Biotechnology and Drug Discovery- A Shifting Paradigm for India

1. Biotechnology and Drug Discovery- A Shifting Paradigm for India Prasanta K Ghosh President Cadila Pharmaceuticals Limited Ahmedabad Lecture delivered at Calcutta University Department of Chemical Technology Friday,November 10,2006

2. Bio-Pharma Industry- A Multi-disciplinary Arena Biochemistry & Chemistry R&D Biophysics & Mathematics Marketing Specialists Marketing Biotechnology Management Molecular Biology Pharmacy & Clinical Practices Bio- informatics Legal, IPR & Regulatory Aspects Microbiology & Cell Biology Application & Production Chemical, Biochemical Engg. & Instrumentation Pharmacology & Physiology

3. DRUG DISCOVERY PLAN Requires at the minimum • High scientific skills • Plenty of resources • A Team Leader and a Team – with high order of skills • and determined motivation • High throughput screening methods through techniques in: • - Genomics • - Proteomics • - Strong Organic chemistry • - Bioinfomatics skills Contd…..

4. DRUG DISCOVERY PLAN Requires at the minimum • AFTER IDENTIFYING THE DRUG…………. • Models for testing Toxicity and Efficacy • - In vitro Models • - In vivo Models • Production modules for enough testing materials under • cGMP condition • - Physiochemical characterization • - Immunological characterization • - Biological characterization • Clinical trial outfits • Manufacturing implements Contd..

5. DRUG DISCOVERY PLAN Requires at the minimum • At the Regulatory level, Marketing level & Societal acceptance level……… • Knowledgeable Regulatory Body with protective but • cautious approach • To obtain steady and time bound Regulatory approvals • Marketing Infrastructure • Societal attitude towards Biotech products • All these requirements are never optimal at one place or even in one country • Optimization is required through deliberate government intervention to ease the process and to catalyze alliance among governments, companies,institutions and public friendly NGO’s

6. A GREAT TIME FOR CHANGES THROUGH BIOTECHNOLOGY • INDIA • Land frontier of over 3 million sq.kms • Coast limit of 7500 kms. • Population of 1.1 billion • One of largest country having diverse and plenty full genetic diversity • Location is unique to create economic influence in the region • Growing economic strength has attracted world attention . • India’s priorities: economic growth to provide better quality of life for all • Stability is necessary to keep the pace up.

7. GLOBAL ECONOMIC ENVIRONMENT • Globalization is presently accepted everywhere for bringing industrial • reforms and economic benefits • Trade is becoming seamless across the countries and efficient ones • are creating more wealth • Socialist world stands transformed and has welcome globalization • Unfortunately religious fundamentalism and terrorism are on the • rise to obstruct the process of globalization • Our relationship with large and small adjoining neighbours is crucial • for sustainance and growth of economy.S&T through biotechnology • alliance can create good relation among neighbors • Societies will reform to pave the paths that are beneficial to all • At the bottom line human beings must survive and prosper

8. Indian scenario in Biotechnology • Biotech industry ranked #2 globally by number of units • Will be the leading industry by 2020 • India considered in world's TOP 11 biotech powers • The industry has grown by 74% in the last 2 years • Estd. 200 biotech Cos - more than Japan or Korea • By 2010, to generate $5 billion and one million jobs • Largest no. of US-FDA-approved plants outside USA

9. Pharma market segmentation BIO-PHARMA SHARE- 2001 PHARMACEUTICAL – Uses Active Pharmaceutical Ingredient – Chemically synthesized BIO-PHARMA SHARE- 2025 BIOPHARMACEUTICAL – Use of microbes or rDNA products made by living modified organisms to produce natural or modified products • 30% drugs in the market 2005 are of Biotech origin & 50% anticipated by 2010 rising to 65% by 2025

10. INTERNATIONAL TREND IN DRUG RESEARCH & THEIR RELEVANCE IN INDIAN SCENARIO

11. To discover block busters for plenty of profits To drive discovery to anticipate usage for longer duration To provide better quality of life with increased longevity To provide relief to the sufferings To create healthy society

12. TOWARDS HEALTH FOR ALL:WHAT IS RELEVANT FOR INDIA Diseases marked in red color indicate indicate high class global research activities being carried out • To Prevent Communicable diseases • Respiratory infection : MMR, Influenza, TB,Meningococcal meningitis, Diphtheria, Chickenpox, Whooping cough etc • Intestinal infection : Diarrhoea,Typhoid, Cholera, Viral hepatitis, Polio, Worms etc • Arthropod born infection : Malaria, Filaria, Dengue, Chickengunya etc • Zoonotic diseases : Yellow fever, JE, Brucellosis, Plague,Salmonellosis, Typhus, Q Fever etc • Others : Tetanus, Leprosy,AIDS, STD How shall we benefit ourselves unless we develop our strong in-house R&D program?

