MOVE YOUR DRUG FROM CONCEPT TO IND WITH CONFIDENCE

Transcription

1 MOVE YOUR DRUG FROM CONCEPT TO IND WITH CONFIDENCE CLINCIAL CANDIDATE IDENTIFICATION LEAD OPTIMISATION PROCESS CHEMISTRY INTEGRATED PRECLINICAL DEVELOPMENT SERVICES ANALYTICAL R & D SAFETY ASSESSMENT DMPK, CP & INVESTIGATIVE TOXICOLOGY PRE - FORMULATION R & D Design and Development of Pre-clinical Plan Druggability Screens in support of Drug Discovery - DMPK, Exploratory Toxicology and Phys-chem Optimization Chemistry Manufacturing Control Regulatory Toxicology Dossier Preparation for IND / IMPD

2 Derisk your IND development process... Integrated Service Provider - Advinus is the leading integrated pre-clinical services and collaborations partner combining Exploratory Studies, CMC, DMPK, Analytical R&D and Regulatory Toxicology. Team The value proposition of Advinus is its knowledge base, know-how and problem solving skills with highly committed and experienced scientific experts of international caliber. The Management team has experience of supporting around 90 INDs and 35 NDAs in their career. Facility Over 220,000 sq ft of state-of-the-art laboratories and more than 450 professionals, Advinus is the leading center of Toxicology services in South Asia being the only GLP facility in India to be successfully inspected by USFDA with no 483s. Study Submissions and IND Filing Advinus has extensive experience of more than 6,000 Regulatory Toxicology study submissions to worldwide agencies. We have completed several IND packages which received FIH approvals from regulatory agencies without any clinical hold; supported several clients with their study designs, protocols, reports and regulatory filings. Assured Quality: Our strong commitment to uncompromising quality for more than 20 years, has helped us establish ourselves as a reliable R & D center. We make sure every study we undertake receives formating attention from our well qualifed team of study directors, which in turn increases the success of INDs. PARTNER WITH ADVINUS... Relationship with Clients: Sponsors across verticals have been the primary source for our successful growth over the years. We highly value our relationship with each of our sponsors. Advinus, being a TATA Enterprise is built on the timeless ethos of trust, tranparency, ethical business practices & mutual respect. Minimization of time and cost involved in the development: Our highly experienced Project Management & Quality Assurance team ensure that every project progresses as per plan & completes on or ahead of time. This not only saves valuable financial resources for our sponsors but also helps them to speed up time-to-market of their potential drug candidates. Greater chances of success of the programs: Our well established processes coupled with highly experienced & qualified research team increases the chances of success of each program. Being the most accredited & experienced testing center in the region further increases the probability of success of the programs. Data protection: We use state-of-the-art information mangament systems across our laboratories. Our eroom protected Firewall FTP server with advanced encryption capabilities ensure security & protection of all critical scientific information. Providing best solutions to the scientific issues: We realise that every new drug idea comes with its own set of scientific challenges. Our research team is previleged to have solved many critical problems over the years and have received many accolades from globally reputed large pharma companies. We consider every new challenge as an opportunity to further human progress.

3 Preclinical Development Services Optimization Studies Chemistry Optimization Stability Phys-chem Properties Salt forms, Polymorphs Custom Synthesis for Exploratory Toxicology Studies In vivo & In vitro Lead Optimization Studies Evaluation of several different formulations in PK Studies Mini AMES and mini herg 2 Dog Telemetry 7 Day Exploratory Toxicology in Rat Process Development and Synthesis Custom Synthesis for Exploratory Toxicology Studies Intermediates and Impurities Salt Forms and Polymorph Selection Process Development for NCEs Scale up facility to support kg quantities for Regulatory Toxicology Studies cgmp capability upto kilo quantity Analytical Validation Analytical R&D and Pre-formulation Process Chemistry Stability studies for API as per ICH Impurity profiling and characterization Physical and Chemical characterization DMPK Full range of in vitro e.g. metabolic stability, CYP assays, protein binding, permeability, drug-drug interaction studies in vivo studies absolute and relative bioavailability Dose proportionality PK in vivo 14 C studies Mass Balance and Tissue Distribution Metabolite profiling and tentative structure elucidation Bioanalysis Method Feasibility, Development and validation GLP Bioanalysis Support for regulatory Toxicology Studies GLP Toxicokinetic Analysis Preclinical and Clinical PK Analysis Clinical-Bioanalysis and PK Analysis from BA / BE and NCE - Clinical Trials Safety Assessment General Toxicology Studies in rodents and non rodents Genotox Studies Reproduction Toxicity Studies Carcinogenicity Studies in rodents including Transgenic mouse model Safety Pharmacology (SINCE 1992) (SINCE 1999) (SINCE 2001) Accreditations: Indian GLP Authorities Since 2005

