Pharmasset, Where innovation is viral

1. www.pharmasset.comwww.pharmasset.com
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2. Attributes of an ideal DAA for HCV
“Must have”
High barrier to resistance
Safety & tolerability to support dosing for the duration
necessary to achieve viral clearance
Additional benefits, or required
Pan-genotype activity
Low risk of drug-drug interactions

3. “Potency” vs “Barrier to resistance”
“alpha” vs “beta” slopes?
-6
-5
-4
-3
-2
-1
0
0 2 4 6 8 10 12 14
Days
HCVRNAChangefromBaseline(log10IU/mL)
Cohort 1: 938 mono

4. EASL 2011: Accepted Abstracts
PSI-7977: PROTON
– Once Daily PSI-7977 plus PegIFN/RBV: Rapid Virologic Suppression in
Treatment Naïve Patients with HCV GT2/GT3 in a Phase 2b Trial (Oral)
PSI-938: NUCLEAR
– PSI-352938, A Novel Purine Nucleotide Analog, Exhibits Potent Antiviral
Activity and No Evidence of Resistance in Patients With HCV Genotype 1
Over 7 Days
– Mechanism of HCV Replicon Resistance to PSI-352938, a Cyclic
Monophosphate Prodrug of 2’-α-F-2’-β-C-Methylguanosine
Latebreaker abstracts
– Once Daily Dual-Nucleotide Combination of PSI-938 and PSI-7977 Provides
94% HCV RNA <LOD at Day 14: First Purine/Pyrimidine Clinical
Combination data ( The NUCLEAR Study)
– Once Daily PSI-7977 Plus Peg-IFN/RBV in HCV GT1: 98% Rapid Virologic
Response, Complete Early Virologic Response: The PROTON Study

5. Which patients will benefit most markedly from
availability of the first generation protease
inhibitors?

6. TVR: PROVE-2 predictors of SVR

7. How much of the patient pool can be
treated with 1st
generation PI regimens?
TVR/SOC Regimen IFN-free Nucleotide Regimens

8. PSI-7977

9. PSI-7977 is a Potent and Specific
Nucleotide Analog Polymerase Inhibitor for HCV
USPTO issued patent (exp. 2025)
– Applications pending – if issue (exp. 2028)
Once-daily broad genotype coverage
Exceptional antiviral activity
– 93% RVR in 28day GT1
– 100% RVR and cEVR in GT2/3
No virologic breakthrough in 12 weeks of therapy (GT2/3)
Generally safe and well tolerated in clinical studies to date
Phase 2b PROTON trial ongoing in HCV GT1, GT2/3
– GT2/3 arm: Interim 12 week data reported1
– GT1 arms completed enrollment1
PSI-7977PSI-7977
O
CH3
FHO
O
N
NH
O
O
P
O
O
N
H
O
O CH3
1
Pharmasset Press Release dated 1/6/2011

10. PSI-7977: What do we know?
Feb 2009 – PSI-7851 Single Ascending Dose (HVT)
– No maximum tolerated dose up to 800mg
June 2009 – Multiple Ascending Dose (HCV GT1)
– ~2 log decline at d3, no resistance
Jan 2010 – Relative Bioavailability Study
– PSI-7977 100mg tablet acceptable to move into Ph 2a
Spring 2010 – 28 day HCV GT1 Phase 2a study
– 200mg & 400mg QD with PEG/RBV yielded 93-94% RVR
– No apparent impact of IL28B genotype
– No evidence of S282T
– SVR24 achieved with <24 weeks PEG/RBV
– No AE-related discontinuations, no dose-related lab changes

11. PSI-7977 Phase 2a:
No impact of IL28B on HCV RNA Response
C/C
C/T or T/T
PSI-7977 200mgQD+SOCIndividuals
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70 77 84
Study Day
HCVRNA(log10IU/mL)
PSI-7977 400mgQD+SOCIndividuals
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70 77 84
Study Day
HCVRNA(log10IU/mL)

