monogram biosciences pharma collaborations -a labcorp center of excellence –
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Monogram BiosciencesPharma Collaborations
-A LabCorp Center of Excellence –
Monogram Biosciences
• Founded as ViroLogic, Nov 1995, South San Francisco, CA• Acquired by LabCorp as wholly-owned subsidiary, Aug 2009• ~225 employees• Virology/Oncology• Commercial Assays
• Clinical management• Drug/vaccine development
• Clinical Reference Laboratory• CLIA/CAP accredited
• Science directed• Over 175 peer-reviewed publications• Ranked highly for intellectual property portfolio
• Has conducted over 200 projects involving every commercially-available HIV antiretroviral
Monogram BiosciencesA LabCorp Center of Excellence
LabCorp’s Platform220,000 customers 31,000 employees
1,500 patient centers 440,000 samples per day40 years
Our mission is to be a leading provider of high science laboratory services that support clinical decision-making, enhance the
management of laboratory information, and improve patient care.
Monogram’s Technologies are Offered Directly at Monogram and through Esoterix Clinical Trials
Services, a Division of LabCorp
Central Labs
Dedicated labs for clinical trials
Cranford, NJMechelen, BelgiumBeijing, ChinaSingapore
Broad, validated test menu
Test method harmonization
8 Centers of Excellence
CoagulationEndocrinology OncologyInfectious disease Anatomic pathology Molecular pathology Flow cytometry
Small and large molecule
Method development and validation
LC/MS/MS
Non-GLP discovery services
Cell-based assays
Discovery and development
GLP biomarker services
MS-based assays
Global expertise: Cranford, NJMechelen, BelgiumSan Diego, CAWest Trenton, NJ
Discovery, development, commercialization
FDA experience
IVD Trial Participation
Successful PMA submission
40,000 ft2 biorepository
Integrated Data Management
Commitment to Quality
Dedicated Project
Management
Bioanalytical Labs Biomarker Discovery
Companion Diagnostics
Esoteric Testing
Testing Services Across all Phases of Development
• Screening drug candidates
• Characterizing resistance
• Screening patients for enrollment
• Optimizing background therapy
• Characterizing treatment failure
• Defining clinical cut-offs
• Enhancing market positioning
Discovery
Preclinical
Clinical
Post-Marketing
HCV Testing Services
• Monogram is designed to be a ‘one stop shop’ to meet virology testing needs for clinical trials
• Monogram is applying its legacy of providing accurate, high throughput HIV testing to HCV
• Current HCV assays– NS3: Sequencing & Phenotyping– NS5b: Sequencing & Phenotyping– NS5A: Sequencing & Phenotyping– IL28B SNP Genotyping– Subtyping/Genotyping and Viral Load– Deep sequencing and clonal analysis
Monogram HCV Assays and Services
GenoSure® HCV – NS3/4a sequencing
Monogram’s GenoSure HCV assay is now available for use in the clinic
Designed to help determine patient susceptibility to the commercially available HCV drugs
Validated to measure VL>2000 copies/ml
Monogram HIV Assays and Services for Clinical Research and Development
• Protease/Reverse Transcriptase Inhibitors• PhenoSense® (phenotype)• GenoSure® MG (genotype)• PhenoSense® GT≤ (combination phenotype/genotype)
• Entry Inhibitor Susceptibility (T20)• GenoSure PRIme® – genotyping PR/RT and Integrase in a single assay• Trofile®, Trofile® DNA (Co-receptor Tropism)• Integrase Susceptibility (phenotype; genotype)• Assembly Inhibitor Susceptibility (phenotype; genotype)• Replication Capacity & Sequencing Subtype• Neutralizing Antibodies – for HIV and Influenza• Clonal Analyses • PhenoScreen® Novel Drug Testing• Database queries• Viral Load (Roche COBAS/Ampliprep TaqMan 2.0, Abbott Real Time)
