Your Drug Discovery Partner · ary design Tier 1 ADME e Ex vivo er Tier 2 ADME selection tic &...
Transcript of Your Drug Discovery Partner · ary design Tier 1 ADME e Ex vivo er Tier 2 ADME selection tic &...
Your Drug Discovery Partner We make it simple.Enjoy our quality with confidence.
Fidelta is a fully integrated CRO offering a broad range of services and solutions in drug discovery research.
TARGET SELECTION HIT FINDING PRE-CLINICALDEVELOPMENT
PHASE 1 ONWARDSH2L LO
FAST FOLLOWER STRATEGY
PHENOTYPIC SCREENING
NON-GLP TOX
SOLID STATE
BESPOKE TARGET
VALIDATIONGLP BIOANALYTICS
EX VIVO ANALYSES FOR BIOMARKER
RESEARCH
CHEMISTRY, PHARMACOLOGY, EARLY TOX, ADME/PK AND TRANSLATIONAL SCIENCE
ADME/PK
In vivo pharmacology
Translational research
In vitro pharmacology
Our state-of-the-art R&D facilities and scientific know-how in Medicinal chemistry, ADME/PK, In vitro / In vivo pharmacology and toxicology ensures seamless transition from one activity to the next.
— ABOUT US
100 customers from allover the world
more than
Medicinal chemistry
Fidelta differentiates by placing a strong emphasis on translational research and ex vivo assays that include patient disease-relevant tissues and clinical isolates.
In vivo ADME and pharmacology
Medicinal chemistry
In vitro ADME and pharmacology
Translational research
TARGET VALIDATION
HTS(primary assays)
Human 1° cells
Human tissue samples
PK
In vivo efficacy
GLP/non-GLP
bioanalysis
GLP analysis of clinical
material
Non-GLP toxicology
Assay development
(biochemical & cell-b
ased)
CADD
Library design
Tier 1 ADME
Solid stateEx vivo analyses fo
r biomarker
selection
Tier 2 ADME
Synthetic & Analytical
chemistry
PK/PD
H2L PRE-CLINICAL DEVELOPMENT
PHASE 1 ONWARDS
HIT ID LO
— SUPPORTING OUR PARTNERS IN DRUG DISCOVERY
We work closely with you to:
> define the required compound profile
> design project strategy and optimize the screening cascade
> prioritize compounds for further evaluation
> interpret the results
Our aim is to generate and select high quality lead compound and to avoid progressing compounds which are unlikely to pass development (solubility issues, tox issues etc.)
Scale up & Process
chemistry
— WHY CHOOSE FIDELTA FOR R&D OUTSOURCING?
• Track-record of success
> 75 integrated projects across a broad range of TA> 180 publications and 96 PCT applications in last two decades
• Integrated drug discovery services (FTE of FFS)
• Development of tailor made assays and animal models
• Ex vivo assays on samples from healthy volunteers and patients
PROJECT PHASE
To Hit Finding To Hit to Lead To LeadOp To PCC
of which 6 in the clinic
9282711
Immunooncology 3%
Oncology 16%
Inflammation incl.
Fibrosis 46%
Infection 28%
CNS 4%Other 3%
— OUR HISTORY
Best of both worlds
- big pharma and biotech experience
19522006
20132010
— STATE-OF-THE-ART R&D FACILITIES
Fully equipped with instruments essential for modern and innovative drug discovery and development
> 4000 square meters of laboratory and office space
> 30 laboratories
> 50 fume cupboards
> A scale-up lab
> AAALAC-I and OLAW accredited animal facility
> GLP certified bioanalysis
GLPGood Laboratory
Practice
— SCIENTIFIC TEAM
> 140 highly qualified scientists with an average of 12 years of industry experience each
> Multidisciplinary and high-performing drug discovery teams
> Flexible resource distribution between Chemistry, Pharmacology and DMPK according to
the project needs
— DRUG DISCOVERY CAPABILITIES
FIDELTA OFFERS — Medicinal chemistry
— ADME/PK
— In vitro pharmacology
— In vivo pharmacology
— Translational research
— MEDICINAL CHEMISTRY
ANALYSIS
DESIGN
SYNTHESIS
TESTING
Biochemical/ functional assaysADME and PK profilingAnimal modelsHuman samples
CheminformaticsDevising project strategyProject management
ANALYSIS Structure based drug designLigand based drug designVirtual screeningKnowledge-based design
DESIGN
Custom synthesisSemi-parallel synthesisModern technologies (MW, flow)Scale up & Process chemistry (up to 1 kg)
SYNTHESIS
TESTING
MED
ICIN
AL
CHEM
ISTR
Y
• Fully integrated with other Fidelta’s / client’s departments
• Extensive experience in synthesis and development of small molecules and macrocycles
• In-depth knowledge of a wide range of target classes; enzymes (protein kinases, epigenetic targets), G protein-coupled receptors, ion channels, protein-protein interactions etc…
We support all aspects of integrated drug discovery from Hit ID to the PCC nomination
DEVELOPMENT / IND SUPPORT
LEAD OPTIMISATION
HIT-TO-LEAD
HIT ID & GENERATION