13. TOWARDS HEALTH FOR ALL………… • 2. To Prevent Non-Communicable diseases & conditions • Hyper tension , • Diabetes, • Cancer, • Rheumatic heart disease, • CHD, • Stroke, • Parkinson's disease, • Genetic disorder, • Kidney disorder, • Gonadal dysfunction , • Rheumatoid & Osteoarthritis, • Mental health improvement, • Nutrition How shall we benefit from global research unless we develop our R&D programs?

14. HARD FACTS OF BIOTECH RESEARCH EXPENDITURE

15. Hard Facts of Drug Development New Entity Cost • Lead or Target (Clinical Candidate) • Animal Model Testing • Toxicity, Efficacy • Phase I Pre-Clinical (toxicity) • Phase II (efficacy) • Phase III (efficacy) • NDA (new drug application) • $190-240 M 2-10,000 • $80-120 M 100 • $60-120 M 20 • $50-150 M 3 • $150-250 M 2 • $20 M 1

16. Expense-Success Rate of Drug Development 20 Out of 2000 to 10,000 nos. screened!!! 20 550-900 150-250 50-150 60-120 80-120 190-240 Phase I Discovery Pre-clinical Phase II Phase III Registration Total • Candidate Drug • Phase I • Phase II • Phase III • 1/20 drugs entering Phase I hit market • Most drugs fail due to adverse side effects in a portion of treated population

17. rDNA Technology • Gene Silencing / Regulation • Genomics • Proteomics • Structural Biology • Pharmacogenomics Rational Drug Design Biotech Drug Discovery Evolution

18. Drug Discovery-Post Genomic Era Target Identification Target Validation Lead Identification Lead Optimization In vitro Validation In vivo Validation Marketing Approvals Phase I Phase II Phase III Regulatory Approvals Number of Targets > 5000

19. Rational Drug Discovery & Development (Schematic) Identify disease Find a drug effective against disease protein (2-5 years) Isolate protein involved in disease (2-5 years) Scale-up Preclinical testing (1-3 years) Human clinical trials (2-10 years) File IND Formulation File NDA FDA approval (2-3 years)

20. Biopharmaceuticals discovery:Genomes to Targets to Products & Diagnostics Genomics Gene therapy Genes DNA-diagnostics Proteins Vaccines Biotherapeutics Target discovery ( For New Chemical Entities)

21. Target universe –post genomics Gene Targets for small molecular drugs ~10,000 • Potential target within human genome: • Addressable by small molecules (47% enzymes, 30% GPCRs, 7% channels, 4% transporters, 4% NHRs, 1% integrins & 1% DNA) Targets for protein therapeutics ~1,800 genes Addressable by protein therapeutics ~10,000 genes Druggable ~3,000 genes Drug targets 600-1500 genes Expression focused target genes (siRNA & anti-sense therapies) ~2,300 genes Disease modifying ~ 4,500 genes Source: Drug Discovery Today, Aug 2005 Nature Reviews 1: 727-230, 2002

22. Combinatorial Chemistry: Small molecules • By correctly identifying molecular “building blocks”, based on certain parameters, we can create very large numbers of different molecules very quickly. • Usually involves selecting a general “scaffold” molecule, and synthesizing sets of compounds which can be tested for activity optimization .

23. Virtual Screening • Build a computational model of activity for a particular target • Use model to score compounds from “virtual” or real libraries • Use scores to decide which to make, or pass through a real screen

24. Benefits of Computational Modeling • We may want to screen: • All of a company’s in-house compounds • A compound collection that could be purchased • A potential combinatorial chemistry library, to see if it is worth making, and if so which to make • A Model may evolve with prediction of how well each molecule will bind,based on, say a score assigned for each molecule • Decide which molecules to be synthesized for real screening

25. Basis of Computational Modeling • Machine Learning Methods • e.g. Neural nets, Bayesian nets, Kahonen nets • Train with compounds of known activity • Predict activity of “unknown” compounds • Scoring methods • Profile compounds based on properties related to target • Fast Docking • Rapidly “dock” 3D representations of molecules into 3D representations of proteins, and score according to how well they bind

26. High Throughput Screening • Drug companies now have millions of samples of chemical compounds • High-throughput screening can test 1,00,000 compounds a day for activity against a protein target • Maybe tens of thousands of these compounds will show some activity for the target protein • The chemist needs to intelligently select the 2 - 3 classes of compounds that show the most promise for becoming APIs ,to follow-up

27. What do we do next after identifying lead compound/s ? Required to generate in-vitro and in-vivo efficacy and toxicity data.

