Company Introduction
THE FRONTAGE ADVANTAGE
Attention, Efficiency, and Expertise
Who is Frontage Laboratories?
• We are an early phase drug development company
• Started in 2002
• Currently 225 people
• We have grown organically and through acquisition (clinical)
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selected as one of the fastest growing companies in the
Philadelphia region – 4 years in a row
• Facilities in US and China
Working with Frontage:
Advantage #1 – Expediting your
development program
ACCOMPLISH MORE WITH ONE SERVICE SUPPLIER
Frontage has all that you need to move your compound
from preclinical development through Phase I – II clinical
studies and beyond
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API synthesis
Preclinical / ADME Services
Dosage form development
GMP manufacturing
Clinical study execution via 72-bed CRU
Bioanalysis & Biomarker / Immunology
Regulatory filing and support
Working with Frontage:
Advantage #2 - 100% Attention
WHAT SETS FRONTAGE APART??
Every project is on the front
burner – 100% attention
Communications are easy to
manage, coordinated, and
routinely scheduled
Our project management
leaders each have a minimum
15 years experience in the industry –
You receive the best project leadership possible
Cross functional project teams allow for smoother working process and
less administration
WE WORK HARD TO MAKE SURE YOUR COMPOUND IS FRONT AND
CENTER !!!
Working with Frontage:
Advantage #3 – Top Scientific Team
YOUR DRUG DEVELOPMENT PROGRAM REQUIRES THE
BEST TALENT
Frontage has a significant number of advanced-degree
scientists – >60% of our team
Extensive personal experiences in all phases of drug
development – from discovery to clinical, from laboratory
to commercial launch
Involved in numerous preclinical, first-in-man, late stage
clinical, generic and OTC development projects
Working with Frontage: Advantage #4 –
Frontage US –China Operation
QUALITY
Globally managed, centralized data (all sites WATSON LIMS)
Globally managed Quality System
SCIENCE
Frontage has the best training system in the industry
• Management team has international experience
• Scientists receive international training, working hands-on at US
facilities
Uniform testing platforms and ability to pool resources to ensure
best scientific coverage
Established method transfer procedures
LOGISTICS
Continuity of Service is guaranteed by Frontage – if there are
any potential shipment issues to China, US laboratory will serve
as back-up facility
FRONTAGE - BACKGROUND
Service Offerings
Our Locations
Hackensack, NJ (NYC area)
Phase I-II Clinical Operations
(72 beds) – expanding to 160 beds in 2010
Princeton, NJ
CRO support services
Malvern, PA
(near Philadelphia)
Bioanalytical and Bioassay services, ADME services
GMP API manufacturing
Exton, PA
(near Philadelphia)
Corporate Headquarters
Pharmaceutical Analysis, Formulation Development and
GMP CTM Manufacturing
Shanghai, China
Bioanalytical and Bioassay services, Pharmaceutical
Analysis and Formulations Development
Zhengzhou, China
Phase I Clinical Operations (130 Beds)
Beijing, China
Clinical Services and Regulatory Affairs,
Future home of Formulation Development
Beijing Pharmaceuticals Manufacturing Site
Alliances with GLP Preclinical
Centers in the US, Shanghai &
Suzhou, China
Preclinical Research centers – rodents, canines and
non-human primates
Our Clients
More than 200 clients around the world: US, EU, JP,
China
Global top 10, mid-size and virtual pharmaceutical and
biotech firms
Chinese generic and innovative drug companies
Frontage has had successful FDA inspections (10+) and
numerous client inspections and audits for both our US
and China facilities
DMPK Preclinical Services
Overview
WORLD-RENOWNED LEADERSHIP
Accomplished team of professionals
Thought leaders in drug metabolism - over 100 years of
collective experience in DMPK and ADME support and published
research
DMPK SERVICES
Support for discovery pharmacokinetic studies
Discovery-stage in-vitro studies metabolism evaluations
Discovery-stage ADME studies
Drug development stage DMPK support and metabolic
evaluations
EFFICIENT SYSTEMS
Technical leadership allows for quick completion of studies
Price leadership
Capabilities in US and China
Discovery DMPK Services:
PK Studies
