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DRUG DISCOVERY OVERVIEW BY DR ANTHONY MELVIN CRASTO Worlddrugtracker
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LINK http://newdrugapprovals.wordpress.com/
is the link to my blog which tracks drugs worldwide US, CANADA, JAPAN, EU CHINA ETC
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Dedicated to my son Lionel Crasto,
He was only in first standard in school (Dec 2007) when I was Paralysed head to toe. His smiling face sees me through day in and day out. Vast readership from academia and industry motivates me, and keeps me going. Helping millions with free advertisement free websites and has million hits on google Thanks for helping me to keep lionel smiling
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Shore Your own will power and determination will reach you to the shore even if you are drowned in the middle of a storm
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Stages in drug discovery
Formulation Preclinical studies Clinical trails Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has passed all regulatory requirements.
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Drug development process
Target Right molecule Candidate drug Preclinical documentation Clinical documentation Drug Development 7 years Drug Discovery 5-7 years
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Drug discovery The process of drug discovery involves the identification of lead and its targets, synthesis, characterization, screening, and assays for therapeutic efficacy of lead. Once a compound has shown its value in in these tests, it will begin the process of drug development prior to clinical trails. The average time required to bring a drug to the market range from 12–15 years at an average cost of $800–1000 million < 2% of new compounds investigated may show suitable biological activity Modification of an existing drug can yield as little as 1% suitable compounds < 10% of these compounds result in successful human clinical trials and reaches the market place
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Candidate selection to FTIH
The Drug Discovery and Development process is a progression from Targets and Leads… to Drugs...to Products Targets & Leads Drugs Products Target selection Target to Lead Lead to candidate Candidate selection to FTIH FTIH to PoC PoC to Commit to Phase III Phase III File & Launch Lifecycle mgt 12-24m 12-24m 30-33m 8-12m 12-44m 0-30m 18-66m 10-13m y Costs ~ $1 billion per successful product
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Drug Discovery and Development
CD(Candidate Drug) NDA(New Drug Application) Launch Drug Discovery Drug Development Registration PhI PhII PhIII PhIV Preclinical Clinical Compound production Manufacturing FDA/EMEA review 0.5-2 years
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Investigational New Drug
QA and regulatory IND Investigational New Drug (first time in man) NDA New Drug Application PhI PhII PhIII Drug Discovery Drug Development Registration Preclinical Preclinical GLP (Good Laboratory Practice) GCP (Good Clinical Practice) GMP(Good Manufacturing Practice)
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Intellectual Property, IP (Patents)
PhI PhII PhIII Drug Discovery Drug Development Registration Preclinical Patents: Structure class Compound specific Synthesis Indication Formulation .... Patent time: 20 years from the filing date Drug development years
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How to find the right molecule?
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Process of drug discovery
Health insurance portability n accountability Product devolp n management associatn Central drug stndrd control organisation
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Drug Discovery Process
Lead optimisation protein target screen and identify lead gene chemical diversity (compound library) test safety&efficacy in animals and humans The target is the protein expressed from a gene that is relevant to a disease of interest. It is the protein that is manipulated with a drug to produce a therapeutic response in humans and it is the protein that is taken into compound screening to identify chemical compounds that interact with the target. These hits from screening are then optimised for desired properties, before being tested – often first in animals then in man. Targets & Leads Drugs Target Validation & Selection Target to Lead (compounds) Lead to candidate Drugs Candidate progress to FTIH and PoC in patients
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Drug development Target :Naturally existing cellular or molecular structure involved in the disease pathology on which the drug acts Targets Types Target validation :Involves demonstrating that a molecular target is critically involved in a disease process & modulation of the target is likely to have a therapeutic effect New Subject of discovery which include proteins whose is discovered by function basic scientific research Established Have a detailed description of its functions in normal pathology involved in human
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Target Selection Approaches to Finding a Drug Target
Genome Disease Select protein of interest Genetics Pathology Historically, new targets were identified by painstaking studies of the disease process and identification of key pathways/targets which could be manipulated in an attempt to treat the disease (right-hand side model). The advent of the sequencing of the human genome and development of genomic technologies has allowed an alternative drug discovery approach to be adopted. In this approach (left-hand side), we start with a gene of interest, which has been selected not because we know it is important in a disease, but because we know that if we were to screen compounds against it, we would probably be successful in finding leads. The challenge then becomes how to find a disease which can be treated by compounds acting on this pre-selected target. To do this, a variety of approaches are pursued. For example, looking at how the gene is expressed in different tissues (e.g. normal versus disease), what happens if the gene is disabled (e.g. gene knockout mice), are any variants in the gene associated with disease. Selection of Biological Target Link with disease or disease process Potential Drug Target
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Screening & design Screening :Investigation of a great number of compounds for a particular problem or feature of them Random Screening Non-random Cross Random involves no intellectualization & assays are done with out structural regards Non-random also known as targeted or focused & more narrow approach. compounds having a vague resemblance to weakly active compounds uncovered in a random screened Whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening
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Screening to Generate Hits
Types of screens Functional assay Binding assay Cell response Compound binds to cell surface receptor - this can be measured in a “binding assay” This can evoke a cellular response - which can be measured in a “functional assay” In order to interact with a target, a molecule must first bind to the target. In some instances, that molecular interaction can lead to a change in the target protein, giving rise for instance to receptor activation. Screens can be set up to either simply detect molecule binding (would pick up both agonists and antagonists) or to pick up target activators.