HIV PR/RT Resistance Testing
PhenoSense HIV Cell Assay
Transfection Infection
Resistance Test Vector DNA
A-MLV env DNA
+
293-A
PseudovirionsRT inhibitors addedPR inhibitors added
Patient virus exhibits reduced susceptibility to the drug
PhenoSense HIV Data
Patient:Control:
GenoSure MG Report
Monogram’s GenoSure MG report combines LabCorp’s genotyping capabilities (for faster turnaround), and Monogram’s proprietary algorithm…
Sequencing
Resistance Mutations
Prediction of DrugSusceptibility
Interpretation
Recombinant VirusTransfection
Measure of Drug Susceptibility
Infection
Patient virus
PR-RT DNA
RT-PCR
Resistance Test VectorVector Assembly
Phenotype Genotype
Bioinformatics
Parallel Phenotype/Genotype TestingPhenoSense GT Assay (PSGT)
Drug Resistance Testing: Genotype vs Phenotype
Benefits and Limitations
Genotyping
• Generates viral sequence (population)
• Identifies virus mixtures • mix of susceptible and resistant virus
species example: K103K/N
• Major Limitation: Interpretation of complex mutational patterns or reliance on algorithm
• Immature algorithms for new agents
Genotyping Phenotyping
• Direct measure of susceptibility
• Ease of interpretation
• Demonstrates effect of complex combinations of mutations
• Resistance and Cross-Resistance
• Re-sensitization
• Partial Activity
• Replication Capacity
• Generates viral sequence (population)
• Identifies virus mixtures • mix of susceptible and resistant virus
species example: K103K/N
• Major Limitation: Interpretation of complex mutational patterns or reliance on algorithm
• Immature algorithms for new agents
Drug Resistance Testing: Genotype vs Phenotype
Benefits and Limitations
Parallel Phenotype/Genotype TestingPSGT Report – Examples of Discordance
Parallel Phenotype/Genotype Testing
PSGT Report – Examples of Discordance
Pol and Integrase Resistance Testing
Monogram’s proprietary Pol assay allows sponsors and investigators to cost-effectively genotype PR/RT and Integrase in a single assay
Please contact Monogram for technical details on this assay
GenoSure PRIme
Integrase Resistance Testing
Monogram offers both genotyping and phenotyping to assist Integrase resistance in the clinical trial setting
HIV Tropism Testing
Transfection
HIV env expression vector containing patient’s PCR-
amplified HIV env fragments
++HIV genomic
luciferase vector
CD4 +CCR5 +
Infection
CD4 +CXCR4 +
virus entryinhibitors
added
B.
A.
C.
D.
E.
F.
The Trofile Assay
Trofile Report
• Trofile identifies the tropism of an individual patient's HIV strain – R5, X4, or a combination of these known as dual/mixed (D/M)
• Highly accurate, reproducible results using the complete HIV envelope (gp160)
• Clinically validated for selecting patients for CCR5 antagonist therapy
Trofile DNA
Test Description: Cell-associated DNA isolated from PBMCs is incorporated into Monogram’s proprietary testing vector and run in a single-cycle recombinant assay to determine tropism.
Product Specifications: Analytically validated to identify tropism in cell associated DNA.
Sample Input: Whole blood; PBMC
Neutralizing Antibodies/Vaccine Development
U5gag
polP
P
R A+
U3
env
luciferase
R
U87:CD4/CCR5/CXCR4
Neutralization Assay:
Incubation with antibodies or patient plasma
Y
Y
YY Y
Y Y
env
lucgag
pol
P A+
a/b c/d
gp120 gp41
(patient env gene)
HEK-293
Vectors:
Clone population of viralenv present in plasma, cell culture, etc.
