CPG
10101 (Actilon) is an investigational toll-like receptor 9 (TLR9) agonist
that directly activates dendritic cells and B-cells and indirectly activates natural
killer (NK) cells. These effects may enhance the body's natural response to hepatitis
C virus (HCV) infection mediated by both innate and adaptive immunity.
As
presented at the 57th Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD) last month in Boston, researchers conducted a study
that included 74 HCV genotype 1-infected treatment-refractory relapsed responders
(patients who initially responded but then experienced virological rebound) who
previously received at least 24 weeks of pegylated interferon plus ribavirin.
Patients
were randomly assigned to 5 arms and initially treated for 12 weeks:
In
all relevant arms, CPG10101 was administered at 0.2 mg/kg by subcutaneous injection,
pegylated interferon was dosed at 1.5 mcg/kg once weekly, and ribavirin was dosed
at 800-1400 mg daily.
In
the second part of the study, patients in the CPG10101-containing arms who achieved
at least a 2 log reduction in HCV RNA at Week 12 (early virological response,
or EVR) were eligible to continue treatment for up to 48 weeks. All subjects in
the pegylated interferon/ribavirin arm were eligible to add CPG10101 after completing
the initial 12 weeks, regardless of viral load.
Results
Results by intent-to-treat analyses are shown in the table below.
The mean log HCV RNA reduction at Week 12 was significantly greater in the CPG10101
+ pegylated interferon + ribavirin arm compared with standard therapy.
A greater proportion of patients receiving CPG10101 + pegylated interferon + ribavirin
achieved rapid virological response (RVR) at Week 4, EVR at Week 12, and undetectable
HCV RNA (< 50 IU/mL) compared with those receiving pegylated interferon + ribavirin
without CPG10101.
In the CPG10101-containing arms, 20 of 24 patients with EVR chose to continue
therapy.
An additional 2 patients receiving CPG10101 + pegylated interferon + ribavirin
and 2 receiving CPG10101 + pegylated interferon achieved undetectable HCV RNA
during the continuation period.
On-treatment response, defined as undetectable HCV RNA at Week 24, was achieved
by 7 of 14 patients (50%) in the CPG10101 + pegylated interferon + ribavirin arm
and 3 of 16 subjects (19%) in the CPG10101 + pegylated interferon group.
14 of 15 patients who started on pegylated interferon + ribavirin rolled over
to triple combination therapy with CPG10101 + pegylated interferon + ribavirin.
During
rollover treatment, 5 patients who had persistent detectable HCV RNA at Week 12
achieved undetectable viral load.
2 additional patients achieved a first HCV RNA reduction of more than 2 logs during
the rollover period.
Adverse events were mostly mild or moderate, including headache, flu-like symptoms,
nausea, and injection site reactions (i.e., the expected side effects of interferon).
Wk 12 HCV
RNA log reduction (Mean ± SEM)
Week 12 HCV
RNA <50 IU/mL
Week 12 EVR
≥ 2 log reduction
EVR patients
continuing
Week 24 on-treatment
response HCV RNA <50 IU/mL
P+R (N=15)
2.33 ± 0.38
(N=15)
2 (13%)
9 (60%)
NA
NA
C+P+R (N=14)
3.26 ± 0.26*
(N=14)
7 (50%)**
12 (86%)
11
7 (50%)
C+P (N=16)
2.37 ± 0.37
(N=13)
2 (13%)
9 (56%)
6
3 (19%)
C+R (N=15)
1.42 ± 0.16
(N=13)
0
3 (20%)
3
0
C (N=14)
0.12 ± 0.08
(N=13)
0
0
NA
NA
P
= pegylated interferon; R = ribavirin; C = CPG10101 *P < 0.05 Wilcoxon Rank
Sum vs P+R **P = 0.05 Fisher's Exact Test vs P+R
Conclusion
"In
this study CPG10101 improved early antiviral activity of pegylated interferon
+ ribavirin in treatment-refractory relapsed responder patients," the researchers
concluded. "CPG10101 in combination with pegylated interferon +/- ribavirin
was generally well tolerated. Continuation treatment with CPG1010 + pegylated
interferon +/- ribavirin has led to additional HCV RNA undetectable responses
beyond Week 12."
Patients
will continue to be followed to assess end-of-treatment response and sustained
virological response.
Weill
Medical College of Cornell University, New York, NY; Liver Institute at Methodist
Dallas, Dallas, TX; Alamo Medical Research, San Antonio, TX; Freilich & Brand
LLC, Kansas City, MO; Henry Ford Hospital, Detroit, MI; Indiana University Medical
Center, Indianapolis, IN; Penn State Hershey Medical Center, Hershey, PA; Coley
Pharmaceutical Group, Inc., Wellesley, MA; Duke University School of Medicine,
Durham, NC.
11/10/06
Reference I
M Jacobson, R. Ghalib, E Lawitz, and others. Early Viral Response and On Treatment
Response to CPG 10101 (ACTILON), in combination with pegylated interferon and/or
ribavirin, in chronic HCV genotype 1 infected patients with prior relapse response.
57th AASLD. Boston, MA. October 27-31, 2006. Abstract 96.
Pegylated interferon + ribavirin (standard therapy);
