1. Cenicriviroc: A Potent Dual Chemokine Receptor Antagonist (CCR5/CCR2) in Phase 2b Development with Potential to Transform HIV Therapy Cenicriviroc: A Potent Dual Chemokine Receptor Antagonist (CCR5/CCR2) in Phase 2b Development with Potential to Transform HIV Therapy Sandra M. Palleja, MD 6 th IAS Conference on HIV Pathogenesis-Rome 2011 ®

2. ® Cenicriviroc (CVC): Key Characteristics Oral CCR5/CCR2 receptor antagonist ─In vitro protein-adjusted EC 90 = 1.2 nM (clinical isolates) ─CCR2 IC 50 = 5.9 nM (inhibition of MCP-1 binding in CHO cells) Once-daily, oral dosing ─Plasma T ½ = 35-40 hours Additive to synergistic activity with other ART classes in vitro 2

3. ® CVC Key Characteristics Attributes Necessary for a Leading HIV Agent 3 Excellent Product Profile Ideal for QD FDCs CCR5/CCR2 Product profile attributes to be a leading antiviral: potency, once daily oral dosing, safety and barrier to resistance Well-suited to form QD, fixed- dose-combinations: low dose and long half-life Unique CCR5/CCR2 dual activity has potential to transform HIV treatment: CV/metabolic benefits to address HIV-associated, inflammation-driven morbidity and mortality

4. ® Unmet Medical Need in HIV Patients on otherwise effective treatment frequently show persistent immune dysfunction; higher-than- expected risk for non-AIDS-related complications – heart, bone, liver, kidney and neuro-cognitive diseases HIV+ people on treatment have shorter life expectancy, including those optimally treated While widely used drugs are generally well-tolerated; short-term toxicities and potential for known and unknown long-term toxicities persist 4 Volberding and Deeks, Lancet July, 2010

5. ® Cascade of Events Due to Chronic Immune Activation and Inflammation Production of pro-inflammatory cytokines possibly due to low level of residual HIV RNA in the virally suppressed patient Persistent, sustained immune activation and inflammation gradually “burns out” the immune system by depleting the pool of naïve T cells Progressive decline in the immune function and prolonged inflammation increase the risk of morbidity and mortality from a variety of non-opportunistic conditions Appay V, et al. J Pathol. 2008;214:231-241. Hazenburgh MD, et al. AIDS. 2003;17:1881-1888. Chronic Inflammation Osteoporosis, Atherosclerosis, Neurocognitive Degeneration, Frailty, Metabolic Syndrome, etc Low-level Viral Replication Secretion of Pro-inflammatory Cytokines Immune Senescence 5

6. ® The Role of CCR2 in Chronic Inflammation CCR2 is a chemokine receptor found on the cell surface of monocytes, dendritic cells (immature), and memory T cells Monocyte chemoattractant protein-1 (MCP-1) is the primary ligand for CCR2 and a potent chemoattractant for monocytes/macrophages Recruitment of Monocytes/Macrophages Systemic Inflammatory Response Initiated Inflammatory Insult Release of MCP-1 Release of Inflammatory Cytokines (ie, TNF-α and IL-6) 6

7. ® 7 HIV Infection New Therapeutic Goals: Suppress Virus and Address Inflammation-Associated Morbidity and Mortality High level viral replication Low level viral replication Immune Cell Death Chronic Inflammation AIDS-related morbidities Cardiovascular Disease, Metabolic Syndrome, Premature Aging, etc. Death Current HIV Drugs Cenicriviroc

8. ® CVC Phase 2a Proof of Concept (POC) Protocol 652-2-201: Trial Design Objective: To evaluate antiviral potency, safety, tolerability, PK, and CCR2 activity* Randomized, double-blind, placebo-controlled, dose-escalating study in HIV-infected, CCR5-tropic, treatment experienced patients 5 dose cohorts: 10-day monotherapy –CVC (n≥8): 25, 50, 75, 100, and 150 mg –Placebo (n=2) MCP-1 measured on Day 1 and Day 10 * Lalezari, et al. JAIDS June 2011 8

9. ® HIV RNA Median Nadir Change from Baseline* HIV RNA Change from Baseline (log 10 copies/mL) 0 -0.2 -0.4 -0.6 -0.8 -1.2 -1.4 -1.6 -1.8 -2.0 -0.8 25 mg -1.7 50 mg -1.8 75 mg -1.6 150 mg -0.3 Placebo *Nadir presented because viral load continues to drop after dosing ends. CVC Phase 2a: POC Efficacy 9

10. ® Cenicriviroc Phase 2 – Patient 3007: 100 mg QD for 10 Days CVC Phase 2a: POC Antiviral Potency and CCR2 Effect 10

11. ® CVC Phase 2b: Protocol 652-2-202 Trial Design Arm A: cenicriviroc 100mg +Truvada* (n=60) Arm B: cenicriviroc 200mg +Truvada (n=60) Arm C: efavirenz 600mg +Truvada (n=30) Randomized, double-blind/double-dummy Treatment naïve, CCR5 tropic patients, n=150 Truvada is open label Sites: US and Puerto Rico *Gilead Sciences has provided Truvada for all randomized patients 11

12. ® 12 CVC Phase 2b: 652-2-202 Trial Objectives Primary Endpoints: –Percent of patients with HIV-RNA <50 copies/mL at week 24 –Safety & tolerability of each CVC regimen vs. comparator (SOC) Secondary Endpoints: –Percent of patients with HIV-RNA <50 copies/mL at week 48, and <400 copies/mL at weeks 24 & 48 –Change from baseline (BL) in HIV-1 RNA at weeks 24 and 48 –Tropism changes and drug resistance in patients with virologic failure –Change from BL in inflammatory biomarkers and immune function at weeks 24 and 48 –Change from BL in metabolic parameters at weeks 24 and 48

13. ® 13 CVC Phase 2b: 652-2-202 Trial Sub-studies Sub-studyInvestigatorsAssessments ImmunologyAlan Landay, PhD (Rush Med Ctr) Flow Cytometry, live and dead cells CD4/CD38/CD3/HLA-DR CD8/CD38/CD3/HLA-DR MetabolicAllFasting glucose & insulin (HOMA-IR) Fasting lipid profile (HDL, LDL, TChol, TG) Waist-to-hip ratio InflammationAllhs-CRP, IL-6, MCP-1, D-dimer, Soluble CD14 CardiovascularPriscilla Hsue, MD (UCSF) Brachial Artery FMD TropismAllConcordance between Trofile-ES and Genotype (3xPopSeq, NGS-454)

14. ® CVC: Summary Oral, Once-daily dosing (unboosted) Potent antiviral activity Phase 2b trial currently underway in HIV-treatment naïve patients to evaluate: –Longer term efficacy and safety –Dose selection for Phase 3 –Concordance between ESTA and genotypic tropism testing –Effect of CCR2 inhibition on inflammatory biomarkers Unique dual CCR5/CCR2 mechanism has potential for CV/metabolic clinical benefits to address HIV-associated, inflammation-driven morbidity and mortality 14

15. ® Against AIDS we will prevail together, for we will refuse to be split, or to cast into the shadows those persons, groups and nations that are affected.” “Against AIDS we will prevail together, for we will refuse to be split, or to cast into the shadows those persons, groups and nations that are affected.” – Jonathan Mann