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Cenicriviroc: A Potent Dual Chemokine Receptor Antagonist (CCR5/CCR2) in Phase 2b Development
with Potential to Transform HIV Therapy
Sandra M. Palleja, MD6th IAS Conference on HIV Pathogenesis-Rome 2011
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Cenicriviroc (CVC): Key Characteristics
• Oral CCR5/CCR2 receptor antagonist─ In vitro protein-adjusted EC90 = 1.2 nM (clinical isolates)─ CCR2 IC50 = 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
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Cenicriviroc
CVC Key CharacteristicsAttributes Necessary for a Leading HIV Agent
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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
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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
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Volberding and Deeks, Lancet July, 2010
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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
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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)
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HIV Infection
New Therapeutic Goals: Suppress Virus and Address Inflammation-Associated Morbidity and Mortality
High le
vel v
iral
replic
ation
Low level viral
replication
Immune Cell Death
Chronic Inflammation
AIDS-related morbidities
Cardiovascular Disease, Metabolic
Syndrome, Premature Aging, etc.
DeathDeath
Current HIV Drugs
Cenicriviroc
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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
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HIV RNA Median Nadir Change from Baseline*
HIV
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hang
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om B
asel
ine
(log 1
0 cop
ies/
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-0.4
-0.6
-0.8
-1.0
-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: POCEfficacy
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020406080
100120140160180200
MCP-1 Concentrations
MCP
-1 C
once
ntra
tions
(pg/
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Day 1 Day 1002468
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hsCRP Levels - 100 mghs
CRP
Conc
entra
tions
(mg/
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Day 1 Day 10
1 3 5 7 9 11 13 15-2.00
-1.50
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-0.50
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0.50Viral Dynamics
Chan
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rom
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Cenicriviroc Phase 2 – Patient 3007: 100 mg QD for 10 Days
CVC Phase 2a: POCAntiviral Potency and CCR2 Effect
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CVC Phase 2b: Protocol 652-2-202Trial 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
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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
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CVC Phase 2b: 652-2-202 Trial Sub-studiesSub-study Investigators Assessments
Immunology Alan Landay, PhD(Rush Med Ctr)
Flow Cytometry, live and dead cellsCD4/CD38/CD3/HLA-DRCD8/CD38/CD3/HLA-DR
Metabolic All Fasting glucose & insulin (HOMA-IR)Fasting lipid profile (HDL, LDL, TChol, TG)Waist-to-hip ratio
Inflammation All hs-CRP, IL-6, MCP-1, D-dimer, Soluble CD14
Cardiovascular Priscilla Hsue, MD(UCSF)
Brachial Artery FMD
Tropism All Concordance between Trofile-ES andGenotype (3xPopSeq, NGS-454)
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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
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“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