Exploratory
Discovery
Pre-Selection
Lead Candidates DT
PK in Pharmacology
Model(s)
Help with POC,
MED exposure
In-Life and Non-GLP Bioanalytical
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PK/PD Biomarker
Assessment
PK in Other
Species including
Rodents and NonRodents
(As Needed)
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PK in Non-Rodent
Target Tissue
Exposure
(Total and Free)
High-dose
Pharmacology
Support
Salt Selection
Linearity
Assessment
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Renal/Biliary
Clearance
(As Needed)
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Ascending Dose PK
Rodent and
Non-Rodent
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TK and Formulation
Support
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Additional Species PK
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Food Effect
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Interspecies Scaling
Discovery DMPK Services:
In-Vitro DMPK Studies
Exploratory
• Metabolite Profiling/
Structure Elucidation
- metabolic soft spots
- structure optimization
• Metabolic Stability
(microsomes /
hepatocytes)
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Intrinsic Clearance
CYP IC50/MBI
Discovery
• Plasma Profiling/
- pharmacology species
- PK and tox species
(rodents, dogs, monkeys)
Pre-Selection
• Cross-species metabolism
(microsomes/hepatocytes)
• Identification/isolation of
major human metabolites
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Plasma/Microsomal
Protein Binding
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Blood/Plasma ratio
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CYP Reaction
Phenotyping
• Caco-2/MDCK permeability
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P-gp Transport/
Inhibition
CYP Induction
(PXR/Human
Hepatocyte)
Lead candidates
• Metabolism in human
plateable hepatocytes
• Metabolic pathways
elucidated
DT
Drug Development Phase DMPK:
Metabolite Studies
Phase 0
IND
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In vitro metabolism - [14C]
compound
14C
Single dose
metabolism
and mass balance (rodent
and
non-rodent)
Multiple dose metabolite
profiles from IND enabling
studies
Phase 1
SAD & MAD
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Enzyme induction
(ex vivo), if needed
Mechanistic studies to
support safety assessment
(as needed)
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Metabolite profiles from
SAD/MAD studies
Phase 2 to
Post-NDA
POC
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Determination of exposure of
major human metabolites in
tox species
DDI support and kinetic
assessment of metabolite
formation [14C] in vitro
Tissue distribution, brain
penetration/target tissue
uptake
3H
mass balance and tissue
distribution
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NDA
Human [14C] ADME study
Metabolism support of
clinical studies (DDI,
pediatric, elderly,
hepatic/renal, QTc, etc.)
Placental transfer, milk
excretion
Discovery ADME Studies
Metabolic stability (2 time points) – microsomes / hepatocytes
Intrinsic clearance – microsomes / hepatocytes
In-vitro metabolite identification for structural optimization
Cross-species metabolite profiles across species – microsomes
/ hepatocytes
CYP-450 inhibition – LC/MS/MS based assays (available May
2010)
CYP reaction phenotyping – cDNA
Plasma protein binding
Discovery ADME Studies
Plasma metabolite profiling
Plasma/blood partitioning studies
Isolation and characterization of metabolites
In-Life PK studies (in-life conduct through partners –
internal small mammal capabilities available June 2010)
CACO-2 / MDCK permeability studies (available July 2010)
Quantitative LC/MS analysis (non-GLP) from PK studies
Development DMPK Studies
Reaction phenotyping (cDNA & chemical inhibition)
Metabolite profiling and identification – Tox/FIH studies
Isolation and characterization of metabolites
Delineation of metabolic pathways
CYP inhibition studies. Definitive IC50 & k1 determinations
(April 2010)
CYP induction in livers of rodents, canines & primates
(June 2010)
Development ADME Studies
Synthesis of metabolites and stable-labeled materials
The Frontage team has specific expertise for
development of Metabolites In Safety Testing (MIST)
packages.
