Product Development Services for Global Registration of Drugs & Biologics th April Contact: kevin.breesch@toxikon.be

Transcription

1 Product Development Services for Global Registration of Drugs & Biologics th April 2014 Contact:

2 CONTENT OF PRESENTATION» History» Company Profile» Current Services» Proof-of-Concept: non-clinical efficacy studies (R&D)» Preclincal Tox: in vivo and in vitro toxicology (GLP)» Analytical: material characterization / Stability (GMP) Lot release testing (CoA) 2

3 Company Profile

4 TOXIKON COMPANY PROFILE C.R.O. - Contract Laboratory Headquarters: Boston, USA European Lab Facility: Leuven, Belgium 30 Years of experience in Preclinical Testing for the Medical Device, Pharma and Biotech Industry About 190 Researchers

5 Quality Credentials System/Authority Europe USA ISO 17025:2005 BELAC ACLASS GMP FAGG FDA GLP WIV FDA FDA registration AAALAC/MSPCA/OLAW NRC (radiolabeling studies) 5

6 US-laboratories

7 EU-laboratories

8 Pharma/Biotech Development: Value Chain Pre-clinical testing of drug candidates provide critical insights into their human safety and therapeutic profiles. Target Identification Drug Candidate Identification Drug Candidate Optimization Pre-clinical Testing IND Clinical Phase I Clinical Phase II Clinical Phase III NDA Production R&D/non-GLP GLP GCP GMP Drug Discovery Pre-clinical Development Clinical Development Lot Release Stability

9 Hit-to-Lead / Lead Optimization

10 Proof-of-concept / Non-Clinical Efficacy» PK/TK studies Single dose multiple dose Different Routes of Administrations (Bioavailability) Interspecies comparison ADME - small Molecules For Dose-Response Relationship Selection of relevant animal Species Biologics: species need to be pharmacological responsive to be clinically predictive» PD studies Therapeutic effect- Mode of Action Product specific endpoints Different formulations Receptor/ligand binding inhibition Assays

11 Animal Disease Models» Oncology (Xenograft Tumor Models) Prostate cancer: LNcap, DU145, PC-3 Lung Cancer:NCI-H460, NCI-H69, HOP-92 Breast cancer: MDA-MB-468, MCF-7, MCF-7 (MDR+), MDA-MB- 231 Liver Cancer: PLC-5, Hep3B Colon: HT29, COLO-205 Pancreatic Cancer:PANC-1 Brain: US7MG Promyelocytic: HL-60, THP-1 B cell lymphoma: Ramos, RaJI These are the models we have validated and using for our clients. However we can develop any other type of tumor models. 11

12 Animal Disease Models» Inflammatory Diseases Rheumatoid Arthritis (RA) Inflammatory Bowel Diseases (IBD) Multiple Sclerosis Atopic Dermatitis Allergic Contact Dermatitis (ACD) Lung Disease Diabetes and Obesity Models» Ocular Programs Dry eye EAU Uveitis Glaucoma / IOP Corneal NV / AMD Choroidal NV / AMD (Subretinal NV) Retinal NV / AMD, DR

13 IND: Preclincal Toxicology (GLP)

14 IND Programs» Investigational New Drug (IND) / Medicinal Product» Biologic Licence Application (BLA) / Biological MP to the FDA / EMA are required for first-in man-studies and require the following: Chemistry Manufacturing and Control (GLP/GMP Certificate of Analysis and characterization) Pharmacology (ADME, Efficacy) Toxicology (GLP Safety) Clinical Phase I plans 14

15 Basic IND Enabling Studies» Repeat dose 28-Day (although 14-Day can be used) in vivo GLP toxicology studies in rodent and non-rodent species are usually required.» Except for biologics or cancer drugs in vitro GLP genotoxicity tests: the Ames bacterial assay, in vitro mammalian chromosomal aberration and rodent in vivo micronucleus assay are preferred» Safety pharmacology (CVS, CNS, Pulmonary) 15

