Biotech Values

[biomaven0]

Very good synergy w/ IFN/rRBV in a 28-day trial. Don't know if the same is true for all nucleotides or not.

ID#


1861

Location:


Hynes: Exhibit Hall C

Time of Presentation:


Nov 02 7:00 AM - 12:00 PM

Category:


R06. HCV Therapy: Preclinical and Early Clinical Development


Clinical synergy of an Anti-HCV Nucleoside Analog with SOC: Viral Kinetics of PSI-7977 with SOC
E. Lawitz1; J. P. Lalezari2; M. Rodriguez-Torres3; K. V. Kowdley4; D. Nelson5; E. DeJesus6; J. G. McHutchison7; A. De La Rosa8; W. Symonds8; M. Berrey8
1. Alamo Medical Research, San Antonio, TX, United States.
2. Quest Clinical Research, San Francisco, CA, United States.
3. Fundacion de Investigacion de Diego, Santurce, PR, United States.
4. Virginia Mason Medical Center, Seattle, WA, United States.
5. University of Florida, Gainesville, FL, United States.
6. Orlando Immunology Center, Orlando, FL, United States.
7. DCRI, Durham, NC, United States.
8. Pharmasset, Inc., Princeton, NJ, United States.


Background: PSI-7977 is a novel uridine nucleotide analog in development for the treatment of HCV which demonstrated a 0.5-2.0 log10 IU/mL decline in a 3-day monotherapy trial. Nucleoside/tide analogs: 1) require intracellular phosphorylation which may result in a slower initial antiviral decline in monotherapy assessments; 2) in vitro select for unfit resistant variants which do not seem to be readily present in the treatment-naïve viral population; and, 3) retain activity against HCV variants with resistance against other classes of antivirals. These characteristics are consistent and predictable, and clinically may be the explanation for the demonstrated potent antiviral activity in combination with alfa-interferon and/or DAA.
Methods: Sixty-three treatment-naïve non-cirrhotic patients infected with HCV genotype 1 (GT-1) were enrolled in a randomized study of PSI-7977 100mg, 200mg, 400mg QD or matching placebo, administered with PEG-IFN/RBV for 28 days. Based upon the 1.0 log10 antiviral decline of PSI-7977 200mg QD in the 3-day monotherapy study, we hypothesized that an additive effect in combination with Peg-IFN/RBV could be predicted by combining the monotherapy response with the observed HCV RNA decline in peg-IFN/RBV alone in the 28-day study.
Results: At study Day 3, subjects receiving placebo with Peg-IFN/RBV had demonstrated a 0.87 log10 IU/mL decline in HCV RNA. A reduction in HCV RNA greater than 1.87 log10 IU/mL [1.0 + 0.87 log10] was considered to be evidence of additive-to-synergistic antiviral activity. 18 patients receiving PSI-7977 200mg QD/SOC demonstrated a 3.3 log10 IU/mL decline at Day 3, or 1.43 logs greater than the anticipated additive antiviral activity of PSI-7977 200mg + Peg-IFN/RBV. 15 patients receiving PSI-7977 400mg QD/SOC demonstrated a 3.6 log10 IU/mL decline, or 0.78 logs greater than the anticipated 2.82 log10 IU/mL additive antiviral activity of PSI-7977 400mg + Peg-IFN/RBV [-1.95 + -0.87 log10 IU/mL]. No patient at any dose of PSI-7977 experienced a virologic breakthrough during the 28 days of drug administration.
Conclusions: PSI-7977 demonstrated greater-than-additive antiviral activity when combined with Peg-IFN/RBV. All patients receiving active PSI-7977 demonstrated continuous declines in HCV RNA, RVR rates of 88-94%, and no viral breakthrough during the 28 days of therapy. These data highlight the potential for a nucleotide-containing combination regimen to produce significant antiviral activity, the extent of which can not be predicted by monotherapy antiviral responses and support additional combination studies to be conducted in the future.

Actually I see now they have similar data on their website, including reductions at the 28 day mark:

http://www.pharmasset.com/pipeline/PSI-7851.asp

# Following 28 days of treatment with PSI-7977 200mg QD with Pegasys plus Copegus, patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 94% (17 of 18) achieved an RVR
# Following 28 days of treatment with PSI-7977 400mg QD with Pegasys plus Copegus, patients achieved a mean 5.3 log10 IU/mL decrease in HCV RNA and 93% (14 of 16) achieved an RVR
# Following 28 days of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.8 log10 IU/mL decrease in HCV RNA and 21% (3 of 14) achieved an RVR