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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
CH3
H3C
OO
N
HN
OS
N
N
CH3
H3C・H3C-SO3H
O
2
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Cenicriviroc
CVC Key CharacteristicsAttributes 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
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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
4
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
5
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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
repli
catio
n
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
RN
A C
ha
ng
e f
rom
Ba
se
lin
e (
log
10 c
op
ies
/mL
)
0
-0.2
-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
MC
P-1
Co
nce
ntr
atio
ns
(pg
/mL
)
Day 1 Day 1002468
101214161820
hsCRP Levels - 100 mg
hsC
RP
Co
nce
ntr
atio
ns
(mg
/L)
Day 1 Day 10
1 3 5 7 9 11 13 15-2.00
-1.50
-1.00
-0.50
0.00
0.50
Viral Dynamics
Ch
ang
e f
rom
Bas
elin
e H
IV
RN
A
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-studies
Sub-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
14
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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