TBR-652, a Potent Dual CCR5/CCR2 Antagonist in Phase 2 Development for Treatment of HIV Infection

1. TBR-652, a Potent Dual CCR5/CCR2 Antagonist in Phase 2 Development for Treatment of HIV Infection David E. Martin, PharmD* Tobira Therapeutics, Inc. *On behalf of TBR-652-2-201 Study Team Abstract 8023, XVIII International AIDS Conference, Vienna, Austria 20 July 2010

2. Half of Deaths in HIV-Infected Patients Now Due to Non-AIDS-Related Causes Cause of Death in HIV+ Individuals Initiating ART (Europe and North America, 1996-2006, n=1597*) Possibly due to ongoing inflammation *N=39,272; total deaths=1876. Antiretroviral Therapy Cohort Collaboration. Clin Infect Dis. 2010;50:1387-1396.

3. The Cascade of Events Due to Chronic Immune Activation and Inflammation Low-level Viral Replication • 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 increases the risk of morbidity and mortality from a variety of non-opportunistic conditions Secretion of Pro-inflammatory Cytokines Chronic Inflammation Immune Senescence Osteoporosis, Atherosclerosis, Neurocognitive Degeneration, Frailty, Metabolic Syndrome, etc Appay V, et al. J Pathol. 2008;214:231-241. HazenburghMD, et al. AIDS. 2003;17:1881-1888.

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

5. CCR2 has been associated with and studied in a variety of inflammation-associated diseases: Metabolic syndrome/insulin resistance Atherosclerosis To date, no significant safety signals have been identified with CCR2 antagonists Clinical Relevance of CCR2 Inhibition

6. Oral CCR5 receptor antagonist In vitro protein-adjusted EC50 = 0.29 nM (clinical isolates) Plasma T ½ = 35-40 hours Once-daily dosing Neither CYP inducer nor inhibitor Additive to synergistic activity with other ART classes in vitro Oral bioavailability of current formulation enhanced with food Structure: TBR-652: Characteristics

7. Inhibition of binding of MCP-1 to CCR2 at 5.9 nM Potent inhibition of in vitro calcium flux in murine and human receptors In vivo dose response in the thioglycollate-induced peritonitis mouse model with a near maximum effect at ~15 mg/kg TBR-652: CCR2 Characteristics

8. Protocol Design TBR-652-2-201 Evaluate antiviral potency, safety, tolerability, PK, and CCR2 activity • Randomized, double-blind, placebo-controlled, dose-escalating study in HIV-infected subjects with: • CD4 ≥250 cells/mm3 • HIV-1 RNA ≥5000 copies/mL • CCR5-tropic virus by Trofile-ES assay • Treatment-experienced, no HIV treatment for ≥6 weeks • 5 dose cohorts • TBR-652 (n≥8): 25, 50, 75, and 150 mg (F1 formulation) • TBR-652 (n=10): 100 mg (F2 formulation) • PBO (n=2) • 10-day monotherapy • MCP-1, hsCRP, and IL-6 measured on Day 1 and Day 10

9. TBR-652 Demographics and Baseline Patient Characteristics 54 patients randomized. 1 early discontinuation during dosing period, not adverse event (AE)-related.

10. TBR-652 Baseline Inflammatory Marker Concentrations Mean (SD). N/D = not done.

11. TBR-652 Safety Profile AEs in 2 patients or more per cohort judged at least possibly related to study drug. SAE=serious adverse event.

12. TBR-652: Median Nadir Change From Baseline *†††† †† †† ††100 mg F2 formulation. *P=0.002. †P<0.001.

13. TBR-652: Dose-Dependent Effect on MCP-1 * * * *P≤0.02 versus placebo.

14. TBR-652: PK/PD Relationship for Changes in MCP-1 Concentrations

15. Antiviral and Anti-inflammatory Effects Patient 3007 100 mg QD for 10 Days 15

16. Conclusions • TBR-652 is a potent inhibitor of CCR5-tropic, HIV-1 replication • Median nadir response up to -1.8 log10 copies/mL • TBR-652 demonstrated potent CCR2 inhibition • Generally safe and well tolerated during short-term use • No study drug–related discontinuations, SAEs, or deaths • No clinically significant trends in AEs, laboratory, vital signs, or ECGs • Favorable and predictable pharmacokinetic profile • TBR-652 warrants further investigation as an unboosted, once-daily, oral CCR5 antagonist with potentially important anti-inflammatory effects • Phase 2b expected to start in early 2011 with a variety of substudies to evaluate the effects of TBR-652 immunologic, cardiovascular, and metabolic end points

17. Acknowledgements • All patients who participated • Investigators and study coordinators • US sites– Argentina sites Cynthia Brinson Javier Altclas Calvin Cohen Pedro Cahn Edwin DeJesus Juan Carlos Cha Torea Richard Elion Fabian Fay Jerome Ernst Jorge Galindez Joseph Gathe Jose Luis Ippolito Jacob Lalezari Carlos Zala Peter Ruane Melanie Thompson • Tobira Study Team–Tobira Consultants Sandra Palleja Richard Pollard David Martin Israel Charo Reynold Driz Robert Grosso Richard Ogden Sally Snyder James Sapirstein • Collaborators ICON Monogram Biosciences Pharsight