartis Pharmaceuticals
Corporation, Roche Pharmaceuticals, and Schering-Plough Corporation;
is a consultant for Bristol-Myers Squibb Company, Gilead Sciences, Inc,
Intercell AG, Schering-Plough Corporation, and Valeant Pharmaceuticals
International; and is on the speakers bureau of Gilead Sciences, Inc,
GlaxoSmithKline, Roche Pharmaceuticals, and Schering-Plough
Corporation.
John G. McHutchison, MD, FRACP, has received grant/research
support from Akros Pharma Inc, Amgen Inc, Bayer Pharmaceuticals,
Biomedicines, Bristol-Myers Squibb Company, Cytel Corporation,
Fujisawa Healthcare, Inc, Gen-Probe, Gilead Sciences, Inc, Idun
Pharmaceuticals, Isis Pharmaceuticals, Inc, Ortho Diagnostic
Systems, Inc, Prometheus Laboratories, Ribozyme Pharmaceuticals,
Inc, Roche Pharmaceuticals, Schering-Plough Corporation,
SciClone Pharmaceuticals, Triangle Pharmaceuticals Inc, and
Vertex Pharmaceuticals, Inc; is a consultant for Amgen Inc, Anadys
Pharmaceuticals, Inc, Centocor, Inc, GlaxoSmithKline, InterMune
Inc, Isis Pharmaceuticals, Inc, National Genetics Institute Inc, Novartis
Pharmaceuticals Corporation, Pfizer Inc, Prometheus Laboratories,
Ribozyme Pharmaceuticals, Inc, and Schering-Plough Corporation; and
is on the speakers bureau of InterMune Inc, Roche Pharmaceuticals,
and Schering-Plough Corporation.
Peer Reviewer has received grant/research support from Roche
Pharmaceuticals, Valeant Pharmaceuticals International, and
Wyeth Pharmaceuticals; is a consultant for Amgen Inc, and Roche
Pharmaceuticals; is on the speakers bureau of Gilead Sciences, Inc, and
Roche Pharmaceuticals; and has received honoraria from Amgen Inc,
Gilead Sciences, Inc, and Roche Pharmaceuticals.
This activity will include a discussion of the investigational uses of
albumin-interferon alfa, CPG 10101, IC41 vaccine, isatoribine,
merimepodib, NM283, and viramidine.
The opinions expressed in this activity are those of the faculty and do
not necessarily reflect those of Projects In Knowledge.
This CME activity is provided by Projects In Knowledge solely as an
educational service. Specific patient care decisions are the responsibility
of the physician caring for the patient.
This independent CME activity is supported by an educational grant
from Valeant Pharmaceuticals International.
2
Introduction
Given the current state of drug development, it
is unlikely that any new therapies for hepatitis C
virus (HCV) infection—regardless of how compelling the early clinical data—will be licensed
in the immediate future. Despite this limitation,
patients and physicians continue to share an
intense interest in novel anti-HCV therapies, and
research in this area is evolving at a rapid pace.
The studies summarized here represent different mechanisms of action and stages of clinical
development, and together provide a snapshot of
the exciting data presented at The Liver Meeting
2004.
Novel agents for the treatment of HCV can be
described as predominantly immunomodulatory
or antiviral in nature. Immune modulators trigger or supplement the endogenous anti-HCV
immune response, whereas antiviral drugs inhibit
HCV replication. As with standard interferon
therapy, some new treatments—particularly
the alternative interferons—may combine both
immunomodulatory and antiviral effects.
Nucleoside Analog
Viramidine
Background
Ribavirin, combined with pegylated interferonalfa, is effective in achieving sustained viral
response (SVR) in the majority of hepatitis C
patients, but it can be associated with hemolytic
anemia. In a review of two trials enrolling
677 HCV patients, Sulkowski and colleagues
found that more than 50% of patients treated
with pegylated interferon-alfa and ribavirin report
decreases in hemoglobin (Hgb) of ≥3.0 g/dL.1
Viramidine, a ribavirin prodrug, escapes this
dose-limiting toxicity by being preferentially
taken up by the liver, resulting in lower ribavirin
levels in the peripheral circulation.2
AASLD Update
Two studies reported in poster sessions clarified the potential role of oral viramidine in
treatment-naive HCV-infected patients. Lin
et al3 found that viramidine yielded lower mean
ribavirin concentrations in plasma and red blood
cells (RBCs) and a smaller mean decrease in Hgb
levels compared with ribavirin. In an open-label,
randomized trial, 87 treatment-naive HCVinfected patients received either viramidine
600 mg twice daily (n = 42) or weight-based
ribavirin 600 mg BID or 600 mg AM and
400 mg PM (n = 45). Measurements of Hgb
and ribavirin levels in plasma and RBCs were
taken at baseline and at weeks 12 and 24.
