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 262

11.4.3.2 Multiple Ascending Dose Study Over Three Days in
Patients Infected with Genotype 1 HCV
PSI-7851 was evaluated following multiple oral doses of 50, 100, 200, and
400mg or placebo administered QD for three days to 40 treatment-naı¨ ve, HCV-
infected patients. Extensive safety, PK, and virology assessments were con-
ducted throughout the study in order to guide the dose escalations and to assess
the acute antiviral activity of PSI-7851. In this study, PSI-7851 was generally
well-tolerated, with no dose-limiting toxicities identified. Plasma PK exposure
to the prodrug, PSI-7851, was negligible, as observed in the preclinical studies.
The nucleoside metabolite (PSI-6206) exhibited low but consistent plasma
exposure, which increased with dose, a profile consistent with a liver-targeted
prodrug. Following three days of treatment with PSI-7851, HCV RNA
declined in a dose-dependent manner, with mean changes from baseline of -
0.49, -0.61, -1.01, and -1.95 log 10 IUmL 1 in the 50, 100, 200, and 400mg QD
cohorts, respectively. No substantial decline in HCV RNA was observed in the
placebo group. 41 This level of antiviral activity with PSI-7851 exceeded that
estimated at day 3 from the RG7128 monotherapy trial of -1.07 log 10 IUmL
following 1500mg BID, which went on to achieve an 85%RVR in combination
with IFN and RBV. 27,42 In addition, there was no pre-existing or treatment-
emergent S282T mutations detected, nor was there evidence of viral resistance
following three days of monotherapy based upon population sequencing of the
NS5B region. These results support the continued development of PSI-7851 for
the treatment of chronic HCV infection in combination with IFN and RBV, or
as a component of small-molecule combination regimens.
11.5 Summary
The current SOC has provided limited and sometimes intolerable options for
those suffering from HCV infection. The drive to find new medicines to treat
patients with HCV has focused to a large extent on identifying small-molecule
direct-acting antiviral agents. With the HCV NS5B RdRp recognized as an
attractive target for drug therapy, the opportunity to develop nucleoside-based
agents became a viable strategy. The 2 0 -F-2 0 -C-methyl nucleoside class repre-
sented by PSI-6130 was discovered to have a unique ecacy, safety, selectivity,
resistance, and genotype profile not seen with other small-molecule HCV
antivirals. The subsequent development of the PSI-6130 prodrug, RG7128,
demonstrated clinically that a nucleoside for HCV could provide exceptional
clinical ecacy; and, because of its broad genotype coverage and compatibility
with other small-molecule HCV agents, RG7128 showed that a nucleoside
could be combined with other small-molecule anti-HCV drugs to serve as the
cornerstone of future HCV combination therapies. The discovery of PSI-7851
has taken the development of novel HCV nucleos(t)ide therapies to the next
level by providing a method to more eciently deliver the active triphosphate
to the liver, and thus further extending the potential of the 2 0 -F-2 0 -C-methyl
class of nucleoside anti-HCV agents.