Drug resistant PR/RT can be used for testing plasmas with RT inhibitors
Monogram Neutralization Assay
• Three control viruses tested with every plasma:• NL43 – neutralization sensitive lab strain• JRCSF – well known primary isolate• aMLV – specificity control:
• A test IC50 must >3X IC50 with aMLV to be called positive (green color)
• HIV+ Plasma Control: • Tested with every virus in every run• One control for every 7 sera tested• N16, Z23 - Broad, low titered neutralizing capability
• Purpose of controls:• Allow Monogram to assess run performance• Allow PI to compare data across time
Neutralization Assay Controls
JRCSF aMLV
Negative curve - No inhibition of aMLV by 2G12
Positive curve - IC50 = 0.56ug/ml
aMLV = specificity controlAnti-HIV antibodies will not inhibit aMLV
Antibody Neutralization AssayInhibition Curve
Multiple formats:
1. HITS – 4 dilutions– For screening large numbers of sera– Report % inhibition at each dilution–
2. CURVES – 10 dilution curves with IC50, 80, 90, 95– Cutoff for positive is >3X IC50 with aMLV
3. CURVES PLUS– 10 dilution curve and IC50, etc. plus % inhibition at each
dilution
Assay Formats
Other Virology Testing and Services
Panel # AMP IDV NFV RTV SQV LPV L10 K20 L24 D30 V32 L33 M36 M46 I47 G48 I50 F53 I54 A71 G73 V77 V82 I84 N88 L901 14.6 250.0 148.7 275.0 96.5 201.2 1 0 1 0 0 1 0 0 0 0 0 0 1 1 1 1 1 0 0 12 10.6 46.9 109.8 275.0 58.4 58.7 1 1 0 0 0 1 1 0 0 0 0 1 1 1 0 0 1 0 0 13 13.2 45.0 50.1 28.5 61.3 11.6 1 0 0 0 0 0 0 1 0 0 0 0 0 0 1 1 0 1 0 14 5.1 48.1 51.9 123.7 39.7 nt 1 0 0 0 0 0 0 1 0 0 0 1 1 1 1 0 1 0 0 15 6.3 31.1 21.0 79.2 20.0 nt 1 0 0 0 0 0 0 1 0 0 0 0 0 1 0 1 1 1 0 16 13.1 11.9 21.5 141.9 15.2 49.6 1 0 1 0 0 1 0 1 0 0 0 0 1 1 0 0 1 1 0 07 8.9 10.6 35.1 191.5 83.2 nt 0 0 0 0 0 0 1 0 0 0 0 0 1 1 0 0 1 1 0 18 2.1 23.6 23.1 42.2 143.1 nt 1 0 0 0 0 0 0 0 0 1 0 0 1 1 0 1 1 0 0 19 12.2 39.5 55.8 29.0 52.9 nt 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 1 0 110 5.5 151.2 91.0 79.9 561.7 60.8 1 1 0 0 0 0 1 0 0 1 0 0 1 1 0 0 1 0 0 011 28.8 250.0 74.2 275.0 550.0 148.8 1 0 0 0 0 1 0 1 0 1 0 1 1 1 0 1 1 0 0 012 4.2 82.6 98.1 116.5 596.6 nt 1 0 0 0 0 0 0 0 0 1 0 0 1 1 0 1 1 0 0 113 17.7 35.8 93.8 275.0 33.8 68.4 1 0 0 0 0 1 1 1 0 0 0 0 1 0 1 0 1 0 0 114 10.4 40.6 97.7 78.1 113.7 68.9 1 0 0 0 0 1 1 1 0 0 0 0 0 1 0 0 0 1 1 115 31.6 58.6 85.0 275.0 550.0 nt 1 0 1 0 0 0 0 1 0 1 0 0 1 1 0 1 1 1 0 016 16.7 11.2 53.5 275.0 69.0 nt 1 1 0 0 0 1 1 1 0 0 0 0 1 1 0 0 1 1 0 117 48.8 14.5 32.5 275.0 36.3 nt 1 1 0 0 0 1 1 0 0 0 0 0 1 0 0 0 1 1 0 018 20.5 20.3 30.1 275.0 27.4 97.1 1 0 0 0 0 1 0 1 0 0 0 0 1 1 1 0 1 1 0 119 2.8 169.2 167.2 89.2 550.0 72.1 1 1 0 0 0 0 1 0 0 1 0 0 1 1 0 0 1 0 0 020 29.6 250.0 297.4 275.0 550.0 156.0 1 1 0 0 0 0 1 1 0 0 0 0 1 0 1 0 0 1 0 121 