Viramidine resulted in lower mean drug concentrations compared with ribavirin in both
plasma (0.931 µg/mL versus 1.88 µg/mL)
and RBCs (145 µg/mL versus 251µg/mL).
Viramidine also caused a smaller mean decrease
in Hgb compared with ribavirin (11.4% versus
19.7%). These effects, observed initially at
week 12, remained steady through week 24.
Overall, the findings of this study suggest that
the potential to develop hemolytic anemia is
much lower with viramidine than with ribavirin.3
In a phase II dose-ranging study of 180 treatment-naive HCV-infected patients, Gish et al4
compared the safety and antiviral efficacy of
viramidine and ribavirin. Participants receiving
subcutaneous pegylated interferon alfa-2a
180 µg/wk were randomized to receive oral
viramidine 400 mg (n = 47), 600 mg (n = 43),
or 800 mg (n = 45) twice daily or ribavirin 1000
to 1200 mg/d (n = 45). Patients with genotype
2 or 3 infection were treated for 24 weeks, and
those with genotype 1, 4, 5, or 6 infection were
treated for 48 weeks.
Patients had a median HCV RNA of
6.5 log10 copies/mL at baseline. At the end of
treatment, no significant differences were found
between the viramidine and ribavirin treatment
groups in the proportion of patients with undetectable HCV RNA levels (range, 55%–63%),
regardless of HCV genotype (Figure 1a, see
page 3). However, the incidence of anemia was
significantly lower among patients treated with
400 mg or 600 mg BID viramidine compared
with those treated with 1000 to 1200 mg/d
ribavirin (P < .01) (Figure 1b, see page 3).
All other adverse events were similar between
treatment arms. Final safety and SVR data are
expected in 2005.
Given the equivalent efficacy and lower incidence of anemia with viramidine compared
with ribavirin, 600 mg BID viramidine was
identified as the best dose to evaluate in phase
III viramidine trials.4
Immune System Modulators
IC41 Vaccine
Background
Vaccination with synthetic HCV peptides
induces IFN-gamma–secreting cytotoxic and
helper T-cells when administered with the T-cell
adjuvant poly-L-arginine.5 The new synthetic
peptide IC41 vaccine, which contains cytotoxic
and helper T-cell epitopes of HCV, may
generate a similar immunologic response.
AASLD Update
Manns et al6 evaluated the safety and immunologic profile of the IC41 vaccine in a phase II,
double-blind, placebo-controlled, multicenter
study of 60 HCV-infected patients who
relapsed after or did not respond to prior antiHCV therapy. Patients were randomized to one
of five groups, including three treatment groups
(2.5–5 mg HCV peptides plus 1.25–2 mg polyL-arginine adjuvant, n = 36) and two control
groups (peptide only and adjuvant only,
n = 24). Patients received a total of six vaccinations during the 20-week treatment period.
Patients were evaluated for immunologic
response at weeks 32 and 44.
TREATMENT REPORTER: G A S T R O E N T E R O L O G Y
Undetectable HCV RNA (%)
80
70
63%
62%
56%
55%
60
50
40
30
n = 47
n = 43
n = 45
n = 45
20
10
0
400 mg BID
600 mg BID
800 mg BID 1000/1200 mg QD
Viramidine
Among the 36 patients receiving active IC41
vaccine, 21 had a T-cell response, and 6 of these
showed transient reduction in HCV RNA.