28. A.D.M.E. Models • Traditionally, animals were used for pre-human testing. Animal tests are expensive, time consuming and ethically undesirable in certain situations. • ADME (Absorption, Distribution, Metabolism, Excretion) techniques help model how the drug is likely to act in the body • These methods can be experimental (in vitro) using cellular tissue, or in silico, using computational models

29. Pharmacogenetics- Impact on Drug Discovery • Quantitative traits • How effective is a drug? • How serious are side effects? • How many loci/alleles control trait? • Population variation • How frequent is a polymorphism? • How many different polymorphisms are present? • Are particular combinations of loci/alleles common?

30. Benefits of Pharmacogenomic Profiling of Population and Candidate Drug • Where do you find the next profitable drug? • The 19/20 drugs that failed AFTER phase 1, but are still efficacious! • How do you decrease the cost of clinical trials? • Don’t enroll people of the “wrong” genotype!

31. Challenges Facing the Rational Drug Discovery... • Huge increase in the volume of information • Genomics & High-throughput screening • How do we use it to make better decisions (earlier) • Immature technology and informatics • Experimental hardware is changing rapidly • Computing needs to meet complex, changing analysis needs • “Fuzzy” science • Even our understanding of the underlying science is constantly changing

32. How India can leverage: More efforts? More resources? More effective planning? More of all of these? Newer innovative efforts?

33. Identify disease area Target Selection Lead Optimization Clinical Trials Market Assay Development Hit Identification Profiling Screens ADME-TOX Target Validation Development of a new drug- Schematic

34. Microbial products Mammalian Cell culture Insect cell culture Transgenic animals Transgenic plants Gene Therapy/DNA vaccine Cell Therapies Infancy Transgenic Chick/Egg/Cow FUTURISTIC BIOPHARMA SCENARIO Deploying Various Techniques Matured Developed Babyhood

35. PLATFORMS FOR PROTEIN PRODUCTION From various published sources Above information from various published sources

36. Transgenic Biopharmaceuticals in Clinicals

37. PHARMING OF FARMACEUTICALS PHARMING OF FARMACEUTICALS

38. LIFESTOCK AS BIOREACTORS

39. INDIA SHOULD MOVE TOWARDS ALTERNATIVE PLATFORMS • Cell culture platform not suitable for making drugs affordable • Companies using cell-culture platform are fast moving to Transgenics • (e.g. Centocor and J&J - Remicade & Reopro using transgenic goats; Amgen,. GSK) • India does not have its transgenic technology for protein production • New developments in transgenic technology has high potential • (cloned transgenics enables selection of 100% female offspring) • Transgenic tech. could boost animal husbandry and farm sector too • Transgenic technology would provide alternative proprietary route • for manufacturing molecules having patented production method

40. HOW PRODUCTS PORTFOLIO COULD BE CREATED? • Biopharmaceuticals are typically covered by two classes of patents: • Product Patents: covers the molecule and formulation composition • Process Patents: covers production / manufacturing processes • Example: Epogen (EPO / Procrit; Epoetin alfa) • Product Patent expired: 2004 • Process Patent expiration: 2014 • Companies with alternative, novel protein production technologies will be able to overcome existing process patents and will have the freedom to manufacture generic biopharmaceuticals whose product patents expire

41. CONCLUDING REMARKS • To choose diseases & conditions to treat Indians to become more healthy • To choose & develop platforms that are unique for biotech drugs • To create organizational infrastructure so that bench workers remain young. • To keep a watch on Patent expiry of effective drugs • Stupendous reward for new drug development and application group • To create highly knowledgeable regulatory authorities • To liberally allocate funds for R&D and product commercialization • To promote alliance : institutions, industries, and inter-governmental bodies. • To have time bound plan for product/process development.

42. Multifaceted International R&D has a big basket requiring very large investment Radical Re-designing of Indian R&D necessary to make a global impact Thank you Sources of all pictures gratefully acknowledged