12. ‘The best way to prevent resistance is to
cure the patient’ M. Sulkowski
0
1
2
3
4
5
6
7
0 28 56 84 112 140 168 196 224
Study Day
HCVRNA(IU/mL)
0
1
2
3
4
5
6
7
0 28 56 84 112 140 168 196 224
Study Day
HCVRNA(IU/mL)
54 yo NA M
HCV GT 1a
IL28B C/C
BMI 25
HOMA-IR 0.84
40 yo WM
HCV GT 1a
IL28B C/C
BMI 22
HOMA-IR 3.2
Peg-IFN dose-reductions:
@ d14 180-135 & d21 135-90
SVR24
SVR24
Study Week
Study Week
4 8 12 16 20 24 28
4 8 12 16 20 24 28
PSI-7977
400mg QD
+ SOC

13. PSI-7977: ELECTRON
How little Interferon is sufficient?
Objective: to explore the role of IFN in combination with PSI-7977
Treatment-naïve patients with HCV GT2 or GT3
Primary efficacy endpoint : SVR
Status: enrolling
Wk 0 4 12 368
PSI-7977 400 mg QD + RBVPSI-7977 400 mg QD + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD + RBVPSI-7977 400 mg QD + RBV
PSI-7977 400 mg QD Peg-IFN + RBVPSI-7977 400 mg QD Peg-IFN + RBV PSI-7977 400 mg QD + RBVPSI-7977 400 mg QD + RBV
PSI-7977 400 mg QD + Peg-IFN + RBVPSI-7977 400 mg QD + Peg-IFN + RBV
SVR
Follow-Up
SVR
Follow-Up
A
n=10
B
n=10
C
n=10
D
n=10
ELECTRON

14. PSI-7977: ELECTRON
Enrollment to date: n=21
HCV GT3 (14) > GT2 (7)
Earthquake 22 Feb 2011
Similar viral kinetics in 1st
4
weeks
No rebound after last PEG
dose while on PSI-7977
First patients complete wk
12 on 04MAR2011
A
n=10
B
n=10
C
n=10
D
n=10
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70
Days
HCVRNA(log10IU/mL)
1: 12w PSI/RBV
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70
Days
HCVRNA(log10IU/mL)
2: 4w PSI/RBV/PEG+8w PSI/RBV
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70
Days
HCVRNA(log10IU/mL)
3: 8w PSI/RBV/PEG+4w PSI/RBV
0
1
2
3
4
5
6
7
8
0 7 14 21 28 35 42 49 56 63 70
Days
HCVRNA(log10IU/mL)
4: 12w PSI/RBV/PEG

15. PSI-7977 Phase 2b PROTON
Enrollment Complete
25 treatment-naïve patients with HCV GT2/3
– “12+0” for all patients
12 Week safety/EOT: 1/6/2011 PR; SVR12 data: 2Q11
125 treatment-naïve patients with HCV GT1
– Response-guided therapy
– IL28B stratified
12 Week Interim analysis: 2Q11
PROTON
Week 0 12 48 7224
PSI-7977 200 mg QD
Peg-IFN + RBV
PSI-7977 200 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
Peg-IFN + RBVPeg-IFN + RBV
Peg-IFN + RBVPeg-IFN + RBV
SVR
Follow-Up
SVR
Follow-Up
Peg-IFN + RBVPeg-IFN + RBV
Non-RVR Peg-IFN + RBVNon-RVR Peg-IFN + RBV
STOP
Non-RVR Peg-IFN + RBVNon-RVR Peg-IFN + RBV
STOP
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
SVR Follow-UpSVR Follow-Up
N=50
N=50
N=25
N=25
Week 0 12 36