4 Chemistry Manufacturing & Controls Advinus Chemistry Services support pre- and early clinical development programs by providing services in the areas of focused Library Synthesis (Medchem FTE), Custom Synthesis to generate few grams to few hundred grams of desired New Chemical Entity for exploratory studies and Chemical Development services. With our best-in-class infrastructure, we can conduct synthesis from milligram to kilogram scale. We have a kilo lab and a versatile cgmp pilot plant with equipment ranging upto 600L vessel. Advinus competence in process research enables development of cost efficient, environment friendly, safe and robust processes that can lead to speedy development of drug candidates for timely delivery. Key Strengths Focused library Custom Synthesis Process Development & Scale-up Non GMP and cgmp Material Generation Analytical Method Development & Validation Stability of API as per ICH guidelines Process Chemistry Services Custom synthesis from few grams to few hundred grams Process Development and optimization Analytical Method Development and Validation Complete process analytical package including impurity profiling & working standards Technology development and transfer services along with the process, analytical and engineering dossier Supply of NCE/ API for Toxicology and clinical studies from cgmp pilot plant Salt Screening and Polymorph Studies Synthesis of Metabolites Isolation, Characterization and Synthesis of Impurities Stability studies as per ICH guidelines Analytical Services Active pharmaceutical ingredient (API) testing Physical characterization Solubility and pka determination Partition coefficient determination Crystal properties and polymorphism Excipient compatibility studies Chemical stability profile Specification for drug substances Specialities World class infrastructure Accomplished chemistry team 18+ process patents during their career 100+ publications in peer reviewed international journal

5 Analytical R & D Advinus Chemistry and Pre-formulation services are fully supported by comprehensive and world class analytical capabilities. Our in-house GLP facilities are geared up to carry out the full array of activities to support client requirements for discovery, development and approval. Analytical R & D Services Structural chemistry Solid state characterization Analytical method development and validation (ICH guidelines) Raw material and reaction monitoring Stability studies for API (ICH guidelines) Material evaluation for pre-clinical and clinical studies Impurity profiling and characterization Preparation of reference and working standards Analytical support for Drug Master Filing Equipment NMR 400 MHz LC-MS/MS Auto Purification System with Mass Selective Detection (MSD) HPLCs with UV, PDA, Fluorescence and RI detectors HPLC with radiochemical detector and fraction collector GCMS GC with head space GC with FID, NPD and ECD Liquid Scintillation counter Biological Sample Oxidizer Polarimeter FTIR, UV- Vis Spectrometer, Auto titration, Micro balance

6 Infrastructure - CMC CASE STUDY Process Optimization of NCE for a US based client Key challenges: y Client Scheme 16 step reaction, desired chiral purity 98% y Chiral induction, ArLi reaction, Cisthermal elimination y Costly reagent in the existing process y Handling reagents like n-bu-li, NaH Advinus approach y Developed Process that was - scalable & robust (validated 3 batches) y Replaced costly RMs with economical RMs reducing costs by more than 25% y Reduced the overall synthetic scheme from 16 to 14 steps

7 Drug Metabolism and Pharmacokinetics The DMPK department has broad capabilities to support various drug discovery and drug development studies. Advinus adopts a parallel and iterative testing mode that is concurrent with the lead optimization process to ensure that compounds optimized for activity and potency are druggable. We have an unparalleled combination of experience and laboratory resources. Key Strengths Group has extensive troubleshooting skills BCS classification assays Validated in-vitro assays in place A dedicated team for in-life phase studies Scientists part of GBC and APA Boston Society in vitro Studies Solubility and Stability at different ph conditions Log D Metabolic Stability CYP Profiling (9 CYPs) CYP Inhibition (9 CYPs) Time Dependent Inhibition and Ki determination Plasma Protein Binding Blood Plasma Partitioning and Stability Permeability Assays (Caco-2, MDCK, PAMPA, MDCK-MDR1, MDCK-BCRP) CYP Induction Stability and Simulated Gastric and Intestinal fluid hpxr activation in vivo PK Studies Formulation development for pre-clinical PK Absolute and Relative Bioavailability Species: Hamster, Mouse, Guinea Pig, Rat, Canine, Human Routes of administration: IV, PO, IM, IN, SC Cannulation techniques: Jugular vein, Carotid artery, Femoral vein, Bile duct, Portal vein Conducted GLP BA/BE studies for regulatory submission. Conducted BA/BE studies in dog for regulatory filing In vivo 14 C ADME Studies Mass Balance Tissue Distribution Toxicokinetics/ Pharmacokinetics Routinely support protocol design and reporting for Toxicology studies Clinical PK analysis and reporting Validated Phoenix WinNonlin 6.3 Bioanalysis: Discovery to Clinical LC/MS/MS based on API-4000 Platform Fit-for-purpose bioanalysis for in vitro and in vivo exploratory studies Regulatory pre-clinical bioanalysis for GLP studies Clinical bioanalysis for Clin Pharm studies from Phase I through Phase III