7.7 27.7 20.0 107.6 4.9 22.3 1 0 0 0 1 1 0 1 0 0 0 0 0 1 0 0 1 1 0 122 42.1 16.9 50.1 275.0 127.6 93.0 1 0 0 0 0 1 0 1 0 0 0 0 1 1 0 0 1 1 0 123 4.9 23.2 41.5 59.5 61.3 nt 1 0 0 0 0 0 1 0 0 0 0 0 1 1 0 0 0 1 0 124 9.0 15.0 30.6 169.2 53.6 nt 1 0 0 0 0 0 0 0 0 0 0 0 1 1 0 1 1 1 0 125 3.3 10.2 39.4 40.2 1.0 6.1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 126 14.6 38.3 55.9 22.8 24.1 nt 1 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 1 0 027 7.0 35.9 64.7 44.4 96.7 13.8 1 1 0 0 0 0 1 1 0 0 0 0 0 0 1 0 0 1 0 128 130.0 22.5 29.4 275.0 550.0 273.1 1 1 0 0 0 1 1 0 0 1 1 0 1 0 0 0 1 0 0 029 13.8 40.8 58.2 132.9 94.4 67.3 1 1 0 0 0 0 1 1 0 0 0 0 1 1 0 0 1 1 0 030 7.0 12.7 30.5 87.3 46.6 38.2 1 0 1 0 0 0 1 1 0 0 0 0 1 0 0 0 1 1 0 031 10.1 20.2 40.1 80.0 74.5 nt 1 0 1 0 0 0 1 0 0 0 0 0 1 1 0 0 0 1 0 032 22.2 55.1 185.9 275.0 226.2 nt 1 1 0 0 0 1 1 0 0 0 0 1 1 1 1 0 1 0 0 133 14.3 25.5 54.5 217.4 68.6 nt 1 0 1 0 0 0 1 1 0 0 0 0 1 1 0 0 1 1 0 034 40.9 28.7 100.7 63.5 96.1 66.5 1 0 0 0 0 1 0 1 0 0 0 0 1 1 0 0 0 1 0 135 11.2 250.0 155.0 275.0 550.0 nt 1 1 0 0 0 0 1 1 0 1 0 0 1 1 0 0 1 0 0 136 12.5 6.7 18.5 60.1 9.5 51.5 1 1 0 0 0 0 1 0 0 0 1 0 1 1 0 0 1 0 0 037 4.9 12.3 13.1 81.7 25.4 nt 1 1 0 0 0 0 0 0 0 0 0 0 1 1 0 0 1 1 0 138 42.5 64.0 215.6 275.0 348.2 149.6 1 1 0 0 0 1 1 1 0 0 0 0 1 1 0 0 1 1 0 139 4.9 10.6 24.4 54.2 68.2 nt 1 1 0 0 0 0 0 0 0 0 0 0 1 1 0 1 1 1 0 140 15.0 11.4 52.0 42.4 126.7 nt 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 0 141 14.1 21.5 74.2 66.1 170.2 15.6 1 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 0 1 0 142 28.2 20.5 69.3 149.2 101.6 65.2 1 0 1 0 0 1 1 1 0 0 0 0 1 1 0 0 0 1 0 043 4.2 18.1 34.1 275.0 41.2 54.2 1 0 0 0 0 1 0 0 0 0 0 1 1 1 1 1 1 0 0 144 15.3 20.5 18.4 85.7 22.8 45.2 1 1 1 0 0 0 0 1 0 0 0 0 0 1 0 0 1 1 0 045 71.8 21.3 104.3 61.7 77.3 43.9 1 0 0 0 1 1 0 1 0 0 0 0 1 1 1 1 0 1 0 1
Novel Drug Characterization
Monogram can leverage its virus library and database to construct panels for drug characterization
Oncology Testing Services: VeraTag technology and
HERmark assay
How VeraTag Works
What is a “VeraTag” (VeraTag Reporter)?
Three components Recognition element (most often antibodies) Cleavable tether (thio-ether or disulfide bond) Fluoroscein reporters (variable mass-charge)
OO OH
HOOC
NHNH
S
OO
HN
O
antigen
antibody tether
fluoroscein
HERmark Assay
HERmark Assay Workflow
HERmark Report
• Classification of HERmark positive, negative, or equivocal
• Lab Developed Test
• Validated to CLIA standards
• Performed in a central, CAP-certified clinical reference laboratory
• All cases reviewed by Board Certified Pathologists
Additional VeraTag Assays
For questions about Monogram technology or assay ordering:
Andrew GaleDirector, Pharma Collaborations