16. HCV GT2/GT3: ACCELERATE
PEG/RBV ~65% achieve RVR, >80% predictive of SVR
PSI-7977/PEG/RBV 100% RVR > ? SVR

17. PSI-7977 Phase 2b PROTON:
HCV GT2/GT3
25 subjects enrolled
– 1 lost to F/U after day 1
– 15 GT2 > 10 GT3 (one lost to F/U)
– 7 CC, 17 CT, 1 TT
24/24 achieved HCV RNA <LOD by week 4 (RVR)
– 7/24 wk 1, 21/24 wk 2, 23/24 wk 3
All 24 remained <LOD through week 12 (EOT/cEVR)
All have had at least one post-treatment visit
22/24 <LOD Wk +8
SVR12 on all 24 by 17 March 2011
All data at EASL (Friday April 1st
)

18. Confidence in PROTON GT2/3 SVR
Number of
Subjects
95% CI 90% CI 85% CI 80% CI
SVR Rate Lower Upper Lower Upper Lower Upper Lower Upper
24 75% 58% 92% 60% 90% 62% 88% 64% 86%
24 80% 64% 96% 67% 93% 68% 92% 70% 90%
24 83% 68% 98% 70% 96% 72% 94% 73% 93%
24 88% 75% 101% 77% 99% 78% 98% 79% 97%
24 90% 78% 102% 80% 100% 81% 99% 82% 98%
24 92% 81% 103% 83% 101% 84% 100% 85% 99%
24 95% 86% 104% 88% 102% 89% 101% 89% 101%
If the SVR is 75% based on the 24 subjects in the study. The 90% CI of (60%-90%) is two sided CI, i.e., we have 5%
chance <60%, and 5% chance>90%.
If we only look at the 1-sided CI, we can claim that we have 95% chance the true response will be >60% based on the
observed response of 75% with sample size of 24.

19. HCV GT2/3

20. PSI-7977 Phase 2b PROTON:
Treatment-naïve HCV GT1
121 subjects enrolled: 2:2:1 200/400/pbo + PEG/RBV
– 34% CC
95/97 on PSI-7977 HCV RNA <LOD by week 4 (98%
RVR)
– 1 SAE wk 2 (psych admission); lost to F/U
– 1 patient with >7 log10 HCV RNA at BL, 23 at wk 4, <LOD wk 6

21. PSI-7977 Phase 2b PROTON:
Treatment-naïve HCV GT1
43 (+5 pending) of 48 on PSI-7977 200mg/PEG/RBV
remain <LOD through week 12 (EOT/cEVR)
37 (+6 pending) of 47 on PSI-7977 400mg/PEG/RBV
remain <LOD through week 12 (EOT/cEVR)
– 4 D/C during 1st
12 weeks with IFN-attributable AEs/SAEs
– wk 2 (ψ), wk 4 (aphthous ulcers), wk 8 (lost to f/u), wk 10 (acute
MI)
– All early d/c subjects were HCV RNA <LOD at last visit
First patients have reached EOT (wk 24)
First 12 weeks’ interim analysis at EASL (latebreaker
poster)

22. Baseline predictors of response

23. ATOMIC: PSI-7977 Duration Finding Study
Week 0 12 24
PSI-7977 400 mg QD + PEG-IFN/RBVPSI-7977 400 mg QD + PEG-IFN/RBVN=50 SVR Follow-UpSVR Follow-Up
PSI-7977 400 mg QD + PEG-IFN/RBVPSI-7977 400 mg QD + PEG-IFN/RBV SVR Follow-UpSVR Follow-Up
PSI-7977 400 mg QD + PEG-IFN/RBVPSI-7977 400 mg QD + PEG-IFN/RBV
PSI-7977 400 mg QDPSI-7977 400 mg QD
PSI-7977 400 mg QD + RBVPSI-7977 400 mg QD + RBV
SVR Follow-UpSVR Follow-Up
48
N=100
N=150
ATOMIC

