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

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Low level viral

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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*

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-1.7

50 mg

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75 mg

-1.6

150 mg

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Placebo

*Nadir presented because viral load continues to drop after dosing ends.

CVC Phase 2a: POCEfficacy

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MCP-1 Concentrations

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hsCRP Levels - 100 mg

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Viral Dynamics

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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-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

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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