Valopicitabine
(NM283), being developed by Idenix Pharmaceuticals, is an oral hepatitis C
virus (HCV) polymerase inhibitor. It is one of several investigational agents
collectively referred to as "specifically targeted antiviral therapy for
HCV," or STAT-C.
In prior studies, valopicitabine demonstrated dose-related
anti-HCV activity, alone or in combination with pegylated interferon, in genotype
1 patients. As previously reported, in a Phase IIb trial, treatment-naive patients
showed significantly greater HCV RNA reductions with valopicitabine plus pegylated
interferon compared with pegylated interferon monotherapy after 4 weeks.
Longer-term
results from this study were presented at the 57th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) last month in Boston.
The
trial enrolled 173 participants with HCV RNA of at least 5 log IU/mL by the TaqMan
PCR assay, ALT less than 5 times the upper limit of normal, compensated liver
disease, and no prior treatment. Subjects were randomly assigned to 5 treatment
arms:
Group
A: no treatment for 1 week, pegylated interferon alfa-2a (Pegasys) 180 mcg/week
monotherapy through Week 4, valopicitabine added in Week 5 with doses ramped from
400 to 800 mg/day;
Group B: valopicitabine 200 mg/day + pegylated
interferon added in Week 5;
Group C: valopicitabine with doses ramped
from 400 to 800 mg/day during Week 1 + pegylated interferon added in Week 5;
Group
D: valopicitabine 800 mg/day + pegylated interferon added in Week 5;
Group
E: valopicitabine 800 mg/day + pegylated interferon from Day 1.
Results
Week 12 and Week 24 virological response data are shown in the table below.
Compared to prior Week 4 results, Week 12 and Week 24 data showed a convergence
of virological response across treatment groups, due to continued viral clearance
in most patients in all groups.
Early virological response (? 2 log drop in HCV RNA at Week 12) was observed in
82%-92% of patients across the study arms.
By Week 24, the percentages of patients with HCV RNA < 20 IU/mL was similar
in all treatment arms.
The 200 mg/day dose of valopicitabine was generally well tolerated.
Gastrointestinal side effects (nausea, vomiting, diarrhea) were more common --
and occasionally severe -- in patients receiving the 800 mg/day valopicitabine
dose.
15 serious adverse events were reported by Week 24, 5 of which were attributed
to valopicitabine (mostly gastrointestinal).
Mean
HCV RNA decrease from baseline (log IU/mL)
Amplicor HCV RNA negative <600 IU/mL (%)
TaqMan HCV RNA negative <20
IU/mL (%)
Treatment
Group
n
Week
12
n
Week
24
Week
12
Week
24
Week
12
Week
24
A
34
-4.10
34
-4.17
68
74
59
62
B
34
-3.86
34
-4.24
68
71
44
68
C
34
-4.11
34
-4.24
74
71
44
59
D
36
-4.55
36
-4.56
81
81
67
67
E
35
-4.04
36
-3.90
69
63
54
49
Conclusion
"At doses as low as 200 mg/day, valopicitabine plus pegylated
interferon markedly suppresses viremia in treatment-naive patients with HCV [genotype
1] infection," the researchers concluded. "By Week 24, most patients
have achieved PCR-nondetectable HCV RNA by the sensitive TaqMan assay."
The
study is continuing after a protocol amendment to reduce the dose of valopicitabine
to 200 or 400 mg/day plus weekly pegylated interferon, which has led to improved
tolerability.
Alamo Medical Research, San Antonio, TX; Tuan Nguyen,
M.D, San Diego, CA Gastroenterology Center of the Mid-South, Germantown, TX;
AGA Clinical Research Assoc., Egg Harbor, NJ; Atlanta Gastroenterology Associates/Emory
University, Atlanta, GA; Northwest Medical Specialties, Tacoma, WA; Maryland Digestive
Disease Research, Laurel, MD; Rocky Mountain Gastroenterology, Lakewood, CO; Idenix
Pharmaceuticals, Cambridge, MA; Mt. Sinai School of Medicine, New York, NY.
11/10/06
Reference D
Dieterich, E Lawitz, T Nguyen, and others. Valopicitabine (NM283) plus Peg-Interferon
in Treatment-Naive Hepatitis C Patients with HCV Genotype-1 Infection: HCV RNA
Clearance During 24 Weeks of Treatment. 57th AASLD. Boston, MA. October 27-31,
2006. Abstract 93.
Week 12 and Week 24 virological response data are shown in the table below. 