• Hit confirmation & rapid SAR exploration• Lead generation suitable for LO progression
• Phys-Chem property consideration; e.g. clogP, TPSA, Ro3, Ro5,solubility, LE, LLE
• ADME & PK assessment• FTO and IP assessment
• Innovative drug-like molecular design• Project management & strategy; devising flexible screening cascade• Pharmacology & DMPK evaluation; target engagement, efficacy, PK and safety projections• Support with IP protection / patent filings• Candidate nomination
• Scale-up/Process chemistry; route development & tech transfer packages
• Solid state • 7-Day toxicology studies
• IVIVE / human dose projections• GLP bioanalysis
• In Silico screening• Macrocyclic libraries for challenging targets• Knowledge-based design• HTS output evaluation • Scaffold hopping
MED
ICIN
AL
CHEM
ISTR
Y
COMPUTER-AIDED DRUG DESIGN (CADD)
SYNTHETIC CHEMISTRY CAPABILITIES
Structure based drug designLigand based drug designCheminformaticsExpertize in macrocycles
Custom synthesis
Modern synthetic transformations and functional group inter-conversions
Contemporary methods and techniques related to synthesis, isolation and identification (microwave and flow assisted synthesis)
Synthesis by request, including development and optimisation of synthetic pathways
Multistep synthesis service (>10 steps) of milligram quantities
Validation of synthetic routes to previously unknown scaffolds
Semi-parallel synthesis
Focused arrays of discrete compounds up to 100 NCEs
— MED-CHEM SERVICESSCALE UP & PROCESS
CHEMISTYRapid transfer from small to large scale (up to 1 kg)
In-process analytical chemistry integrated part of scale up
Non GMP production
Redesign and synthetic routes optimization
Medicinal chemistry is tightly integrated
with CADD, Synthetic, Scale up and
Analytical chemistry
MED
ICIN
AL
CHEM
ISTR
Y
ANALYTICAL CHEMISTRY
NMR structural studies
Structure determination of by-products, impurities, degradation products, unexpected result of chemical reaction
NMR instruments: automated; open-acess
Stability and solubility studies
STABILITY STUDIES: - Solid state (regulatory and ICH conditions): VT, VRH, light stability; - Solution stability: Buffers, bio-relevant media (SGF, FeSSIF, FaSSIF)
SOLUBILITY STUDIES IN VARIOUS MEDIA: Buffers, bio-relevant media, organic solvents
Solid state characterization
XRPD (RT, VT, VT/VRH)
DSC, TGA
Hot stage and optical microscopy
Karl-Fisher
Single crystal X- ray diffraction, SEM, particle size (all subcontracting)
Discovery analytical services
Achiral and chiral purity assessment (LC)
UPLC/HPLC method development and transfer
MS - and UV-directed purifications
Purification of libraries
Isolation of impurities/degradants
Reference substance characterization with Certificate of Analysis or full scientific report
MED
ICIN
AL
CHEM
ISTR
Y
— DRUG METABOLISM AND PHARMACOKINETICS
We offer comprehensive in vitro ADME assays, pharmacokinetic studies and bioanalytical services including GLP and non-GLP to support medicinal chemistry programs.
All studies are performed in line with SOPs to ensure quality, rapid turnover and efficient service.
AD
ME/
PK
— IN
VIT
RO
AD
ME
PLA
TFO
RM PHYSCHEM
PERMEABILITY
BINDING
METABOLIC STABILITY
DDI
METABOLITE PROFILING & ID
Kinetic solubilityThermodynamic solubility- pH, SGF, FeSSIF, FaSSIFChromLogDChemical stability
Cellular permeabilityMDCK MDCK-MDR1Caco-2
Plasma protein bindingBlood partitioningTissue bindingMicrosomal binding
Microsomes, S9, HepatocytesRecombinant enzymesPlasma and bloodSGF, FeSSIF
InhibitionCYP450 direct inhibition & MDI (recombinant, HLM)Reactive metabolitesGlutathione trapping
Aldehyde Oxidase reactionPhenotypingMetabolite identificationInterspecies profiling A
DM
E/P
K
— FL
EXIB
LE IN
VIV
O P
K S
TUD
Y D
ESIG
NS ROUTES OF
ADMINISTRATION
SAMPLING METHODS
SAMPLE TYPES
TYPES OF STUDIES
Intravenous, oralsubcutaneous, intraperitoneal, intramuscular, intradermal, topicalintranasal, intratrachealintracolonic
Serial samplingTail- vein, saphenous veinCatheter (jugular, femoral)Heart puncture (terminal)
Whole blood, plasma, serumTissues/organsExcreta (urine, feces)Cerebrospinal fluid (rat)
Rapid screening studies to assess exposurePK studies to estimate disposition kinetics and bioavailabilityDose proportionalityRoutes of excretion (metabolic cages)Customized studies (CSF sampling, intestinal loops)Single and repeated dosing
— BIOANALYTICAL CAPABILITES
Sample analysis are in compliance with internal SOPs and in-line with regulatory bioanalytical guidelines and white papers.