24. Viral Dynamics

25. Modeling Viral Response Discussion Outline
PSI-7977: brief study and disposition background
Relationship of PSI-7977 formulation, exposure and
viral response
Preliminary viral dynamic modeling from NUCLEAR
study
Upcoming endeavors

26. PSI-7977 Dosing and PK-PD Link
previously dosed as PSI-
7851 (mixture of PSI-7977
and PSI-7976) in SAD, 3-
day monotherapy studies
relative bioavailability
study
two PSI-7977 formulations
employed in patient
clinical studies
importance of measuring
6206 given short-lived
prodrug
PSI-7977
(prodrug)
PSI-7409
(uridine-TP)
PSI-7410
(uridine-DP)
PSI-6206
(uridine)
PSI-7411
(uridine-MP)
PSI-352707
PSI-352707
PSI-7411
(uridine-MP)
Plasma
Hepatocyte
PSI-7977
PSI-6206
(uridine)


27. PSI-7851 3 Day Monotherapy Viral Load
Responses
1 2 1 4
0 m g Q D
0 0 m g Q D
0 0 m g Q D
0 0 m g Q D
M e a n
M e a n
M e a n
M e a n
e a n

28. Predicted Vs. Actual HCV RNA
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0 1 2 3
Time (Day)
MeanHCVRNAChangefrom
Baseline(log10IU/mL)
prediction, 100 mg + SOC actual, 100 mg + SOC
prediction, 200 mg + SOC actual, 200 mg + SOC
prediction, 400 mg + SOC actual, 400 mg + SOC

29. PSI-7977 7 Day Monotherapy Viral Load
Responses
Subsequent examination of exposure with different formulations as an
explanation for PD differences undertaken
-7
-6
-5
-4
-3
-2
-1
0
0 1 2 3 4 5 6 7 8
Days
HCVRNAChangefromBaseline
(log10IU/mL)
PSI-7977 400 mg
Median--Nuclear
Median--7851 MAD

30. Enhanced Exposure = Enhance Antiviral Activity
-1.00
0.00
1.00
2.00
3.00
4.00
5.00
0 2000 4000 6000 8000 10000 12000 14000
PSI-6206 AUCtau (ng*hr/mL)
ChangefromBaselineHCVRNA
(log10,IU/mL)
50 mg 7851 MAD 200 mg 7851 MAD 400 mg NUCLEAR predicted data
100 mg 7851 MAD 400 mg 7851 MAD combined placebo
400mgPSI -7977
+PEG -IFN/RBVx
28days
EC50
Emax
200mgPSI -7977
+PEG -IFN/RBV
x28days
100mgPSI -7977
+PEG -IFN/RBV
x28days
-1.00
0.00
1.00
2.00
3.00
4.00
5.00
0 2000 4000 6000 8000 10000 12000 14000
PSI-6206 AUCtau (ng*hr/mL)
ChangefromBaselineHCVRNA
(log10,IU/mL)
50 mg 7851 MAD 200 mg 7851 MAD 400 mg NUCLEAR predicted data
100 mg 7851 MAD 400 mg 7851 MAD combined placebo
400mgPSI -7977
+PEG -IFN/RBVx
28days
EC50
Emax
200mgPSI -7977
+PEG -IFN/RBV
x28days
100mgPSI -7977
+PEG -IFN/RBV
x28days
Data support better systemic delivery of 7977 with new formulation
as measured by PSI-6206, which mediates the interstudy
differences in HCV RNA declines with PSI-7977
400 mg dose is superior to lower doses early in therapy

31. How can we use the monotherapy data to
predict the time to cure?
Goal: to determine the duration of nucleotide therapy
necessary to eradicate virus based on viral decline in GT-1
subjects to support QUANTUM, ATOMIC regimen durations
On-treatment monotherapy data included in analysis
(recently completed 14 day dual nuc data not yet examined)
Utilized individual subject data with simple 2 compartment
modeling describing alpha and beta phases vs. physiologic
viral model involving infected and uninfected hepatocytes and
epsilon
Assumptions:
– Continuous viral decline (i.e., no emergence of resistance)
– Virus considered eradicated when HCV RNA < 6.7 x10-5
IU/mL
(< 1 IU/15 L)