IC41 immunization induced CD4+ helper
T-cells in all three treatment groups and in
the poly-L-arginine control group, but not in
the peptide-only control group. This suggests
that poly-L-arginine must be present to
induce IFN-gamma–secreting T-cells. CD8+
cytotoxic T-cells were induced in the three IC41
treatment groups only. Increasing numbers of
vaccinations led to higher response rates and
more robust responses.
IC41 was well tolerated, with transient local
injection-site reactions, including pain, itching,
induration, edema, and erythema. These
reactions did not worsen with an increasing
number of vaccinations. Discontinuations due
to adverse events were rare (1.67%).
These findings suggest that IC41 is a safe, welltolerated fully synthetic therapeutic peptide
vaccine. Additionally, in nonresponders to and
relapsers following standard therapy, IC41 vaccine is capable of inducing both IFN-gamma–
secreting cytotoxic and helper T-cells.
CPG 10101
Background
CPG 10101 is a member of a new class of
synthetic antiviral immune modulators that act
as agonists of toll-like receptors, which play a
critical role in the recognition and activation of
pathogens by the immune system. CPG 10101
selectively induces cytokines and chemokines,
including IFN-alpha, IFN-gamma inducible
protein-10 (IP-10), and 2’5’- oligoadenylate
synthetase (OAS), an interferon-stimulated gene.
Figure 1b. Incidence of Anemia (Hgb < 10g/dL) at Any Time
During Therapy in Patients Treated With 400 mg,
600 mg, or 800 mg BID Viramidine or
1000/1200 mg/d Ribavirin
30
27%
Patients with Anemia (%)
Figure 1a. Overall End-of-Treatment Response
(Intent-to-Treat Analysis)
25
20
*P < .01 vs ribavirin
15
11%
10
5
0
*
0%
400 mg BID
Ribavirin
AASLD Update
In the first clinical trial of this agent,
McHutchison and colleagues showed that
CPG 10101 induces high levels of endogenous
interferon gamma, helping to restore immune
function that is compromised by chronic viral
infection.7 In the phase Ib study, 31 patients
who either had relapsed after interferon-based
therapy or were treatment naive for anti-HCV
therapy were randomized to control (n = 7) or
CPG 10101 (n = 24) in five sequential dose
groups (0.25 mg, 1 mg, 4 mg, 10 mg, 20 mg).
Data from an ongoing fifth treatment arm of
CPG 10101 20 mg was not included in this
analysis. Patients received subcutaneous CPG
10101 twice weekly for 4 weeks and were
monitored for an additional 4 weeks.
Innate immune response was activated 24 hours
after the first CPG 10101 injection in patients
treated with low-dose CPG 10101, including
0.25 mg (n = 4) and 1.0 mg (n = 6). Compared
with baseline, serum IP-10 levels increased
1.2- to 8.4-fold. This CPG 10101-induced immunologic response also translated into antiviral
activity. Among those who received 1, 4, or
10 mg CPG 10101 (n = 18), six patients had a
≥1-log reduction in HCV RNA and three had
a ≥2-log reduction. RNA reductions were seen
in patients with HCV genotypes 1a (n = 3), 1b
(n = 2), and 2b (n = 1). Viral RNA levels were
reduced from days 1 to 29 but rebounded after
dosing was completed.
Local injection site reactions, which reflect the
immunostimulatory action of CPG 10101, included erythema, pain, pruritus, inflammation,
and swelling. At the highest dose (10 mg), there
was one report each of grade 3 fatigue, asthenia,
pyrexia, rigors, and back pain, and two reports
*
2%
600 mg BID
800 mg BID 1000/1200 mg QD
Viramidine
Ribavirin
each of arthralgia and myalgia. One patient
(4 mg) developed grade 3 neutropenia and one
other patient (10 mg) withdrew due to grade 2
vomiting and diarrhea. No clinically significant
changes in alanine aminotransferase (ALT), aspartate aminotransaminase (AST), or creatinine
phosphokinase were observed. Results of additional dose escalation to 20 mg are pending.7
Isatoribine
Background
Another toll-like receptor agonist, isatoribine
is a guanosine analog that activates innate
immunity. Although isatoribine has no direct
in vitro activity against RNA or DNA viruses,
it is thought to accelerate HCV clearance by
increasing localized cytokine signaling.