GLP BIOANALYSIS
NON-GLP BIOANALYSIS
Method development and validation
Sample analysis from GLP toxicology studies and clinical studies
Successful GLP inspection in 2017
High throughput bioanalysis to support in vitro ADME screening
Metabolite ID and reactive metabolite screening
Method development for preclinical PK, PD and TK studies
Biomarkers
GLPGood Laboratory
Practice
AD
ME/
PK
— IN VITRO PHARMACOLOGY
Fidelta biology team has extensive experience in developing biochemical and cell based assays to support hit and lead identification and optimization.
TARGET VALIDATION
BIOCHEMICAL ASSAYS
TRANSLATIONAL RESEARCH
• Expression in healthy and diseased tissue- qRT-PCR or western blot• Knock-down or overexpression- siRNA and antisense oligonucleotides- Adenoviral and lentiviral transduction
• Broad target experience- GPCRs, nuclear receptors, ion channels, epigenetic targets, kinases, peptidases, hydrolases, other enzymes, transporters, etc • Various readouts - Fluorescence, luminescence, TRF, absorbance, alphaLISA
CELL BASED ASSAYS
• Disease relevant assays in human primary cells- Cells from healthy volunteers or patients- Mediator release- Cell surface and intracellular markers expression- Proliferation- Chemotaxis
• In vitro assays on human tissue samples (healthy donors and patients)• Ex vivo analyses for biomarker selection
IN V
ITR
O P
HA
RM
ACO
LOG
Y
ONCOLOGY
• Target validation- Expression in diseased tissue- Silencing or overexpression
• Cell proliferation- 2D- 3D
INFLAMMATION
• Disease relevant assays in human primary cells and tissues
• Indications in focus:- Fibrosis- Respiratory- Gastrointestinal - RA
— THERAPEUTIC AREAS
IN V
ITR
O P
HA
RM
ACO
LOG
Y
INFECTION
• Bacteria- In house strain collection- Access to clinically relevant pathogens- Antimicrobial susceptibility testing - Compound profiling ∙ resistance development propensity∙ time-kill∙ biofilm studies • Viruses- Rhinovirus and influenza virus- Antiviral activity IMMUNO - ONCOLOGY
• Immune checkpoints
HOST-PATHOGEN INTERACTIONS
• Modulation of host response to viral infection
Fidelta pharmacology team is experienced in using animal models as an irreplaceable tool for a wide range of applications.
IN V
IVO
PH
AR
MA
COLO
GY
— ANIMAL MODELS/THERAPEUTIC AREAS
INFECTION • Bacterial• Viral
FIBROSIS
INFLAMMATION
• Respiratory• IBD• RA• Dermatology
• Pulmonary• Renal• Liver
• >60 animal disease models characterized and validated against clinically relevant pharmacological standards
- Full packages of validation data available
• Flexible usage
- Target validation
- Efficacy testing
- PK/PD relationship
- Mechanistic studies
- Translational studies
- Safety read-outs
IN V
IVO
PH
AR
MA
COLO
GY
— COMPREHENSIVE IN VIVO PROFILING
CLINICAL PATHOLOGY
• Clinical biochemistry• Haematology • Coagulation • ImmunochemistryTAILORED STUDY
DESIGN
• Local and systemic routes of administration• Osmotic pump delivery• Clinical read-outs • Functional read-outs• Biomarkers• Safety read-outs
HISTOPATHOLOGY
• Automated tissue processing• Standard & special staining• IHC/IF and double staining• In situ hybridization (single/double)• Morphometry• Frozen sectioning • Quantitative digital image analysis• Slide scanning IN
VIV
O P
HA
RM
ACO
LOG
Y
TARGET EXPRESSION
COMPOUND TESTING
PHASE I EFFICACY
• Expertise and track record in integrated drug discovery and development up to Phase II• Experience with clinical studies, human sample collection and analysis
TRA
NSL
ATI
ON
AL
RES
EAR
CH
— TRANSLATIONAL RESEARCH AND PATIENT SAMPLE STUDIES
— ETHICAL AND REGULATORY COMPLIANCE
• High quality ethically obtained human tissues from consented patients
• Procedures harmonized with international legislature
› The Human Tissue Act 2004, EU laws and regulations, etc.
• SOP-s covering human sample collection and management
• GCP compliance
TRA
NSL
ATI
ON
AL
RES
EAR
CH
Protocoland ICF
PI selection
Ethics committee approval & contract with the clinical site
Patient recruitment & sample collection
Sample shipment
Sample analysis
CLIENT
CONTACT
Fidelta d.o.o.Prilaz baruna Filipovića 2910000 Zagreb, Croatia
P. +385 1 888 63 00E. [email protected]. www.fidelta.eu