16 TYPICAL TOXICOLOGY MEASUREMENTS (parameters, areas of evaluation)» Formulation, Dosing (Dose Analysis: Needs Method Development /Validation, HPLC)» Clinical signs (e.g. OE, ECG in 28 day-study)» Eye toxicity and heart evaluations, pre and post dose» Mortality and morbidity» Body weight change and Food Consumption» Clinical Pathology (Hematology, Blood Chemistry, Coagulation, Urinalysis)» Necropsy and Gross Pathology» Histopathology of at least 44 tissues» TK (Day 1 and Day 28: Evaluate potential for accumulation effects): Need Method Development/Validation for Bio-analysis (LC-MS/MS or ELISA)» Recovery Animals (Evaluate delayed toxicity and reversibility effects)

17 IND example NCE strategy for dosing 1month in humans MONTHS Analytical Chemistry GMP bartch recertification Method development and validation in Plasma Method development and validation in Formulations Acute Toxicity Maximum Tolerated Dose and Repeat Dose Ranage finding in Rat Maximum Tolerated Dose and Repeat Dose Ranage finding in Dog Subacute Toxicity 28 day dosing in Rat 28 day dosing in Dog Safety Pharmacology Cardiovascular telemetry in Dog Respiratory Safety in Rat CNS effects in Rat Genotox Studies AMES assay Chromosome abberation Assay Rat Micronucleus Test 17

18 Preclincal Toxicology (GLP) Biological License Application (BLA)» A BLA for a biologic drug (i.e. recombinant proteins, antibodies, mab fragments, mab drug conjugates, cytokines, etc.) follows ICH Guidance S6 which specifies a case-by-case program design: Single dose and repeat dose toxicity Genetic toxicology: AMES, Chromab and MNT Reproductive end developmental toxicity Carcinogenicity Tissue-Cross-Reactivity (mab)» Study desings in order to mimic the clinical dosing regimen, using preferably GMP material, as intended for Marketing Authorizations» No ADME studies since proteins i.e. break down to native amino acids and so are safe and produce safe metabolites.» Biopharmaceuticals are not likely to enter cells and interact with DNA, no genotoxicity tests are typically required. 18

19 IND Programs Biological License Application (BLA) Enabling Studies (cont.)» Toxicity mechanisms are: off-target effects and exaggerated pharmacology requiring tox studies in at least one relevant or surrogate species. Primates are often the tox species.» Safety Pharmacology on major physiological systems CNS, CVS (telemetry) and respiratory can be integrated in toxicity studies» Biologics, require immunotoxicity/ neutralizing antibody evaluations with assay development and validation to examine blood samples. 19

20 BLA example Biologic strategy for dosing 1month in humans MONTHS Assay Validation PK (ELISA) PD (Ligand-binding inhibition) Immunogenicity (ELISA) Tissue-Cross-Reactivity (Immuno Histo Chemistry), Human tissues General Toxicology Single-dose Tox in NHP with 1 Month Recovery* 28 day Repeat Dose in NHP with 2 Month Recovery* * including Immunogenicity, PK, PD, safety Pharmacology 20

21 Analytical Services material characterization / Stability (GMP)

22 Analytical Services (GMP/GLP) Analytical chemistry In support of:» Impurities, Extractables & Leachables» Stability & Lot Release testing State of the Art Technology:» GC/MS, HS-GC/MS, PTV-GC/MS, GC-TOF, GC-FID» LC-UV (DAD), LC/MS-Ion Trap, LC-MS/MS, Orbitrap» ICP-OES, ICP-MS AAS, IC, TOC, IR Microbiology testing Services» Sterility Testing (EP / USP <71>)» Sterilization & Cleaning Validation Studies» Bioburden (MLT EP ) testing, EM & microbial identification (MID)» Bacterial Endotoxin testing (EP )

23 Analytical Services (GMP/GLP) - Biologics» Compound purity and stability (ICH Q5C) SEC HPLC SDS-PAGE IEF Cell Potency assay ELISA» Other parameters Particulate matter Osmolarity Sterility (14 day Conventional or 4 hours RAPID) Endotoxins Mycoplasma (28 day Conventional or 4 hours RAPID) Residual DNA Viral clearance

24 THANK YOU!