32. Typical HCV Response Patterns
n = 56 subjects in Parts 1 and 2 dosed with a nucleotide
– 12 subjects-- appeared to have monoexponential HCV RNA decline
– 20 subjects-- could not estimate parameters with reasonable certainty
– 24 subjects-- data provided reasonably certain estimates for all
parameters (CV% low)
Approximately 13% of on-treatment HCV RNA values were < LOD

33. Viral Modeling Output
Biased towards slowest responders
PSI-938
100 mg
QD 7 days
PSI-938
100 mg
BID 7 days
PSI-938
200 mg
7 days
PSI-938
300 mg
7,14 days
PSI-7977
400 mg
7 days
n 5 3 3 10 3
Baseline HCV
RNA (median;
log10 IU/mL)
6.62 6.51 6.39 6.93 6.51
Alpha half-life
(hours; median,
range)
13.4
(8.4, 15.4)
14.4
(13.0, 14.6)
17.0
(11.9, 21.7)
13.6
(10.5, 22.8)
14.0
(8.2, 15.3)
Beta slope*
(HCV RNA log10
drop/week;
median, range)
0.52
(0.35, 1.23)
0.49
(0.31, 0.68)
0.77
(0.27, 0.89)
0.48
(0.21, 1.02)
0.67
(0.64, 1.01)
Weeks to HCV
<1 IU/15 L
(median, range)
20.8
(9.0, 31.9)
18.9
(16.1, 35.4)
12.3
(11.4, 39.8)
21.2
(10.8, 51.6)
16.3
(10.9, 17.3)
* Includes only data points with >15 IU/mL

34. Viral Modeling Output
Biased towards slowest responders
PSI-938
100 mg
QD 7 days
PSI-938
100 mg
BID 7 days
PSI-938
200 mg
7 days
PSI-938
300 mg
7,14 days
PSI-7977
400 mg
7 days
n 5 3 3 10 3
Baseline HCV
RNA (median;
log10 IU/mL)
6.62 6.51 6.39 6.93 6.51
Alpha half-life
(hours; median,
range)
13.4
(8.4, 15.4)
14.4
(13.0, 14.6)
17.0
(11.9, 21.7)
13.6
(10.5, 22.8)
14.0
(8.2, 15.3)
Beta slope*
(HCV RNA log10
drop/week;
median, range)
0.52
(0.35, 1.23)
0.49
(0.31, 0.68)
0.77
(0.27, 0.89)
0.48
(0.21, 1.02)
0.67
(0.64, 1.01)
Weeks to HCV
<1 IU/15 L
(median, range)
20.8
(9.0, 31.9)
18.9
(16.1, 35.4)
12.3
(11.4, 39.8)
21.2
(10.8, 51.6)
16.3
(10.9, 17.3)
* Includes only data points with >15 IU/mL

35. Viral Modeling Output
Biased towards slowest responders
PSI-938
100 mg
QD 7 days
PSI-938
100 mg
BID 7 days
PSI-938
200 mg
7 days
PSI-938
300 mg
7,14 days
PSI-7977
400 mg
7 days
n 5 3 3 10 3
Baseline HCV
RNA (median;
log10 IU/mL)
6.62 6.51 6.39 6.93 6.51
Alpha half-life
(hours; median,
range)
13.4
(8.4, 15.4)
14.4
(13.0, 14.6)
17.0
(11.9, 21.7)
13.6
(10.5, 22.8)
14.0
(8.2, 15.3)
Beta slope*
(HCV RNA log10
drop/week;
median, range)
0.52
(0.35, 1.23)
0.49
(0.31, 0.68)
0.77
(0.27, 0.89)
0.48
(0.21, 1.02)
0.67
(0.64, 1.01)
Weeks to HCV
<1 IU/15 L
(median, range)
20.8
(9.0, 31.9)
18.9
(16.1, 35.4)
12.3
(11.4, 39.8)
21.2
(10.8, 51.6)
16.3
(10.9, 17.3)
* Includes only data points with >15 IU/mL

