20-F-20-C-Methyl Nucleosides and Nucleotides for the Treatment of Hepatitis C Virus: from Discovery to the Clinic - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 252

defined as the proportion of patients with HCV RNA below the limit of
detection after 28 days of treatment, versus 20% of the SOC patients. 28,29
As part of this study, phenotypic and sequence analyses were performed on
clinical isolates to monitor for the development of viral resistance in vivo.
Sequence analysis of the entire NS5B coding region from all baseline samples
showed no pre-existing S282T mutation and no common amino acid sub-
stitution across the patients treated with RG7128 that could be a predictor of
lack of response to treatment. Phenotypic characterization of the NS5B clinical
isolates obtained from these patients showed that susceptibility to RG7128 and
to IFN was similar between baseline and end-of-treatment samples. These data
show the lack of selection of resistance to RG7128 in HCV genotype 1 after
four weeks of treatment with RG7128 in combination with SOC. 30

11.3.2.4 28-Day Combination Study with RG7128 Added to
SOC in HCV Genotype 2 or 3 Infected Subjects Who
Had Failed Previous Interferon-Based Treatment
Based upon the preclinical data demonstrating similar antiviral potency across
multiple viral genotypes and the excellent antiviral activity observed in HCV
genotype 1-infected patients, a final cohort was studied to demonstrate the
utility of RG7128 for patients infected with HCV genotypes 2 or 3. Thus, a
cohort of HCV genotype 2 or 3 subjects who were non-responders to prior
IFN-based treatment were recruited to receive a 28-day treatment with SOC
alone or 1500mg BID of RG7128 added onto SOC. As was observed in gen-
otype 1 subjects, 1500mg BID plus SOC was generally well-tolerated, with
adverse events similar to those commonly reported for IFN and RBV. Fol-
lowing 28 days of therapy, the combination of RG7128 plus SOC resulted in a
5.03 log 10 decrease from baseline in plasma HCV RNA, versus a 3.26 log 10
decrease from baseline in patients who received SOC alone. Higher rates of
RVR were observed in the RG7128 1500mg BID plus SOC treatment group
versus the SOC only group, with 40% (2/5) of SOC patients achieving RVR
versus 90% (18/20) in the RG7128 1500mg BID plus SOC cohort. 31
As with the HCV genotype 1-infected subjects, phenotypic and sequence
assessments of resistance selection to RG7128 were performed as part of this
combination study in HCV genotypes 2- or 3-infected subjects. Sequence
analysis of the entire NS5B coding region from all baseline samples showed no
pre-existing S282T mutation and no common amino acid substitution across
the patients treated with RG7128 that could be a predictor of lack of response
to treatment. Phenotypic characterization of the NS5B clinical isolates
obtained from these patients showed that susceptibility to RG7128 and to IFN
was similar before and at the end of treatment. These data showed the lack of
selection of resistance to RG7128 in HCV genotypes 2 or 3 after four weeks of
treatment with RG7128 in combination with SOC. 30 This success of RG7128
against genotype 2 and 3 infection represented the first time that a direct-acting
antiviral showed ecacy against non-genotype 1-infected patients,

thus