AASLD Update
Horsmans and colleagues reported that treatment with isatoribine significantly reduced
plasma HCV RNA while avoiding the adverse
effects associated with interferon-based therapy.8
Of the 25 patients enrolled in the proof-of-concept trial, 15 were treatment-naive and 10 had
relapsed from interferon-based therapy. Patients
were treated with intravenous isatoribine
(60–80-min infusion) 200 to 800 mg once daily
for 7 days, during which serial blood samples
were collected and assayed for plasma isatoribine, plasma HCV RNA, and expression of 2’5’OAS, which is typically induced by interferon.
Isatoribine was eliminated with a short half-life
(~2 h) and plasma clearance (~30 L/h) that
was independent of dose. Isatoribine did not
accumulate in plasma during once-daily dosing.
After 7 days of treatment, OAS expression in
blood was increased and plasma HCV RNA
was decreased, with changes from baseline that
3
R E P O R T E RSM : Pipeline Innovations in Hepatitis C Treatments
more frequent with NM283
doses ≥400 mg/d.
Table 1. Effects of Isatoribine on Plasma HCV RNA and OAS Levels
Patients
(N)
HCV
Genotype 1
N (%)
Mean ± SD Baseline
Plasma HCV RNA
(Log IU/mL)
Mean ± SD Log
Viral Load Change,
EOT Minus Baseline
Mean ± SD Blood
OAS Ratio
EOT, Baseline
200
4
3 (75%)
6.4 ± 0.1
-0.03 ± 0.16
3.4 ± 2.3
400
4
1 (25%)
5.7 ± 0.2
-0.39 ± 0.44
4.5 ± 3.1
600
5
3 (60%)
5.9 ± 0.6
-0.24 ± 0.28
7.5 ± 2.0*
800
12
10 (83%)
5.5 ± 0.6
-0.76 ± 0.81*
7.5 ± 5.3*
Isatoribine
(mg/d)
*P < .01, paired t-test versus baseline; EOT = end of treatment; OAS = oligoadenylate synthetase.
were statistically significant at the 800 mg/d
dose (Table 1). After a 7-day washout, OAS
expression and plasma HCV RNA returned
to pretreatment levels.
Isatoribine appears to be safe and well tolerated,
with no reports of serious adverse events and no
discontinuations due to adverse events or clinical laboratory abnormalities. The most frequent
adverse events were insomnia (n = 4), joint pain
(n = 4), and asthenia (n = 3), all of which were
mild or moderate.
Inhibitors of Viral Replication
Merimepodib
Background
Merimepodib selectively inhibits inosine
monophosphate dehydrogenase, an enzyme
believed to be important to HCV replication.
At the annual meeting of the European
Association for the Study of the Liver in
April 2004, Marcellin et al reported that
merimepodib improved the antiviral effect
of peginterferon alfa-2b and ribavirin
combination therapy in patients who did not
respond to standard interferon plus ribavirin.9
AASLD Update
75%, and 80% of patients in quartiles 1, 2, 3,
and 4, respectively, of merimepodib exposure,
this relationship appears to follow a linear doseresponse curve. Younger age and ribavirin Ctrough
levels were the only other significant predictors of
virologic response at week 12. In addition, anemia
was correlated with ribavirin Ctrough levels but
not with merimepodib exposure. On the basis of
these findings, higher doses (50 and 100 mg every
12 hours) of merimepodib are being explored in a
phase IIb study.10
NM283
Background
NM283 is an RNA polymerase inhibitor with
antiflavivirus activity in vitro and in HCVinfected chimpanzees. Earlier this year, Godofsky
et al reported findings from a phase I/II study
that showed NM283 has consistent, dose-related
antiviral activity against genotype 1 HCV.11
AASLD Update
Afdhal and colleagues reported findings of a
phase I/II dose-escalation study of NM283 in
difficult-to-treat, predominantly nonresponding
patients infected with genotype 1 HCV.12
Patients in eight sequential cohorts were
randomized to increasing doses (50–800 mg/d)
of NM283 or placebo for 15 days and
monitored for an additional 2 weeks. Among
the 94 patients who completed the study,
13% were treatment naive and 87% were prior
nonresponders to interferon-based therapies.
