1. Antiretroviral Activity and Tolerability of Reverset (D-d4FC), a New Fluoro-Cytidine Nucleoside Analog when used in Combination Therapy in Treatment- Experienced Patients: Results of Phase IIb Study RVT-203 C. Cohen, C. Katlama, R. Murphy, J. Gathe, C. Brinson, G. Richmond, P.-M. Girard, J. Fessel, A. Liappis, E. Puglia, B. Rodwick, J. Nadler, W. O’Brien, K. Arasteh, M. Otto, S. Erickson-Viitanen, R. Levy 3 rd IAS Conference July 24-27, 2005 Rio de Janeiro, Brazil

2. Background Preclinical studies demonstrated Active with viral mutants resistant to 3TC, AZT, TDF, other NRTIs, NNRTIs and PIs Long intracellular half life (17 hours) No mitochondrial toxicity or lactic acid increase (in vitro) 10-day add-on dosing demonstrated VL decrease of 0.8 logs with 200 mg qd dosing in therapy-experienced patients VL decrease of 1.8 logs with 200 mg qd in therapy-naïve patients N O N O F HO NH 2 Reverset ™  -D-2’,3’-didehydro-2’,3’- dideoxy-5-fluorocytidine (D-D4FC)

3. RVT-203 Study Design Treatment experienced patients viremic (>2000 c/mL) on current regimen: N=199 Randomized, placebo-controlled, double-blind, parallel dose group: 50, 100, 200 mg once daily USA, France, Germany, 25 centers total Stratification by TAMs: 0-3 and 4-6 based on screening genotype 3 phases: 2-Wk Add-on 14-Wk treatment with Optimized Background Regimen 8 Wk Placebo  Cross-over 0 2 16 24 Weeks on study

4. Endpoints  Primary  Mean Change in viral load (VL) to week 2 and 16  Safety  Secondary  Proportion with >1 log decline in VL  Virologic response in patients who did / did not optimize at Week 2

5. Baseline Characteristics Overall mean baseline viral load = 4.5 log Overall mean baseline CD4 count = 248 cells/mm 3

6. Change in Viral Load from Baseline 2-Week Add-On Phase

7. Effect of NRTIs in Baseline Regimen on 2-week Viral Load Decline with RVT 200 mg

8. Effect of RT Mutations on 2-Week Viral Load Decline With 200 mg RVT Note data for K65R and M184V alone are pooled for all doses

9. Study RVT-203: 16 week Efficacy Results Placebo N=40 RVT 50 mg N=42 RVT 100 mg N=42 RVT 200 mg N=43 Difference 200 mg vs Placebo Decrease in VL (log) from BL All Non-optimizers 0.8 0.07 0.9 0.3 0.8 0.4 1.2 0.6 0.4 0.5 Responder Rate (% > 1 log decrease in VL) All Non-optimizers 40% 8% 38% 0% 31% 11% 54% 31% 14% 23%

10. Sub-Group Analyses at Week 16 Sub-GroupΔ VL% > 1 log Decrease Placebo200 mgPlacebo200 mg Triple Class Resistant Patients N=47 -0.5-0.926%43% No 3TC/FTC All patients N=29 Non-Optimizers N=9 -0.5 +0.3 -1.4 -1.5 25%* 0% 80%* 80% * p < 0.05

11. Effect of Concurrent 3TC/FTC on Week 16 Response Rates Use of 3TC/FTC not randomized Post-hoc analysis % Pbo No 3TC/FTC Pbo with 3TC/FTC 200 mg No 3TC/FTC <40025%36%66% <5025%29%60%

12. Presence of M184V Does Not Impact 16-Week Response to 200 mg RVT Presence/absence of M184V with TAMs

13. Moderate to Severe Clinical Adverse Events to 16 Weeks Events Considered at Least Possibly Related AEPlacebo N=47 RVT 50 mg N=49 RVT 100 mg N=50 RVT 200 mg N=52 Nausea0%4.1%2.0%1.9% Headache0%2.0% 3.8% Diarrhea4.3%2.0% 1.9% Pancreatitis0% 2.0%0% Myalgia0%4.1%0% No other events were reported in more than one patient

14. Hyperlipasemia – Grade 4 ParameterPlacebo50 mg100 mg200 mg Patients not on ddI1/39 3% 1/37 3% 2/34 6% 2/37 5% Patients on ddI0/8 0% 1/11 9% 4/15 27% 7/14 50% RVT should not be used with ddI

15. Pancreatitis Cases of pancreatitis, all on 100 mg RVT  N=3 symptomatic pancreatitis  One patient taking full dose (400 mg) ddI + tenofovir  One patient taking 250 mg ddI plus 1.5X dose of tenofovir (450 mg)  One patient with ongoing alcohol abuse  N=1 abnormal ultrasound but normal CT scan in an asymptomatic patient with grade 4 lipase  Taking recommended doses of ddI + tenofovir  All patients recovered  Rapid, symptomatic and radiographic recovery  No complications  Lipase/amylase levels recovered more slowly

16. Other Possibly Related Serious Adverse Events in Patients on RVT Anemia (1 patient on 200 mg RVT) Also receiving AZT Neutropenia (1 patient on 200 mg RVT) Worsening neutropenia when started on TMP-SMX for PCP Hypertriglyceridemia (1 patient on 100 mg RVT) Developed worsening hypertriglyceridemia when started on fosamprenavir 1400 mg and ritonavir 200 mg once daily Pancytopenia (1 patient on 200 mg RVT) Developed anemia (Grade 3), neutropenia (grade 3) and thrombocytopenia (Grade 2), resolved with discontinuation of study medication

17. Conclusions  200 mg Reverset provides antiviral suppression in highly ARV-experienced patients 2-week add-on:-0.7 logs -1.1 logs without 3TC/FTC 16 weeks: 54% response overall (> -1.0 logs) 80% response without 3TC/FTC vs. 46% placebo with 3TC/FTC -1.4 logs without 3TC/FTC  Reverset is generally well tolerated Asymptomatic hyperlipasemia when used with ddI RVT should not be used with ddI  Reverset activity retained with key mutations To date, no novel mutations identified in RVT-exposed patients No K65R emerged in RVT-exposed patients  Reverset warrants further development Phase III trial planning in progress

18. Acknowledgments  Participating Subjects  Investigators United StatesFrance Calvin CohenRob MurphyChristine Katlama Joseph GatheCynthia BrinsonPierre-Marie Girard Jeffrey FesselGary Richmond Angelike LiappisEdgardo Puglia Germany Barry RodwickJeffrey NadlerKeikawus Arasteh William O’BrienSteven O’MarroDirk Schurmann Jeffrey GalpinGeorge BeattySchlomo Staszewski Donna MildvanKathleen SquiresHans-Juergen Stellbrink Corklin SteinhartGerald PieroneAlbrecht Stoehr  Sponsors  Incyte CorporationPharmasset, Inc.