1. 1 Depletion of naïve CD4+T cell compartment by immune hyperactivation can be rapidly reversed by AntiViral- HyperActivation Limiting Therapeutics (AV-HALTs) D.V. Baev, E. Katabira, R. Maserati, P. Cahn, D. De Forni, B. Poddesu, M.R. Stevens, F. Lori on behalf of the VS411 Study Team WELBX03

2. AV-HALTs AntiViral-HyperActivation Limiting Therapeutics 2 Oral agents combining antiviral and immunomodulating properties to both reduce viral load and decrease immune-activation Anti Viral - Hyper Activation Limiting Therapeutics ViroStatics AV-HALTs VS411: Proof of Concept 2 nd generation AV-HALTs: To be developed

3. Why decrease immune activation? AV-HALTs A New Class of Antiretroviral Drugs 3 Scientific Rationale behind AV-HALTS

4. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles Dec 10, 1981 The first reports of what is now known as HIV-disease/AIDS indicated that the individuals’ immune systems were experiencing excessive activation despite low CD4+ cell counts 4 1 45 57 0 59 0 2 47 52 0 59 0 3 49 57 10 79 0.18 4 67 47 2 81 0.04 Mean ± S.D. 52 * 53.3 † 3.0 † 69.5 0.05 ± 10.1 ± 4.7 ± 4.76 ± 12.1 ± 0.08 Normal subjects 71.0 28.0 46.0 15.0 1.6 (n = 16 [mean ± 10.0 ± 8.0 ± 12.0 ± 6.6 ± 0.74 ± S.D.]) T10 is now known as CD38. The CD38 protein is a marker of cell activation. A 4- to 5-fold increase above healthy normals Table 3. Characterization of T-Lymphocyte Subsets G ROUP L YMPHOCYTE S UBSET L EU 3/ L EU 2 R ATIO LEU 1 LEU 2 LEU 3 T10 per cent lymphocytes reactive with monoclonal antibodies Patients

5. HIV disease is driven by immune system hyperactivation Immune hyperactivation is not normalized by HAART Cardiovascular Bone loss Neurological Impairment Accelerated aging Mortality Why Decrease Immune Activation ? 0.7 5 1.0 0.5 0 0.2 5 0 25 30 35 40 45 50 55 60 65 70 Ι Ι Ι Ι Ι Ι ΙΙ Ι Ι Life Expectancy (years) Pre-HAART (1995 – 1996) Early HAART (1997 – 1999) Current HAART (2000 – 2005) Population Controls  10 years  Probability of Survival Life Expectancy, years Adapted from: Lohse N et al. Ann Intern Med 2007;146-95

6. 6 The ViroStatics AV-HALT Drug Development Program Proving the AV-HALT concept in humans and Moving novel agents into clinical development

7. First Generation AV-HALT VS411 Proof of Concept Achieved in HIV/AIDS Contained two readily available generic drugs One acted as an “AV” (didanosine) One acted as a “HALT” (hydroxyurea) Multinational Phase 2a Clinical Trial AV-HALTs Drug Development Program

8. AV-HALT properties proven AV: Viral load up to -1.8 logs, AV: CD4 cell counts up to +135 cells/mm 3 HALT: - 30% hyperactivation decrease in only 28 days, similar to what HAART achieves after months/years AV-HALTs Drug Development Program First Generation AV-HALT VS411 Proof of Concept Achieved in HIV/AIDS

9. VS411 Proof of Concept Phase 2a Trial A 28-day Randomized, Double-blinded Study Safety precautions: Standard didanosine and hydroxyurea dosages reduced by one-half or more Didanosine Cmax blunted in Phase I 9 DidanosineHydroxyurea 200 mg300 mg 200 mg 600 mg 200 mg900 mg 400 mg300 mg 400 mg600 mg 58 ART naïve subjects (50% female; 50% black) Safety - Viral Load Reduction – CD4 + Counts - Immunological Assays Low dose ddI High Dose ddI Countries Uganda 1 Argentina 2 Italy 3 Russia 4 1 Elly Katabira, MD President - International AIDS Society 2 Pedro Cahn, MD Past President - International AIDS Society; Sergio Lupo, MD; Arnaldo Casiro, MD; Jorge Contarelli (Buenos Aires, Rosario) 3 Renato Maserati, MD; Giancarlo Pasetti, MD (Pavia, Parma) 4 Aza Rakhmanova, MD; Natalia Zakharova, MD (St. Petersburg) Investigators VS411 was safe and well tolerated, no SAE