8 Infrastructure - DMPK CASE STUDY 1. Discovery DMPK for Active Lead Optimization Programs for Large Pharmas y Tier 1: Solubility, Microsomal Metabolic Stability, CaCo-2 permeability y Tier 2: CYP Inhibition in HLM by LC/ MS/MS, Plasma Protein Binding and Microsomal Binding y Tier 3: Bioavailability studies in rat and dog y Advinus turns around data within 1 week of receiving compounds y Advinus has developed and validated the in vitro assays 2. GLP Bioanalysis: Large Pharma ran a blinded bioanalytical trial y Task: Sensitivity of pg/ml with 10,000 fold dynamic range y Result: Advinus developed and validated a suitable method with two overlapping CCs y Currently four full INDs completed for client; bioanalytical partner for Phase I clinical trials in US 3. Clinical Bioanalysis support for US based Industry Leader y Trials are managed by a US based CRO; Patient group in continental US y Samples received at Advinus within 72 hours of sample collection y Data reported within 72 hours to enable exposure-guided dose escalation

9 Safety Assessment With over two decades of experience in GLP compliant Toxicology testing, Advinus confidently offers a wide range of toxicity studies in several species. A well-known integrated facility helps one to achieve safety evaluation programs under single facility and in timely manner. Toxicology team is backed by study directors having more than 14 years of experience on an average. Advinus has highly accredited GLP labs with certifications since It has world class laboratories and largest vivarium in India. Advinus has demonstrated a higher level of consistency and expertise required for long term studies and has experience for conducting more than 50 Carcinogenicity studies. All regulatory studies are conducted in accordance with the guidelines prescribed by international agencies including USFDA, ICH, EMA, USEPA (OPPTS), OECD, EEC, JMAFF and CIB of India. In-life data capture via Provantis - a modern, fully integrated Windows-based system is used in all Toxicology/ Pathology Laboratories. Exploratory Development Studies Mini Ames Mini herg (herg screening) Dose range finding studies CVS function screening in telemetered dogs Regulatory Studies - Genetic Toxicology in vitro mutagenicity y Ames test y Chromosomal aberration test y Mammalian gene mutation test y Micronucleus test in vivo mutagenicity y Micronucleus test y Chromosomal aberration test y Dominant lethal test Safety Pharmacology y herg Assay y Pulmonary Function (Rats) y Modified Irwin Test/Functional Observation Battery in rats (FOB-Rats) y CVS function assessment using telemetered dogs General Toxicology (Rodents & nonrodents) y Single dose studies y Repeated dose sub-acute and sub-chronic studies (7, 14, 28 & 90 days) y Chronic toxicology studies (6, 9 & 12 months) y Combined chronic and carcinogenicity studies y Carcinogenicity studies in rodents y Carcinogenicity studies in Transgenic mouse models

10 Infrastructure - Safety Assessment Development and reproduction toxicology Segment I - Fertility studies Segment II - Embryo-fetal studies Segment III - Perinatal and postnatal studies Two generation reproduction toxicity studies Juvenile toxicity studies Immunotoxicology y Immunotoxicity assay humoral response y LLNA - skin sensitization Neurotoxicology y Irwin Test Infrastructure: Hematology and Clinical Chemistry y ADVIA Hematology y Smart-4 coagulation analyzer y Hitachi 704 & Roche Hitachi 902 Clinical Chemistry y Easylyte - Electrolytes y Urilux Urine y ETI-Lab Automated Elisa Reader Histology y Automatic tissue processors y Automatic motorized microtomes y Automatic stainer y Auto cover slipper y Efficient system for specimen collection, identification, storage and archiving of tissues CASE STUDY Case I: Oncology Pre-formulation and alternate routes of administration Client nominated 2 lead series with 3 compounds each Advinus approach y Scored all three compounds on mini AMES and screening herg y One compound scored better y Showed toxicity in 7 day rat studies y Mechanism of toxicity analyzed y Literature reports identified for the client linking the mechanism of toxicity to high doses of one of the Excipients used for efficacy studies y Proposed alternate formulations y Result a 14 day rat study conducted with no overt side effects observed Current status In the new formulation, the compound did not show any toxicity up to high doses Working on obtaining higher doses in the new formulation Case II: Diabetes Leading compound reported liver toxicity Advinus approach y Detailed liver toxicity as end point in the exploratory rat study y Nominated compound had higher chances of success in IND and early clinical studies y Other end points were also included based on clinical observations of front running trials Current status: y Program in Phase II y Can comfortably claim no liver toxicity with the compound

11 Infrastructure - Safety Assessment

12 get the ADVINUS ADVANTAGE Contact: Advinus Therapeutics Ltd. 21 & 22, Phase II, Peenya Industrial Area, Bengaluru INDIA. T : F : E : bd@advinus.com