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Approaches Nature of sources Chemical sources Rational approches
Molecular modelling Combnitorial chemistry Biotechnology Bioinformatics Preclinical studies Clinicaltrails
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Microbial metabolites
Nature of source Plant species provide a potenial source of strating or crude material for the drug discovery Many cardiotonics are plant derived Microbes are the main source of antimicrobial drugs Streptomyces species have been a source of antibiotics. Marine environments are potential sources for new bioactive agents. Arabinose neucleosides discovered from marine invertebates Plant derivatives Marine invertebrates Microbial metabolites
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Virtual screen ( in silico)
Ligand based Knowledge of other molecules that bind to the target Build on known pharmacophore Structure based Knowledge of three dimensional structure of the target (X-ray or NMR) Docking
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Potency In vitro In vivo Species differences!
Functional cell-based assays (FLIPR) Intracellular calcium mobilization (GCRP) In vivo Species differences! Potency in vivo? Agonist induced models ( NK1 and NK2) Effective in IBS? Disease related models
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Bioavailable Permeability Metabolism
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Organic Chemistry involved in Synthesis & Purification
Involvement of different branches of Biological Sciences in New Drug Development Organic Chemistry involved in Synthesis & Purification Organic chemists synthesize new drug compounds as well as isolate and characterize natural products, such as alkaloids. In each case, there is interest in the complex relationships between chemical structure and pharmacological action. The pharmacological activity of a compound is an involved function of the structure, and very small changes may pro- foundly modify the pharmacological effect. These structural modifications may involve replacing one group with another at a specific point in the molecule, shifting the same group from place to place in the parent molecule, saturating valence bonds or modifying the acidity or basicity. Total synthesis is made possible by knowledge of chemical structures and, in many instances, is important economically in reducing the cost of the drug.1 Chromatographic techniques have been widely used for the purification of newly synthesized compounds.
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Instrumental Techniques for Product Characterization
The first step in product characterization is to establish the precise chemical identity of the product. It is important to determine whether the material is a compound, i.e. a single chemical entity, a mixture of closely related compounds, mixture of isomers, or merely a loose molecular complex of readily dissociable components. Such information is fundamental to a proper evaluation of the biological properties of the material. For compounds of synthetic origin, identity is usually clearly defined in the great majority of cases by the synthetic route employed. However, it is essential not only that identity be confirmed by alternative means but that the means employed should be capable of providing rapid verification whenever this may be required at any stage of the development program. Modern spectroscopic techniques, such as as1H and 13C NMR and infrared spectroscopy are sensitive tools for such purposes.