36. Viral Modeling Output
Biased towards slowest responders
PSI-938
100 mg
QD 7 days
PSI-938
100 mg
BID 7 days
PSI-938
200 mg
7 days
PSI-938
300 mg
7,14 days
PSI-7977
400 mg
7 days
n 5 3 3 10 3
Baseline HCV
RNA (median;
log10 IU/mL)
6.62 6.51 6.39 6.93 6.51
Alpha half-life
(hours; median,
range)
13.4
(8.4, 15.4)
14.4
(13.0, 14.6)
17.0
(11.9, 21.7)
13.6
(10.5, 22.8)
14.0
(8.2, 15.3)
Beta slope*
(HCV RNA log10
drop/week;
median, range)
0.52
(0.35, 1.23)
0.49
(0.31, 0.68)
0.77
(0.27, 0.89)
0.48
(0.21, 1.02)
0.67
(0.64, 1.01)
Weeks to HCV
<1 IU/15 L
(median, range)
20.8
(9.0, 31.9)
18.9
(16.1, 35.4)
12.3
(11.4, 39.8)
21.2
(10.8, 51.6)
16.3
(10.9, 17.3)
* Includes only data points with >15 IU/mL

37. Viral Modeling Data in Context
Nuc monotherapy alpha phase is deeper, beta-
slope comparable to RG7227+RG71281
Predictions for viral eradication with telaprevir +
PEG/RBV
– Garg: 10-11 weeks triple therapy needed for 95% to
achieve SVR assuming PI-resistance variants remain
sensitive to IFN/RBV2
– Perelson: 95% could clear HCV within 6 weeks, assuming
no loss of telaprevir effectiveness due to resistance3
1
Morcos et al., AASLD 2009
2
Garg et al., DDW 2007
3 Guedj and Perelson, AASLD 2010

38. Viral Modeling Supports Ongoing
Program
PSI-7977 400 mg QD is optimal dose
↑ AUC
– Antiviral effect
Improved alpha of PSI-7977
– New tablet formulation
Viral eradication possible with 12 and 20 weeks
of monotherapy with no resistance
12 and 24 week regimens to be explored in
ATOMIC and QUANTUM

39. Safety Summary

40. 40
Safety Review
P7977-0221 (Phase 2a study)
P7977-0422 (PROTON)

41. Study Number of
subjects
Dose/Duration Number of
subjects
discontinuing
P7851-1101
(SAD)
33 25mg-800mg x 1D 0
P7851-1102
(MAD)
32 50mg-300mg x 3D 0
P7977-0111
(Bioavailability)
24 200mg x 1D 0
P7977-0221
(Safety & tolerability study with
PEG/RBV)
49 100mg, 200mg,
400mg QD +
PEG/RBV x 4W
0
P7977-0422
(Dose finding study with
PEG/RBV)
96 200mg, 400mg
QD +PEG/RBV x
12W
0
234 0
No subject discontinuation to date due to
PSI-7851 or PSI-7977

42. 42
PSI-7977 Phase 2a Safety
No study drug discontinuations related to AEs
No SAEs during the first 28 days of the study
– 1 SAE of abdominal pain occurred at Week 14
– 1 SAE of acute anemia occurred at Week 40
– 1 SAE of right lower extremity ischemia with pain at Week 31
– All 3 of the SAEs were deemed to be unrelated to study drug
Majority of AEs were mild and unrelated to study drug
Most common AEs reported: fatigue, nausea, arthralgia
No dose-related laboratory abnormalities