In a phase IIa study reported by Zha et al,
merimepodib enhanced the antiviral effect of
peginterferon/ribavirin combination therapy
without exacerbating ribavirin-associated
anemia.10 The study enrolled 31 patients with
genotype 1 infection who were nonresponsive
to interferon/ribavirin therapy. Patients were
given peginterferon/ribavirin and one of three
study treatments: placebo, merimepodib 25 mg
every 12 hours, or merimepodib 50 mg every
12 hours. Pharmacokinetic and pharmacodynamic parameters included steady-state area
under the plasma concentration-time curve
(AUC0-12h) and trough plasma concentration
(Ctrough) of ribavirin.
NM283 consistently reduced HCV RNA
levels in all dose groups, ranging from a mean
0.2 log10 reduction at the lowest dose (50 mg/d)
to a mean 1.2 log10 reduction at the 800 mg/d
dose. Among those treated with 800 mg/d,
individual patient HCV RNA reductions ranged
from 0.41 log10 (61% reduction) to 2.37 log10
(>99% reduction). By contrast, HCV RNA
levels rose by 0.03 log10 (7% increase) among
patients treated with placebo.
At week 12, patients were categorized as virologic
responders (≥2-log drop in HCV RNA viral
load) or nonresponders. Virologic responders had
a significantly higher merimepodib AUC0-12h
compared with nonresponders (P = .0103). Given
that virologic responses were seen in 0%, 60%,
No serious adverse events, treatment-limiting
toxicities, patterns of laboratory abnormalities,
or adverse-event–related discontinuations were
reported in this study. The most common
adverse event was nausea with occasional
vomiting, which was mild, self-limited, and
4
In addition to reporting results
of the dose-escalation study,
Afdhal also presented initial
findings of an ongoing phase
II trial of NM283 in combination with peginterferon. For
the 28-day trial, 30 patients
were randomized to NM283
monotherapy (n = 12 patients)
or NM283 plus 1 µg/kg subcutaneous peginterferon on days
8, 15, and 22 (n = 18). In all
patients, NM283 was titrated
to 800 mg/day by day 8.
To date, 19 patients have completed 28 days
of treatment. Overall, these patients have
experienced a mean 0.7-log reduction in HCV
RNA. Among the 12 patients who received
combination therapy, nine patients achieved
≥1-log10 reduction by week 4, suggesting that
the combination of NM283 and peginterferon
may result in synergistic antiviral activity.
Given the promising early findings of the phase
II trial, expanded clinical testing of NM283,
alone and in combination with peginterferon,
is currently under way.12
Alternative Interferon
Albumin-interferon alfa
Background
Albumin-interferon alfa is a new 87.5 kDa
recombinant polypeptide consisting of
interferon-alfa genetically fused to human
serum albumin. The resulting fusion protein
combines the antiviral properties of interferonalfa with the long serum half-life of albumin.13
AASLD Update
Balan and colleagues presented data that show
that nearly half of HCV-infected patients who
have failed prior interferon-based therapy can
achieve an antiviral response with the albumininterferon alfa fusion protein.14
The phase I/II, open-label, albumin-interferon
dose escalation study enrolled 119 patients
(93% HCV genotype 1) who failed prior
interferon-based therapy. Patients received
7 to 900 µg albumin-interferon in one or two
subcutaneous injections every 2 weeks for a
mean treatment period of 68 weeks.14
Albumin-interferon reduced HCV RNA by at
least 0.5 log10 in each dose group (Figure 2, see
page 5). Among patients receiving 120 to
900 µg albumin-interferon (n = 78), 47%
achieved an antiviral response (>1-log reduction
at any time point). In addition, gene expression
analysis showed that interferon response genes
were induced. Viral kinetics shows a biphasic
decline of HCV RNA after administration of
albumin-interferon.
TREATMENT REPORTER: G A S T R O E N T E R O L O G Y
Over the 120 to 600 µg dose range, median
terminal half-life was approximately 143 hours.
Given its reduced clearance and extended halflife, the pharmacokinetic profile of albumininterferon supports dosing every 2 to 4 weeks.
Therefore, albumin-interferon may be dosed
less frequently than peginterferon.