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Statistical approaches in Drug Discovery
Once a new pharmaceutical lead compound has been discovered, extensive and costly efforts usually are made to prepare a series of analogues in the hope that even better activity will be found. In an effort to improve the efficiency of analogue development, a variety of statistical methods have been introduced. They range from the Hansch approach, in which analysis of variance is used to derive an equation expressing the quantitative relationships between functional group changes and biologic activity, to pattern recognition and factor analysis methods
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Preclinical documentation
Phase I Phase II Phase IIII Registration Non-clinical risk and benefit assessment for estimation of an initital safe starting dose in human to support the clinical program Studies Pharmacodynamics Pharmacokinetics Toxicology Regulatory guidelines Quality requirements
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Carcinogenicity studies
Rat and mouse 2 years dosing Expensive Critical timeline Phase I Phase II Phase IIII
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Part 2: Selecting a Drug Candidate
Topics Lead optimisation – addition of extra properties (ADME) Safety testing Molecules into Medicines Testing in Humans
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Optimizing Lead Compounds is an Iterative Process
Lead compounds from Screening Hypothesise, design molecules and synthesise Biology Test hypothesis Medicinal Chemistry Developability During lead optimization, chemists work from the structure of the lead compounds, and understanding of the interaction with the target, to synthesize additional compounds, in search of one or more that meet all the criteria for a candidate for clinical testing. Chemists are making many analogues of each compound. In addition to further testing in biological assays, compounds are evaluated for their developability, which refers to the many characteristics of a chemical that determine whether it can be successful as a drug. DMPK Analyse/ rationalise results Candidate selected for testing in man
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Chemical source These include semisynthetic drugs
It has organic and inorganic sources Mineral resources are one of it. New source of chemical synthesis is Combinatorial Chemistry Combinatorial chemistry: involves the synthesis or biosynthesis of chemical libraries (a family of compounds having a certain base chemical structure) of molecules with in a short period of time for the purpose of biological screening, particularly for lead discovery or lead modification. Chemical source
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Methods There different types of combinatorial synthesis
Split Synthesis: Peptide Libraries Encoding Combinatorial Libraries Nonpeptide Libraries The main differences among the various combinatorial approaches are the solid support used, the methods for assembling the building blocks, the state (immobilized or in solution) and numbers (a fraction of the total library or individual entities)
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Rational approches Hit -Lead:
Hit confirmation Re-testing, dose response curve,secondaary screening,chemical amnebilty,biophysical techs &hit ranking and clustering Hit expansion Affinity, molecular weight and lipophilicity can be linked in single parameter such as ligand efficiency and lipophilic efficiency to assess drug likness Lead optimization This optimization is accomplished through chemical modification of the hit structure, with modifications chosen by employing SAR as well as structure-based design Hit -Lead:
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Technological Approach
ssss Target Identification Genetics Molecular Biology Bioinformatics Structure Determination X-ray Crystallography NMR Spectroscopy Computer-Aided Design Molecular Modeling Computer Graphics Biological Assays High-Throughput Screening Computer-Based Screening Synthetic Chemistry Peptidomimetics Combinatorial Chemistry Pre-clinical Trials
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Preclinical studies Acute Studies :The goal is to determine toxic dose levels and observe clinical indications of toxicity. Data from acute toxic studies helps determine doses for repeated dose studies in animals and Phase I studies in humans. Repeated Dose Studies :These are repeated dose studies may be referred to as sub acute, sub chronic, or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required. Genetic Toxicity Studies :These studies assess the likelihood that the drug compound is mutagenic or carcinogenic.
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Reproductive Toxicity Studies : Segment I reproductive toxic studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development Carcinogenicity Studies :Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions Toxicokinetic Studies :These are typically similar in design to PK/ADME studies except that they use much higher dose levels. They examine the effects of toxic doses of the drug and help estimate the clinical margin of safety
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Preclinical studies & Clinical trails
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Animals to Man To complete safety evaluation and assist in dose selection for first clinical trials, Safety Assessment has to: Conduct initial non-clinical safety studies to assess developability and potential risks for first administration to humans Conduct additional studies to build confidence that longer term clinical trials can be conducted safely, and the medicine can be approved for use Step 1. is some small-scale studies to make sure the compound is not overtly toxic and is fundamentally developable. We set out to define the toxicologic profile of the drug from doses close to those predicted for humans to the maximum tolerated From this date we would hope to estimate safety margins and also a idea of what might ‘go wrong’(ie:), and what we could look for as indicators of that effect, if toxicities do occur in humans. If the initial human studies are OK we can then reinforce the initial data with longer studies, look at different endpoints (eg: reprotox) and use this data, in conjunction with the emerging clinical safety data, to assess the safety and developability of the compound.
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Aspects of a Safety Assessment
One dose Lifetime use Reproduction Development Chronic Effects Acute Responses Slides shows the progression in study duration and the variety of endpoints we want to monitor. Also to show the DIVERSITY of biological systems we are trying to look for potential effects in. These are not like classical scientific experiments where you have a single endpoint (hypothesis) to test - this is a screen intended to be as broad as practicable to detect unpredictable adverse events. That detection may have to be followed by specialist studies to establish a mechanism or explanation. Emphasise the progressive nature of the program to BUILD CONFIDENCE that the product is likely to be safe. Genetic damage? Carcinogenicity?