43. 43
PSI-7977 28 day dosing with P-IFN/RBV:
Safety Summary
Standard safety monitoring employed in this study
There were no significant safety issues identified, key observations
included:
– Hematology
– Mean ~0.5 g/dL hgb difference in combined active arms vs pbo/SOC 1st
28d; no
dose response
– Appropriate response in reticulocytes in all patients
– No effect on any other cell lines
Liver
– Rapid decrease in ALT in all active arms
– No bilirubin signal
Renal
– No signal in Scr or urine protein:creatinine
Cardiac
– No signal in standard vitals/ECGs
No additional safety monitoring required for Phase 2b studies

44. PSI-7977 Phase 2b PROTON Study
25 treatment-naïve patients with HCV GT2/3
125 treatment-naïve patients with HCV GT1
– Response-guided therapy
– IL28B, HCV RNA stratified
PROTON
Week 0 12 48 7224
PSI-7977 200 mg QD
Peg-IFN + RBV
PSI-7977 200 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV Peg-IFN + RBVPeg-IFN + RBV
Peg-IFN + RBVPeg-IFN + RBV
SVR
Follow-Up
SVR
Follow-Up
Peg-IFN + RBVPeg-IFN + RBV Non-RVR Peg-IFN + RBVNon-RVR Peg-IFN + RBV
STOP
Non-RVR Peg-IFN + RBVNon-RVR Peg-IFN + RBV
STOP
PSI-7977 400 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV SVR Follow-UpSVR Follow-Up
N=50
N=50
N=25
N=25
Week 0 12 36

45. PROTON GT1 Patients on PSI-7977
PSI-7977 200mg/PEG/RBV
– All 48 remain on therapy through week 12
PSI-7977 400mg/PEG/RBV
– 43 of 47 remain on therapy through week 12
– 4 D/C during 1st
12 weeks with IFN-attributable AEs/SAEs
• wk 2 (SAE: ψ admission)
• wk 4 (aphthous ulcers)
• wk 8 (lost to f/u)
• wk 10 (SAE: acute MI)
96 of 97 subjects randomized to PSI-7977 200 mg or 400 mg
will be eligible to stop all therapy at week 24 (12+12)

46. MedDRA System Organ Class/
Preferred Term
P7977-0422
GT1 200mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT1 400mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT2/3 400mgQD
+PEG + RBV
(n=25)
P7977-0422
GT1 Placebo/PEG
+ RBV
(n=26)
General Disorders &
Administration Site Conditions
Fatigue
Chills
Pain
Pyrexia
38 (79.2)
31 (64.6)
18 (37.5)
14 (29.2)
12 (25.0)
40 (83.3)
31 (64.6)
19 (39.6)
12 (25.0)
10 (20.8)
15 (60.0)
9 (36.0)
9 (36.0)
8 (30.8)
4 (16.0)
21 (80.8)
15 (57.7)
10 (38.5)
8 (30.8)
8 (30.8)
Nervous System Disorders
Headache
26 (54.2)
17 (35.4)
26 (54.2)
18 (37.5)
16 (64.0)
11 (44.0)
18 (69.2)
15 (57.7)
Gastrointestinal Disorders
Nausea
Diarrhea
Vomiting
25 (52.1)
14 (29.2)
7 (14.6)
4 (8.3)
30 (62.5)
18 (37.5)
11 (22.9)
5 (10.4)
14 (56.0)
12 (48.0)
1 (4.0)
5 (20.0)
15 (57.7)
9 (34.6)
2 (7.7)
2 (7.7)
Skin & subcutaneous tissue
disorders
Rash
Pruritus
28 (58.3)
16 (33.4)
11 (22.9)
21 (43.8)
12 (25.0)
5 (10.4)
9 (36.0)
5 (20.0)
3 (12.0)
14 (53.8)
5 (19.2)
2 (7.7)
Psychiatric Disorders
Insomnia
Depression
22 (45.8)
9 (8.8)
6 (12.5)
28 (58.3)
15 (31.3)
4 (8.3)
7 (28.0)
4 (16.0)
2 (8.0)
15 (57.7)
9 (34.6)
3 (11.5)
PSI-7977 Phase 2b PROTON Study
Preliminary Safety: Most AEs common to PEG/RBV