Albumin-interferon was well tolerated with no
discontinuations. Adverse events were transient,
and most were mild to moderate. Most
common adverse events were headache (49%),
fatigue (41%), injection site erythema (31%)
and pyrexia (27%). Reversible neutropenia
(ANC < 750) occurred in 23% of patients.
these and other agents will allow us to optimize
outcomes in patients with HCV.
As previously mentioned, no novel therapy
is likely to be licensed in the next few years
given the protracted drug approval process,
even if clinical trials progress within a reasonable time frame. Therefore, in patients with
strong indications for treatment, therapy
should not be deferred in the hope of being
able to access alternative agents soon. Many
nonresponders to standard therapy are highly
Figure 2. Albumin/IFN Fusion Protein and HCV RNA Reduction—Maximum HCV
RNA Reduction by Dose Group
Patients
Conclusions
Several novel agents have the potential to address the unmet need for anti-HCV treatment
in nonresponders to standard IFN-based
therapy. Some new treatments may offer the
same efficacy but reduce the dose-limiting adverse events associated with current therapies,
such as ribavirin-induced hemolytic anemia.
Immune modulators enhance or supplement
the body’s innate immunity, resulting in the
increased clearance of HCV. Antiviral agents
directed against key enzymes serve to cripple
HCV replication and boost the efficacy of
peginterferon. Interferon alternatives, such as
albumin-bound interferon, offer the potential
for prolongation of half-life, and therefore, less
frequent dosing. Each of these represents an important advance in the treatment of HCV infection, and findings from ongoing clinical trials of
motivated to participate in clinical trials of
new agents and should be encouraged to do so.
Two important patient groups to be included
in future investigations are nonresponders, particularly those with advanced fibrosis/cirrhosis,
who may not be eligible for participation in
the early phase of novel drug development,
and the growing population of relapsers to
peginterferon and ribavirin, in whom novel
agents combined with standard therapy might
prove particularly effective. TX
24 –
22 –
20 –
18 –
16 –
14 –
12 –
10 –
8–
6–
4–
2–
0–
Single Injection
Double Injection
20
>0.5 log
>1.0 log
16
14
12
8
6
7
8
6
3
3
0
7-80
120-240
320-500
600-900
7-80
400-900
Albumin/IFN Dose (µg)
References
1. Sulkowski MS, Wasserman R, Brooks L, et al. Changes in hemoglobin during interferon alpha-2b plus ribavirin combination therapy for chronic hepatitis C virus infection.
J Viral Hepat. 2004;11:243-250.
2. Lin CC, Philips L, Xu C, et al. Pharmacokinetics and safety of viramidine, a prodrug of ribavirin, in healthy volunteers. J Clin Pharmacol. 2004;44:265-275.
3. Lin CC, Xu C, Teng A, et al. Dosing with viramidine in HCV patients resulted in lower plasma and RBC ribavirin levels and exhibited smaller decreases in hemoglobin
compared to ribavirin dosing [abstract 515]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004;
Boston, Mass.
4. Gish RG, Arora S, Nelson D, et al. End-of-treatment (EOT) response in therapy-naïve patients treated for chronic hepatitis C with viramidine in combination with pegylated
interferon alfa-2a [abstract 519]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004; Boston, Mass.
5. He XS, Rehermann B, Lopez-Labrador FX, et al. Quantitative analysis of hepatitis C virus-specific CD8(+) T cells in peripheral blood and liver using peptide-MHC tetramers.
Proc Natl Acad Sci U S A. 1999;96:5692-5697.
6. Manns MP, Berg T, Wedemeyer H, et al. Immunization with the therapeutic hepatitis C virus (HCV) peptide vaccine IC41 in 66 chronic hepatitis C non-responder patients
[abstract 195]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004; Boston, Mass.
7. McHutchison JG, Bacon BR, Gordon SC, et al. Human pharmacologic activity of a new TLR9 agonist antiviral, CPG 10101 (ACTILON™) [abstract 1224]. Presented at: 55th
annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004; Boston, Mass.