Identification of metabolites
Quantitation of metabolites
AUC determinations (using non-radiolabeled compounds)
Mass balance studies in rodents – 14C and 3H and tissue
distribution studies will come on line second half of this
year
DMPK Leadership Team
• Abdul Mutlib:
(PhD)
• Jack Wang:
• Jim Burleigh:
(BS)
• Peter Liu:
(MS)
Twenty years of experience in pharmaceutical industry,
DuPont-Merck, Pfizer, Hoechst-Roussel (Aventis), Wyeth
Five years post-doc in academia, 60+ publications, patents
Editoral Board: Chemical Research in Toxicology
Experienced technical supervisor with over 25 years of experience
in conducting ADME studies in laboratory animals
Experience in developing, validating and implementing complex
LC/MS/MS assays for the quantitation of drugs in biological
matrices in a GLP, GLP-like and non-GLP environments. Twenty
years experience in bioanalysis.
DMPK Leadership Team
Team Member
Background Description
Abdul Mutlieb (PhD)
Twenty years of experience in pharmaceutical industry,
DuPont-Merck, Pfizer, Hoechst-Roussel (Aventis), Wyeth
Five years post-doc in academia, 60+ publications, patents,
Editoral Board: Chemical Research in Toxicology
Jack Wang (PhD)
More than 20 years of experience in mass spectrometry,
structure elucidation, drug metabolism and analytical
chemistry. 30+ publications, patents, book chapter.
Jim Burleigh (BS)
•Experienced technical supervisor with over 25 years of
experience in conducting ADME studies in laboratory
animals
Peter Liu (MS)
•Experience in developing, validating and implementing
complex LC/MS/MS assays for the quantitation of drugs in
biological matrices in a GLP, GLP-like and non-GLP
environments. Twenty years experience in bioanalysis.
DMPK Leadership Team
continued:
Team Member
Background Description
Li Shen (PhD)
More than 10 years of experience in Development Drug
Metabolism. Experience in mass balance studies,
metabolite profiling, enzyme ID and kinetics, drug-drug
interaction, enyme induction and inhibition. Expert in DM
studies to support projects from pre-IND through
post-registration.
Seonghee Park (PhD)
Experience in Caco-2/MDCK permeability assays, other
transporter assays, sandwich-cultured hepatocytes, protein
binding & in vitro metabolism.
Bioanalytical Services
INDUSTRY - LEADING TECHNICAL CAPABILITIES
Highest ratio of advanced degreed scientists working on the bench
From data management and sample handling to analysis platforms,
Frontage has invested in state-of-art technology, including global
Watson LIMS system
Streamlined method development - typically completed within 1
week
Analyte stabilization techniques help Frontage to overcome tough
technical challenges – prevents degradation of analytes
One of the largest laboratories on the East Coast, USA and China
EFFICIENT PROJECT MANAGEMENT
Global study support
Over 35,000 samples analyzed per month in US and China
Bioanalytical Services
LC / MS / MS
Bioanalytical Services
GC & LC/MS/MS METHOD DEVELOPMENT & VALIDATION
Demonstrated success in developing methods for compounds
requiring high sensitivity measurements (picogram / mL)
Small and large molecule analysis
One of the most proficient labs in US and China – tackling
technically challenging projects globally
IMMUNOASSAY DEVELOPMENT & VALIDATION
MSD Electrochemiluminescence Platform
ELISA
Antibody and platform development
BIOMARKER ASSAY DEVELOPMENT & VALIDATION
State-of-Art Equipment and
Processes
17 LC/MS/MS systems in USA (10 API 4000, 3 API 5000, 3
4000 API Q-trap, API365),
6 LC/MS/MS in China (4 API 4000, 1 API 5000, 1 API 4000
Q-trap)
More than 30 HPLC systems
3 MSD Electro-chemilluminescence Instruments
Watson LIMS system – centralized data for US and China
Tomtec and Tecan Liquid handling systems
Ultrasonic Tissue Processing Equipment
Emergency Power Back up
Monitoring system for storage freezers
State-of-Art Equipment and
Processes
High Throughput Sample Preparation
State-of-Art Equipment and
Processes
Electrochemiluminescence – Large Molecule Analysis
State-of-Art Equipment and
Processes
Covaris Ultrasonic Extractor – Tissue Processing
Exton
CMC Facilities
• Analytical Labs– 8,000 Sq Ft
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GMP Analytical Instrumentation
ICH Stability Storage
• Formulation Development & GMP Area ( 10,000 Sq Ft)
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Solids R&D
Liquids / Creams / Ointments R&D
Potent Compounds suite (GMP)
Solids Dosage Manufacturing (GMP)
Liquids / Creams / Ointments (GMP)
Sterile Compounding (GMP)
CMC Services Analytical
GMP & GLP ANALYTICAL SERVICES
Method Development, Validations and Transfers
• HPLC (25 systems), UPLC, GC, LC/MS/MS, GC/MS
ICH Stability Evaluations – over 4,500 cubic feet of storage
• Standard and Custom Conditions
Dissolution Testing
• Comparator Study Capability with On-line HPLC & UV
Unknown Impurity Identifications
