D.V. Baev, E. Katabira, R. Maserati, P. Cahn, D. De Forni, B. Poddesu, M.R. Stevens, F. Lori

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

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

4. 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 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 dysfunctionH Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles Table 3. Characterization of T-Lymphocyte Subsets T10 is now known as CD38. The CD38 protein is a marker of cell activation. GROUP LYMPHOCYTE SUBSET LEU 3/ LEU 2 RATIO LEU 1 LEU 2 LEU 3 T10 per cent lymphocytes reactive with monoclonal antibodies Patients 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.]) A 4- to 5-fold increase above healthy normals

5. Why Decrease Immune Activation ? Life Expectancy (years) Cardiovascular Bone loss Neurological Impairment Accelerated aging Mortality 1.0 Population Controls 0.75  10 years  Current HAART (2000 – 2005) 0.50 Probability of Survival Early HAART (1997 – 1999) 0.25 Pre-HAART (1995 – 1996) 0 Ι Ι Ι Ι Ι Ι Ι Ι Ι Ι 25 30 35 40 45 50 55 60 65 70 Life Expectancy, years Adapted from: Lohse N et al. Ann Intern Med 2007;146-95 HIV disease is driven by immune system hyperactivation Immune hyperactivation is not normalized by HAART

6. The ViroStaticsAV-HALT Drug Development Program Proving the AV-HALT concept in humans andMoving novel agents into clinical development

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

8. AV-HALTsDrug Development Program Proof of Concept Achieved in HIV/AIDS First Generation AV-HALT VS411 • AV-HALT properties proven • AV: Viral load up to -1.8 logs, • AV: CD4 cell counts up to +135 cells/mm3 • HALT: - 30% hyperactivation decrease in only 28 days, similar to what HAART achieves after months/years

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

10. VS411: Phase II Study Results CD4+ Increases up to +135 cells/mm3 The “blunting” of CD4+ cell increases historically seen with the didanosine/hydroxyurea combination was not seen with VS411

11. VS411: Phase 2a Antiviral [AV] Results Mean Viral Log Reduction (ITT) DAY 14 400 mg ddI 600 mg HU 400 mg ddI 300 mg HU Lamivudine – 3TCDay 12 200 mg ddI 300 mg HU 200 mg ddI 600 mg HU 200 mg ddI 900 mg HU Log10 reduction from baseline DAY 28 200 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 21 200 mg ddI 300 mg HU Log10 reduction from baseline Historical nucleoside analogue comparators Viral load was suppressed below 50 copies/ml in only two individuals

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

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

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

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

16. VS411 VS1-002 Ideal AV-HALT 100 80 60 % compared to not treated control 40 20 0 Screening for Second-Generation AV-HALTs (Lack of) Cell toxicity MeasuresofToxicity (Lack of) Mitochondrial Toxicity (Lack of) Apoptotic effect Measures of Activity Antiproliferative capacity Antiviral effect in activated cells Ideal AV-HALT VS2-091 VS2-102 Antiviral effect in resting/stimulated cells 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 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 VS2-091 and VS2-102 approach the criteria of an Ideal AV-HALT At nanomolar concentrations In a single molecule VS411 combines low doses of two drugs (didanosine and hydroxyurea) to approach the criteria for an Ideal AV-HALT

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