8. Horsmans Y, Berg T, Virchow-Klinikum C, et al. Isatoribine, a toll-like receptor 7 agonist, significantly reduced plasma viral load in a clinical proof-of-concept study in patients with
chronic hepatitis C virus infection [abstract 270]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004; Boston,
Mass.
9. Marcellin P, Horsmans Y, Nevens F, et al. A phase II, placebo-controlled study of merimepodib (VX-497), in combination with pegylated interferon-alfa, and ribavirin in patients
with chronic hepatitis C non-responsive to previous therapy with interferon-alfa and ribavirin. Program and abstracts of the 39th Annual Meeting of The European Association
for the Study of the Liver; April 14-18, 2004; Berlin, Germany. Abstr 492.
10. Zha J, Garg V, McNair L. Pharmacokinetic-pharmacodynamic relationships of merimepodib and ribavirin in pegylated interferon-alfa/ribavirin/merimepodib treated genotype-1
HCV patients non-responsive to previous therapy with interferon-alfa/ribavirin [abstract 193]. Presented at: 55th annual meeting of the American Association for the Study of
Liver Diseases; October 29-November 2, 2004; Boston, Mass.
11. Godofsky E, Afdhal N, Rustgi V, et al. The first clinical results for a novel antiviral treatment for hepatitis C: a phase I/II dose escalation trial assessing tolerance, pharmacokinetics,
and antiviral activity of NM283. Program and abstracts of the 39th Annual Meeting of The European Association for the Study of the Liver; April 14-18, 2004; Berlin, Germany.
Abstr 96.
12. Afdhal N, Godofsky E, Dienstag J, et al. Final phase I/II trial results for NM283, a new polymerase inhibitor for hepatitis C: antiviral efficacy and tolerance in patients with
HCV-1 infection, including previous interferon failures [abstract LB-03]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October
29-November 2, 2004; Boston, Mass.
13. Osborn BL, Olsen HS, Nardelli B, et al. Pharmacokinetic and pharmacodynamic studies of a human serum albumin-interferon-alpha fusion protein in cynomolgus monkeys.
J Pharmacol Exp Ther. 2002;303:540-548.
14. Balan V, Sulkowski S, Nelson D, et al. Albuferon™- a novel therapeutic agent for hepatitis C: results of a phase I/II study in treatment experienced subjects with chronic
hepatitis C [abstract 265]. Presented at: 55th annual meeting of the American Association for the Study of Liver Diseases; October 29-November 2, 2004; Boston, Mass.
1708
5
CME Posttest
SM
PEER REVIEW PROVIDED BY
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF MEDICINE
OFFICE OF CME
Pipeline Innovations in Hepatitis C Treatments
CME Instructions
To receive CME credit for your participation in this CME activity, please complete the following steps:
1. Read this newsletter carefully.
2. Complete the CME Posttest below, selecting the most appropriate response to each question.
3. Complete the CME Evaluation.
4. Send photocopies of the Posttest and Evaluation to Projects In Knowledge, Overlook at Great Notch, 150 Clove Road, Little Falls, NJ 07424,
or fax to: 973-890-8866 by January 26, 2006. Please note that we cannot issue certificates of CME credit without both documents.
If you complete these steps and score 70% or higher, Projects In Knowledge will mail you an acknowledgment of participation within 6 weeks of receipt
of your materials. If you score lower than 70%, you will be notified by mail and given another opportunity to retake the test.
Name __________________________________________________________________ Degrees/Credentials __________________
Mailing Address ______________________________________________________________________________________________
City _____________________________________________________________________ State ________ ZIP ________________
Office Phone ___________________________________________ Office Fax ____________________________________________
E-mail ______________________________________________________________________________________________________
Please select the most appropriate response to each question.