• Fraction Collection, Purification, Synthesis, ID by MS & NMR
Finished Product Release Testing & Customer Complaint
Investigations – CTM and Commercial Products
Particle Size Analysis and Wet Chemistry
Analytical
Equipment
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25 HPLC Systems – UV/PDA, CAD, Refractive Index, Fluorescence
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Three vendor platforms for ease of method transfer / robustness
(Waters, Agilent, Shimadzu)
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UPLC Systems – PDA and MS
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3 GC Systems – FID with Headspace
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Ion Chromatography (Dionex)
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LC/MS/MS and GC/MS - Impurity ID
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10 Dissolution Systems
with on-line HPLC and UV analysis
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Particle Size Analysis & Wet Chemistry (KF, Titrations)
CMC Services Stability
• Stability Chambers Are Fully Compliant With ICH Guidelines
• 7 Walk-in Stability Chambers And 5 Reach-ins With Over 4,500
Total Cubic Feet
• Smaller Chambers And Photo stability Chamber For Special
Studies
• Lab Watch Monitoring System
• Emergency Back-up Power
Generator for continuous
operation
CMC Services Formulations
FORMULATION DEVELOPMENT
Rational Development Processes (CTD / QBR formats)
Pre-formulation characterization and screening
• Physicochemical evaluations
• Excipient compatibility
Immediate and Controlled Release Development Expertise
• Oral Solid Dosage Forms – Immediate and Controlled delivery
systems
• Sterile – Parenteral, Lyophilized, & Ophthalmic Forms
• Creams, Ointments and Gels
• Nasal Sprays (including characterization – droplet size,
geometry
• High Potency Suites
Proof of Concept Studies in Animals via China facilities
Process Optimization and Improvements
Clinical Manufacturing
• Phase I –II Scale
• Full Range of Capabilities
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Oral Solids -High Shear,
Encapsulation, Compression,
Tablet Coating, Fluid Bed
Sterile manufacturing
utilizing disposable bag system
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Semi Solids
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Liquids capabilities to 100 L
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High Potency Suites
CMC Services
GMP CONTRACT MANUFACTURING – CLINICAL TRIAL MATERIALS
Oral Solid Dosage Forms
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API filling in Capsules – Accurate Dosing System
Standard Tablet and Capsule filling
Tablet in Tablet technology (Tri-layer Tablet Press)
Liquid – filled Capsules
Enteric Coating
Sterile Dosage Forms
• Aseptically-filled vials using disposable mixing and filling technology
• Nasal Sprays
• Suspensions
Topical Dosage Forms
• Creams, Ointments, Gels
API’s via chemical synthesis
CMC Services
API SYNTHESIS AND RESEARCH CHEMISTRY
GMP Synthesis of Small Molecules – up to 5 kg scale
Reference Standard Synthesis
Metabolite Synthesis & Cold Labeling
Impurity Identification and Purification Projects
Process Development & Optimization
Sourcing & Scale-up to Commercial
Collaborations
BEIJING PHARMACEUTICALS GROUP
Large Scale, FDA-inspected GMP manufacturing
PIERRE FABRE (FRANCE)
Patented Nanotechnologies for enhancing bioavailability of low permeability
/ low solubility drugs
Taste masking of bitter API’s
HERAEUS (GERMANY)
Cytotoxic API Manufacturing via chemical synthesis and fermentation
SINCLAIR RESEARCH (MISSOURI) & CALVERT LABORATORIES (PA)
GLP Preclinical research centers
PRECLINICAL RESEARCH CENTERS IN CHINA
Frontage - supervised studies for non-GLP evaluations
Biomarkers & Biologics
Frontage Laboratories will provide a full range of
technology platforms, flexibility and customization to
meet all your Biomarker and Biological Analytical
requirements across various stages of preclinical &
clinical development
• Our collective experience ranges from all phases of drug development
• Our team can provide guidance on issues that range from assay development,
validation to biomarker, Pharmacokinetics and Immune response analysis
• Comprehensive portfolio of technology platforms to accommodate virtually all of your
biomarker testing requirements
• Flexibility in choosing from assays commercially available or previously developed. We
also work with you to develop and validate custom assays
• 21CFR Part 11 compliant (adherence to 21 CFR Part 58 GLP)
Biomarker and Biologics
5 staff (3 Ph.D., 2 M.S.), experienced in biologics method development and validation,
biomarker assay development and testing
Preclinical and Clinical Stages of development
3 MDS electro-chemi-luminesence (ECL) ELISA platforms, robotic liquid handling
platforms.