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Clinical trails Phase I:No blinding screening,open label & done in single centre Number of subjects 20-40 max 50 Healthy volunteers Sometimes patients are exposed to drug one by one Associated members Carried out by qualified clinical pharmacologist & trained physician Dose is given in cumulative manner to achieve the effective dose Purpose of study P’kinetics,P’dynamics Emphasis of safety and tolerability
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Phase II :Therapeutic exploration & dose ranging
May be blind or open label (4centre’s or more) Number of subjects patients or volunteers According to specific inclusion and exclusion criteria Associated members Physicians These are trained as investigators Purpose of study To establish therapeutic efficacy of drug ,dosage regimen & ceiling effect in controlled settings Tolerability & p’cokinetics are studied as phase I extension
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Phase III :Therapeutic confirmation or comparison Done in multicentre
Number of subjects Associated members physicians Purpose of study To establish value of drug in relating to existing one ADR’S on wide scale in which P’cokinetic data may be obtained Randamised double blind comparitive trails are done Indications are finalized & guidelines for therapeutic use are formulated Submission of NDA for licensing is done who if satisfied grants permission for marketing
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Molecules to Medicines
Drug Product (DP) Drug Substance (DS) Chemical Development (CD), in collaboration with Pharmaceutical Development (PD), is charged with delivering a cost effective, efficacious medicine... Throughout the development of a compound, synthetic chemists, analytical scientists and pilot plant staff work together to ensure availability of suitable quality DS for toxicology and clinical studies and, ultimately, to delivery a cost effective, efficient and validatable synthetic process and associated analytical methods to Manufacturing. Pharmacy has responsibility for similar deliverables concerning the drug product. A key interface between the two groups concerns the physicochemical properties of the drug substance and how it formulates to provide drug product.
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Drug Substance synthesis: Scale - up
Lab scale 10-100kg Factory scale
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Consult with Regulatory Authorities
FDA: US Food and Drug Administration Reduce risk of conducting long, expensive studies that don’t lead to approval MHLW: Japan Ministry of Health Labour & Welfare Agencies provide helpful insight into study design and doses Some of the key regulatory agencies are - FDA, EMEA & MHLW. Seek regulatory input during this phase of development to ensure on track with Phase III plans. We do this through our Regulatory Affairs departments at GSK - main liaison for communication between the Clinical Matrix Team & the approving agency. Not all Regulatory Authorities (RA) give advice. In general, interactions with FDA are more acceptable - both informal dialogue, as well as more structured, regularly scheduled meetings (e.g., End of Phase II meeting to discuss phase III plans - more next slide) More difficult to obtain scientific advice from the EMEA - no requirement for them to hold drug development advice meetings with developers. Each European country also has its own regulatory authority. It can be easier to meet individual regulatory authorities in Europe rather than to work with the EMEA. Examples: UK Medicines and Healthcare products Regulatory Agency (MHRA) French Agence Francaise Securite Sanitaire des Produits du Sante (AFSSAPS) German Federal Institute for Drugs and Medical Devices (BfArM). Health Protection Board (HPB) - Canada May change Phase III clinical plan based on feedback EMEA: European Medicines Evaluation Agency Any issues with patient compliance or drop-out rate? Is there sufficient evidence that Phase II results support proposed Phase III doses and endpoints? Do we have the right patient profile? Are we selecting the right patients? Have we selected right comparator arm & endpoints? Are there any serious safety issues?
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Regulatory Authorities
Food and Drug Administration Therapeutic Goods Administration Ministry of Health Labour and Welfare International Conference on Harmonisation There are many different authorities around the world - traditionally these have had different requirements regarding the type and amount of studies and other information required to assure them of the quality, safety and efficacy of a drug. Major authorities listed. In EU, there are also individual authorities in each member state e.g. UK MPRA, German BPharm. Some differences still exist and when we develop drugs we need to be aware of the different requirements. Flags on right are Australia and Canada Since early nineties we have had ICH I.e. ICH is a joint initiative between the regulatory authorities and industry bodies in Japan, EU and the US, the aim is to harmonise, where possible, aspects of the drug development process. Over 50 Guidelines issued in respect to quality testing, animal testing and clinical trials, and other topics. Different authority requirements, and different national clinical practices, have resulted in the past with the same product being registered around the world with different efficacy claims and safety restrictions. International in GSK terms means Asia Pacific, Latin America, Middle East and North Africa, Sub Saharan and South Africa Health Canada European Medicines Agency Over 120 ‘International’ markets
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Way to success Build on knowledge – creative ideas
Scilled medicinal chemists Dedicated project team Serendipity and luck - prepared mind Chemistry Toxicology Pharmacology Metabolism PK
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amcrasto@gmail. com DR ANTHONY CRASTO chemistry sites https://sites
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DR ANTHONY MELVIN CRASTO Ph.D amcrasto@gmail.com MOBILE-+91 9323115463
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA web link my-own-on-the-net Congratulations! Your presentation titled "Anthony Crasto Glenmark scientist, helping millions with websites" has just crossed MILLION views.
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