10. Didanosine/ hydroxyurea 200mg/300mg Didanosine/ hydroxyurea 200mg/600mg Didanosine/ hydroxyurea 200mg/900mg Didanosine/ hydroxyurea 400mg/300mg Didanosine/ hydroxyurea 400mg/600mg Mean Change From Baseline cells/mm 3 OT + 71.9+ 56.9+ 95.7+ 67.4+ 50.7 Mean Change From Baseline cells/mm 3 ITT + 48.0+ 56.9+95.7+ 67.4+ 50.7 Median Change From Baseline cells/mm 3 OT + 24.0+ 52.0+ 135.0+ 54.0+ 67.0 Median Change From Baseline cells/mm 3 ITT + 1.5+ 52.0+ 135.0+ 54.0+ 67.0 VS411: Phase II Study Results CD4 + Increases up to +135 cells/mm 3 10 The “blunting” of CD4 + cell increases historically seen with the didanosine/hydroxyurea combination was not seen with VS411

11. DAY 28 DAY 14 Historical nucleoside analogue comparators Log 10 reduction from baseline 200 mg ddI 300 mg HU 200 mg ddI 600 mg HU 200 mg ddI 900 mg HU 400 mg ddI 300 mg HU 400 mg ddI 600 mg HU Lamivudine – 3TC Day 12 200 mg ddI 300 mg HU 200 mg ddI 600 mg HU 200 mg ddI 900 mg HU 400 mg ddI 300 mg HU 400 mg ddI 600 mg HU Tenofovir – TDF Day 21 VS411: Phase 2a Antiviral [AV] Results Mean Viral Log Reduction (ITT) 11 Viral load was suppressed below 50 copies/ml in only two individuals

12. VS411: Phase II [HALT] Results Comparison of VS411 200/900 to HUNT et al. 2003 12 Hunt P, et al. JID 2003;187:1534-1543 8% 4% 1% 20 - 10 - 0- 30- Day 0 Day 28 6.7% 4.3% Percentage of Activated CD4 + cells CD38 + /HLA-DR + Percentage of Activated CD4 + cells CD38 + /HLA-DR + 20 - 10- 0- 30 - VS411, 28 days ddI 200mg / HU 900mg P =.001 HAART, 21 months VL <1,000 CD4 + T lymphocytes

13. Naïve – but not Central Memory – CD4 T Cell Depletion Correlates with CD4 T Cell Activation 13 Naïve Central Memory (CM) Total Proliferating

14. Reversion of Naïve CD4 T Cell Depletion by AV-HALTs 14 Naïve, Change from BaselineCM, Change from Baseline Total Proliferating % CD4 + CD38 + HLA-DR +

15. Screening for Second-Generation AV-HALTs In vitro Clinical Proof of Concept Prediction Compound 1 Compound 2 Compound 3 AV-HALT profile AV efficacy HALT efficacy Toxicity Following VS411 Pathway  Viral Load  CD4  Hyperactivation Comparator Prototype Clinical Screening 15  Viral Load  CD4  Hyperactivation 2 nd generation

16. Ideal AV-HALT VS411 combines low doses of two drugs (didanosine and hydroxyurea) to approach the criteria for an Ideal AV-HALT An ideal AV-HALT would have: - Low mitochondrial and cellular toxicity - Little if any apopototic effect (cell death) - Activity in both activated and resting T helper cells, and - Limit, but not completely block, cell proliferation (Lack of) Cell toxicity (Lack of) Apoptoticeffect Antiproliferative capacity Antiviral effect in resting/stimulated cells Antiviral effect in activated cells (Lack of) MitochondrialToxicity Ideal AV-HALT VS411 VS1-002 % compared to not treated control 0 20 40 60 80 100 VS1-002 provides both antiviral and hyper-activation reducing activity comparable to VS411 with: - a long patent life - less potential toxicity - in a single molecule 16 Measures of Toxicity Measures of Activity VS2-091 and VS2-102 approach the criteria of an Ideal AV-HALT At nanomolar concentrations In a single molecule VS2-091 VS2-102 Screening for Second-Generation AV-HALTs

17. There are two kinds of people: those who do the work, and those who take the credit Try to be in the first group. There is less competition there… Indira Gandhi Thank you to the Study Subjects, Investigators and the ViroStaticsTeam ViroStatics Porto Conte, Italy Princeton, New Jersey Montreal, Canada 17