1. The biggest therapeutic limitation of ribavirin is:
A. Dose-limiting renal toxicity
B. Dose-limiting hepatic toxicity
C. Dose-limiting hemolytic anemia
D. Narrow safe dosing range
2. Which of the following is true of pegylated interferon/viramidine combination therapy?
A. Its on-treatment antiviral activity is comparable to that of pegylated interferon/ribavirin
B. It has similar efficacy to pegylated interferon and ribavirin in all HCV genotypes
C. Compared with ribavirin, it is associated with a significantly lower incidence of anemia
D. All of the above
3. The IC41 vaccine induces what type of immune response?
A. Activation of CD4+ T cells
B. Activation of CD8+ T cells
C. Activation of B cells
D. A & B only
4. Which of the following is an effect of isatoribine?
A. Acceleration of HCV clearance
B. Stimulation of innate immunity
C. Promotion of localized cytokine signaling
D. All of the above
5. Which of the following is not a feature of the albumin/IFN fusion protein?
A. The antiviral properties of IFN
B. The long serum half-life of albumin
C. Dose-limiting toxicity
D. Efficacy in patients who have failed IFN-based therapy
1708PT
CME
Evaluation Survey
SM
PEER REVIEW PROVIDED BY
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF MEDICINE
OFFICE OF CME
Pipeline Innovations in Hepatitis C Treatments
Name _____________________________________________________ Degrees/Credentials _______________________________
Address ___________________________________________________________________________________________________
City ______________________________________________________ State _______________ ZIP _______________________
Instructions: Please complete this survey, along with the CME Posttest, and mail or fax (both sides) to Projects In Knowledge, 150 Clove Road,
Little Falls, NJ 07424; fax: 973-890-8866. We cannot issue CME certificates of credit without both documents.
1.
Please rate the extent to which you achieved the learning objectives:
●
Excellent
Very Good
Good
Satisfactory
Poor
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
❑
Identify the mechanisms of action and pharmacokinetics of
novel agents being evaluated for the treatment of HCV infection
and relate how these may be associated with improved antiviral
efficacy or improved tolerability compared with current standard
anti-HCV therapy.
●
Evaluate the emerging safety and efficacy data of new immune
modulators, antiviral agents, and alternative interferon therapies.
●
Incorporate an understanding of the timeline for drug development
into a rationale for current treatment decisions.
●
Counsel HCV-infected patients regarding current and future
therapeutic approaches to the nonresponder population.
2.
Please rate the extent to which this activity achieved the stated goal:
The goal of Pipeline Innovations in Hepatitis C Treatments is to provide
physicians with the latest clinical information and insights on novel
treatments of HCV as reported from The Liver Meeting 2004.
Strongly
3.
Course was free from commercial bias:
Strongly
Agree
Agree
Disagree
Disagree
❑
❑
❑
❑
If you “Disagree” or “Strongly Disagree,” why?.....................................................................................................................................................
..................................................................................................................................................................................................................................
Strongly
4.
5.
Course was objective and independent:
Please rate the level of the material presented:
Strongly
Agree
Agree
Disagree
Disagree
❑
❑
❑
❑
Just Right
Too Advanced
Too Basic
❑
❑
❑
1708 EM—Page 1 of 2
Name ______________________________________________________________________________________________________
CME
Evaluation Survey
SM
PEER REVIEW PROVIDED BY
UNIVERSITY OF PENNSYLVANIA
SCHOOL OF MEDICINE
OFFICE OF CME
(cont’d)
Pipeline Innovations in Hepatitis C Treatments
6. Please list any changes in your practice that you would consider making as a result of participating in this activity:
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
7. Please rate your interest in self-directed or distance learning in the following formats:
Very Interested
Moderately Interested
Not Interested
a. Audioconference
❑
❑
❑
b. Videoconference
❑
❑
❑
c. Enduring materials (audio CDs, videotapes, monographs)
❑
❑
❑
d. Internet (online discussions with experts, educational activities)
❑
❑
❑
e. Multimedia (online, CD-ROM)
❑
❑
❑
8. Please tell us exactly how long it took you to complete this course (circle minutes):
Minutes: 0
15
30
9. Please list topics and/or experts you would find interesting and professionally relevant for future CME activities:
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
10. Follow-up:
As part of our ongoing continuous quality-improvement effort, we conduct postactivity follow-up surveys to assess the impact of our
CME courses on professional practice. Please indicate your willingness to participate in such a survey:
❑ Yes, I would be interested in participating in a follow-up survey.
❑ No, I’m not interested in participating in a follow-up survey.
11. Additional comments about this activity: ............................................................................................................................................................
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
..................................................................................................................................................................................................................................
Thank you for your participation.
1708 EM—Page 2 of 2