Immunogenicity, enzyme assay, cell-based assay, protein and peptide identification
Method development, validation and transfer, within US and to China.
CLIA certification, GLP compliant.
Competitive cost structure for study-based projects or FTE programs
Immunoanalytical Testing
(Ligand-Binding Assays)
PHARMACOKINETICS
• Method development/ method transfer
• Method validation
• Preclinical and clinical sample PK analysis
IMMUNOGENICITY
• Method development/method transfer/validation
• Antibody screening
• Antibody titration
• Antibody specificity
Specialized Assays & Services
PROTEOMICS
ELISA DEVELOPMENT/SAMPLE ANALYSIS
MULTIPLEXED BIOMARKER ASSAYS ON MSD PLATFORM (HUMAN, MOUSE, RAT)
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Inflammation panel
Angiogenesis panel
Onco panel
Metabolic panel
INDIVIDUAL ELISA’S
ENZYME ASSAYS
• Westerns/Imaging
PROTEIN/PEPTIDE IDENTIFICATION
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De novo protein/peptide sequencing
PTM analysis
Protein-protein interaction analysis
Protein/peptide characterization
Biologics:
Assays & Services
PHARMACOGENOMICS & MOLECULAR BIOLOGY
TESTING
• SNP
• RT-PCR
• Oligo synthesis & DNA sequencing
• qPCR,
• genotyping
• microsatellite DNA repeat analysis
• gene sequencing
• siRNA & miRNA construction
• Gene construct and expression and microarray
Biologics:
Assays & Services
CELL-BASED ASSAYS (PRE-CLINICAL AND CLINICAL)
• Potency assay
• Cytotoxicity and Proliferation assays
• Immune function assays
• Flowmetric assays
• Tissue processing/staining for IHC
• Custom assay development for client needs
USA AND CHINA
• Frontage provides these services at both facilities
• Possible expansion to other countries
US Clinical Research Center:
Background
Founded in 1994 – 16 year track record of service
excellence
72-bed unit located in Hackensack, New Jersey
On-site, full-time principal investigator with 20 years of
emergency medicine experience
Phase 1 and 2a studies
On-site pharmacy (temperature controlled, limited
access) for study drug storage, packaging / labeling and
retention
Extensive subject database (healthy volunteers / special
populations) and dedicated recruiting staff
Local clinical laboratory with 24-hour turn-around
Central IRB (rapid review process)
Clinical Research Centers:
Phase 1 and 2 Studies
PHASE 1 AND 2A STUDY EXPERIENCE
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First-in-human
Pharmacokinetics
Single dose escalation / repeated dose
Absolute and relative bioavailability
Bioequivalence studies (pilot, pivotal, fed, fasted)
Drug-drug interaction (DDI), drug-alcohol and drug-food
interaction studies
Oral, injectable, inhaled, intranasal NCEs, peptides, hormones
Thorough QT (TQT) study evaluations
PD assessments / Biomarkers Safety and tolerability
assessments
Clinical Research Centers:
Subject Recruitment
Proactive recruitment planning & execution
Extensive volunteer database (5000+ subjects)
Wide-ranging media options – newspapers and local
publications, employment guides, local flyers and
postings, radio
Local networking – schools, businesses, health fairs
Dedicated recruiting staff
Clinical Research Centers:
Proof-of Concept Studies
Proof of concept studies
• Cardiovascular – endothelial dysfunction, HTN, early CV disease
(Endo-PAT vascular compliance devices)
• Metabolic – Type 1 and 2 DM, obesity, metabolic syndrome,