47. 47
PSI-7977 Phase 2b PROTON Study Preliminary Safety:
W4, W6, W12 Mean Change from Baseline: Hematology
Lab P7977-0422
GT1 200mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT1 400mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT2/3 400mgQD/PEG
+ RBV
(n=24)
P7977-0422
GT1 Placebo/PEG
+ RBV
(n=26)
Hb (g/dL)
W4
W6
W12
-2.55
-3.08
-3.20
-2.43
-2.50
-2.31
-2.15
-2.00
-2.19
-2.77
-2.69
-2.82
Retic, %/abs
W4
W6
W12
+2.40/+0.08
+2.23/+0.07
+1.70/+0.05
+2.11/+0.06
+2.03/+0.06
+1.24/+0.03
+1.65/+0.06
+1.63/+0.06
+1.55/+0.20
+2.68/+0.08
+2.56/+0.08
+1.85/+0.05
ANC (x10^3/uL)
W4
W6
W12
-2.05
-1.93
-2.22
-1.99
-2.03
-2.75
-1.97
-1.69
-1.68
-1.73
-1.60
-2.05
ALC (x10^3/uL)
W4
W6
W12
-0.66
-0.8
-0.92
-0.58
-0.69
-0.75
-0.58
-0.61
-0.77
-0.61
-0.70
-0.82
WBC (x10^3/uL)
W4
W6
W12
-2.99
-3.05
-3.46
-2.80
-2.97
-2.88
-2.82
-2.58
-2.76
-2.64
-2.64
-3.14
PLT(x10^3/uL)

48. 48
PSI-7977 Phase 2b PROTON Study Preliminary Safety:
W4, W6, W12 Mean Change from Baseline: Chemistry
Lab P7977-0422
GT1 200mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT1 400mgQD/PEG
+ RBV
(n=48)
P7977-0422
GT2/3 400mgQD/PEG
+ RBV
(n=24)
P7977-0422
GT1 Placebo/PEG
+ RBV
(n=26)
ALT (IU/L)
W4
W6
W12
-43.60
-40.27
-37.54
-38.93
-41.84
-40.42
-32.74
-34.70
-28.74
-43.63
-47.22
-47.0
AST (IU/L)
W4
W6
W12
-21.19
-20.13
-16.22
-27.11
-28.91
-23.58
-14.70
-18.00
-13.57
-21.08
-22.52
-23.14
Total Bilirubin
(mg/dL)
W4
W6
W12
+0.14
+0.12
+0.03
+0.06
+0.03
-0.04
+0.13
+0.20
+0.06
+0.13
+0.14
-0.01
Direct Bilirubin
(mg/dL)
W4
W6
W12
+0.007
-0.007
-0.005
-0.02
-0.04
-0.02
+0.03
+0.02
+0.02
+0.02
+0.004
0
Creatinine
(mg/dL)
W4
W6
W12
-0.07
-0.05
-0.06
-0.06
-0.04
-0.05
-0.006
-0.03
-0.02
-0.02
-0.02
-0.06

49. 49
PSI-7977 Phase 2b PROTON Study
Preliminary Safety Summary
Hematology
– No difference between active treatment arms and placebo
– No dose-dependent hemoglobin decline; most significant
decline in 1st
4 weeks
– Appropriate response in reticulocytes in all patients
– No effect on any other cell lines
Liver
– Rapid decrease in ALT coincident with HCV RNA suppression
Renal
– No signal in Scr or urine protein:creatinine
Cardiac
– No signal in standard vitals/ECGs
– Dedicated QTc Study ongoing
PROTON