1. Tobira Therapeutics, Inc. *On behalf of TBR-652-2-201 Study Team
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 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, , n=1597*)
Possibly due to ongoing inflammation
*N=39,272; total deaths=1876.
Antiretroviral Therapy Cohort Collaboration. Clin Infect Dis. 2010;50:

3. Low-level Viral Replication Secretion of Pro-inflammatory Cytokines
The Cascade of Events Due to Chronic Immune Activation and Inflammation
Chronic Inflammation
Osteoporosis, Atherosclerosis, Neurocognitive Degeneration, Frailty, Metabolic Syndrome, etc
Low-level Viral Replication
Secretion of Pro-inflammatory Cytokines
Immune Senescence
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
Appay V, et al. J Pathol. 2008;214:
Hazenburgh MD, et al. AIDS. 2003;17:

4. The Role of CCR2 in Chronic Inflammation
Recruitment of Monocytes/Macrophages
Systemic Inflammatory Response Initiated
Inflammatory Insult
Release of MCP-1
Release of Inflammatory Cytokines (ie, TNF-α and IL-6)
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

5. Clinical Relevance of CCR2 Inhibition
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
Source: Investigator brochure

6. TBR-652: Characteristics
Oral CCR5 receptor antagonist
In vitro protein-adjusted EC50 = 0.29 nM (clinical isolates)
Plasma T ½ = 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:
Source: Investigator brochure

7. TBR-652: CCR2 Characteristics
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
Source: Investigator brochure

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
Source Protocol TBR

9. TBR-652 Demographics and Baseline Patient Characteristics
TBR-652 QD Doses Evaluated
25 mg
(n=8)
50 mg
75 mg
(n=9)
100 mg
(n=10)
150 mg
Placebo
Gender (M/F)
8/0
7/1
9/0
8/2
6/3
9/1
Age (mean) 41 38 40 34
Median HIV-1 RNA (log10 copies/mL),
(min-max)
4.2
( )
4.5
( )
4.6
( )
4.4
( )
4.0
( )
( )
Mean CD4 (cells/mm3)
415
456
442
449
503
495
Source data from Table numbers
total n, gender, age
median viral loads
mean CD4
Notes 54 randomized and 6 early discontinuations all for “other” reasons
54 patients randomized.
1 early discontinuation during dosing period, not adverse event (AE)-related.

10. TBR-652 Baseline Inflammatory Marker Concentrations
TBR-652 QD Doses Evaluated
25 mg
(n=8)
50 mg
75 mg
(n=9)
100 mg
(n=10)
150 mg
Placebo
MCP-1 (pg/mL)
20.0 (14.8)
12.6 (12.0)
26.6 (32.2)
16.0 (8.94)
31.6 (29.0)
22.4 (13.6)
hsCRP (mg/L)
N/D
1.76 (1.57)
1.12 (0.864)
11.2 (22.9)
1.58 (1.33)
1.67 (1.83)
IL-6 (pg/mL)
<5.0
Source data from Table numbers
total n, gender, age
median viral loads
mean CD4
Notes 54 randomized and 6 early discontinuations all for “other” reasons
Mean (SD).
N/D = not done.

11. TBR-652 Safety Profile TBR-652 Dose Cohort Placebo 4 3 5 8 1 2 25 mg
(n=9)
50 mg
(n=7)
75 mg
100 mg
(n=10)
150 mg
Any SAE
Any AE 4 3 5 8
Headache 1 2
Diarrhea
Abdominal pain/
discomfort
Fatigue
Nausea
Pyrexia
Source: Table Treatment-Emergent Drug-Related Adverse Events by System Organ Class and Preferred Term
Table Listing of Treatment-Emergent Serious Adverse Events
Safety Data Population
Note to Cal from Sandie-
The fevers were in pts with viral syndrome/sinusitis and abscess. These fevers occured in single pts in each of the cohorts, from my recollection and they were low grade.
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
* † † † † ††
Source Table medians rounded to nearest tenth ††
††100 mg F2 formulation.
*P=0.002.
†P<0.001.

13. TBR-652: Dose-Dependent Effect on MCP-1* * *
Source Table Analysis of MCP-1 (pg/mL) by Study Visit
*P≤0.02 versus placebo.

14. TBR-652: PK/PD Relationship for Changes in MCP-1 Concentrations
Source Table Analysis of MCP-1 (pg/mL) by Study Visit

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