dyslipidemias (dietician, on-site Hologic Dexascanner)
• Gastroenterology – sigmoidoscopies, colonoscopies,
gastroesophageal reflux, irritable bowel syndrome, diarrhea
• Women’s health – pre- and postmenopausal women, osteoporosis,
hormone replacement, sexual dysfunction
• Men’s health – testosterone replacement, osteoporosis, sexual
dysfunction
• Dermatologic – acne, actinic keratosis, psoriasis
• Inflammation – osteoarthritis, rheumatoid arthritis
• Ophthalmologic assessments
• Cognitive assessments
• Excellent access to specialty physicians as needed
Clinical Research Centers:
Study Time Lines
Rapid IRB submission process (Central IRB)
Study-specific approval typically within 8 business days of
submission
Able to begin screening immediately with IRB-approved
generic ICF
Dosing within 3 weeks
of contract execution
Same-day shipment of plasma
samples from CRC to
Frontage BioA laboratory
Prompt (within 48 h) report of preliminary PK/BE results
Clinical Research Centers:
Study Metrics
Since 2006, we have performed:
Over 25 bioequivalence studies (pilot and pivotal)
2-way and 3-way cross-over
Fed and Fasted
Over 700 healthy male/female volunteers enrolled
Enrollment rate >98%
Completion rate >90%
Over 25 Phase 1 studies
Over 1000 healthy male/female volunteers and special populations
enrolled
First-in-human, single and multiple dose, bioavailabilty, formulation,
DDI, PK, safety/tolerability
Enrollment rate >98%
Completion rate >93%
Clinical Services
Moving Forward
New US clinic to be constructed
160-bed state-of-the-art Phase 1 clinic
Northern New Jersey location
Access to public transportation and diverse subject population
Ability to run 3 separate 24/36 subject panels simultaneously
Separate area with hospital beds
Operational 24 hours per day / 7 days per week
On-site pharmacy (storage/preparation/retention)
Flexible site use / expanded recreation & dining areas
Expected to be operational Q2/Q3 2010
2009: 120-bed clinic became operational in Zhengzhou,
China
CRO Support Services
Full-service CRO for Phase 1-3 studies
Headquarters in Princeton, NJ
Experienced Senior Management Team
Protocol Design, ICF and CRF Development
Project Management
Clinical Data Management (Oracle Clinical)
SAS Programming
Biostatistical & Pharmacokinetic (WinNonlin) Analysis
Medical Writing
Regulatory Support / Submissions
China
Clinical Research Center
• Dedicated 130 bed unit
located in Zhengzhou, China
Fit-Out completed in Q2 2009
Supported by the First
Affiliated Hospital of
Zhengzhou University (4,000
bed hospital)
ICH GCP compliance
SOPs strictly follow
Frontage’s U.S. practices
Clinical Pharmacology &
Regulatory Affairs
CLINICAL PHARMACOLOGY CONSULTATION
CONSULTATION ON DRUG DEVELOPMENT & REGISTRATIONS
Clinical Pharmacology
CMC
Toxicology
Regulatory Project Management
REGULATORY FILINGS (IND, NDA, & ANDA)
FDA COMMUNICATIONS
Agent representation
FDA Meeting Management
Liaison Activities
Get the Attention You Deserve
OUR ORGANIZATION HAS BEEN BUILT WITH YOU IN
MIND!
Project management and program managers have proven
industry experience
Key leaders of each business unit have proven track
records in the industry
We are sufficiently staffed in each area to manage
individual service projects or integrated programs
Proven Quality – strong compliance and technical record
in the industry
DISCUSSION & NEXT STEPS