Biotechnology and Drug Discovery- A Shifting Paradigm for India

Prasanta K GhoshPresident

Cadila Pharmaceuticals LimitedAhmedabad

Lecture delivered at Calcutta University Department of Chemical Technology

Friday,November 10,2006

Bio-Pharma Industry- A Multi-disciplinary Arena

Biochemistry&

Chemistry

Microbiology &Cell BiologyPharmacology

& Physiology

Molecular Biology

Biophysics &Mathematics

BiotechnologyManagement

Chemical,Biochemical Engg. & Instrumentation

Pharmacy &Clinical Practices

Legal, IPR &Regulatory Aspects

Bio-informatics

MarketingSpecialists

R&D

Application & Production

Marketing

DRUG DISCOVERY PLANRequires 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…..

DRUG DISCOVERY PLANRequires 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..

DRUG DISCOVERY PLANRequires 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

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.

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

•Biotech industry ranked #2 globally by number of unitsBiotech industry ranked #2 globally by number of units

•Will be the leading industry by 2020Will be the leading industry by 2020

• India considered India considered in in world's world's TOP TOP 111 1 biotech powersbiotech powers

• The industry The industry hashas grown grown by 74% in the last 2 years by 74% in the last 2 years

• Estd. 200 Estd. 200 biotech biotech CoCoss - more - more than Japan or Koreathan Japan or Korea

• By 2010, to generate $5 billion By 2010, to generate $5 billion and one and one million jobsmillion jobs

• Largest no. of US-FDA-approved plants outside USALargest no. of US-FDA-approved plants outside USA

Indian scenario in BiotechnologyIndian scenario in Biotechnology

PHARMACEUTICAL –

Uses Active Pharmaceutical

Ingredient – Chemically synthesized

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

Pharma market segmentation

BIO-PHARMA SHARE- 2025

BIO-PHARMA SHARE- 2001

INTERNATIONAL TREND IN DRUG RESEARCH

&

THEIR RELEVANCE IN INDIAN SCENARIO

DRIVING FORCES FOR DRUG DISCOVERY

0

2 0

4 0

6 0

8 0

1 00

1 2 0

0 1 2 3 4 5 6Service providly philosophy

Pro

fit

Ph

ilo

sop

hy

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

TOWARDS HEALTH FOR ALL:WHAT IS RELEVANT FOR INDIA

1. 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

Diseases marked in red color indicate indicate high class global research activities being carried out

How shall we benefit ourselves unless we develop our strong in-house R&D program?

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?

HARD FACTS OF BIOTECH RESEARCH

EXPENDITURE

• 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

Hard Facts of Drug Development

Cost New Entity

• 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

Expense-Success Rate of Drug Development 20 Out of 2000 to 10,000 nos. screened!!!

Discovery Pre-clinical

Phase I Phase II Phase III Registration Total

190-24080-120

60-12050-150

150-25020 550-900

Biotech Drug Discovery Evolution

rDNA Technology

Gene Silencing / Regulation Genomics

Proteomics

Structural Biology

Pharmacogenomics

Rational Drug Design

Drug Discovery-Post Genomic Era

Target IdentificationTarget ValidationLead IdentificationLead Optimization

In vitro ValidationIn vivo Validation

Phase IPhase IIPhase IIIRegulatory Approvals

Marketing Approvals

Number of Targets > 5000

Identify disease

Isolate proteininvolved in disease (2-5 years)

Find a drug effectiveagainst disease protein(2-5 years)

Preclinical testing(1-3 years)

Formulation

Human clinical trials(2-10 years)

Scale-up

FDA approval(2-3 years)

File

IN

D

File

NDA

Rational Drug Discovery & Development (Schematic)

Biopharmaceuticals discovery:Genomes to Targets to Products & Diagnostics

Target discovery( For New Chemical Entities)

Genes DNA-diagnosticsGene therapy

BiotherapeuticsVaccines Proteins

Genomics

Addressable by protein therapeutics ~10,000 genes

Gene Targets for small molecular drugs ~10,000

Disease modifying ~ 4,500 genes

Expression focused target genes (siRNA & anti-sense therapies)

~2,300 genes

Druggable ~3,000 genes

Targets for protein therapeutics ~1,800 genes

Target universe –post genomics

Potential target within

human genome:

• Addressable by small

molecules (47% enzymes,

30% GPCRs, 7% channels,

4% transporters, 4% NHRs,

1% integrins & 1% DNA)

Source: Drug Discovery Today, Aug 2005Nature Reviews 1: 727-230, 2002

Drug targets 600-1500 genes

• 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 .

Combinatorial Chemistry: Small molecules

• 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

Virtual Screening

• 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

Benefits 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

Basis of Computational Modeling

• 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

High Throughput Screening

What do we do next after identifying lead compound/s ?

Required to generate in-vitro and in-vivo

efficacy and toxicity data.

• 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

A.D.M.E. Models

• 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?

Pharmacogenetics- Impact on Drug Discovery

• 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!

Benefits of Pharmacogenomic Profiling of Population and Candidate Drug

• 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

Challenges Facing the Rational Drug Discovery...

Can we have more successes?

At least 2-4 N C Es / Yr.

Can we have some block busters? How?

More drugs should have blockbuster potential if R&D is rightly structured. Higher Success rate in Clinical Research need to be achieved.

How reduce marketing time?

Target:Market introduction time from 15-20 yrs to <7 years. Policy change?

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

Development of a new drug- Schematic

Identify disease

area

Target Selection

Target Validation

Assay Development

Hit Identification

LeadOptimization

ProfilingScreens

ADME-TOX

ClinicalTrials

Market

FUTURISTIC BIOPHARMA FUTURISTIC BIOPHARMA SCENARIOSCENARIO

Deploying Various TechniquesDeploying Various Techniques

Transgenic Chick/Egg/CowInfancy

Microbial products

Mammalian Cell culture

Insect cell culture

Transgenic animals

Transgenic plants

Gene Therapy/DNA vaccine

Cell Therapies

Matured

Babyhood

Developed

PLATFORMS FOR PROTEIN PLATFORMS FOR PROTEIN

PRODUCTION PRODUCTION Host

system E. coli Yeast Insect Cell Mammalian Cells

Transgenic Plants

Transgenic animals

Time to Engineer (gene-to-protein)

+ ++ ++++++

3 months++++

4 months+++++

0.5 – 2 years

Capital Investment

$ 0.2-0.5M / m3

$ 0.2-0.5M/m3

Not available

$2-3 M/ m3 $ 10/m2 $0.5-1 M

$ Cost / gram raw material 5 - 25 5 - 25 Not

available 150 0.05 1-2

Expression level 1-5 g/L 1-5 g/L 1-5 g/L 0.1 – 3 g/L 5 g/ Kg Leaf 2-35 g/L Milk

Cost to produce 1.0 gram protein

++$50-100/g

++$300-500/g

+++$500-1000/g

+++$500-5000/g

+$10-12/g

+$1-4/g

Product localization

Secretion periplasmic

Intra-cell/ Secreted Secreted Secreted

Secreted only by Moss

Secreted in Milk

Protein folding Refolding required

Refolding (at times)

Correct folding

Correct folding

Correct folding

Correct folding

N / O-linked glycosylation

No Metabolic Engineering in progress

High mannose GluNAc

Simple, No Sialation

ComplexPlant-specific gly-cosylation knocked out

Similar to that in Human proteins

Safety concerns

Endotoxins(pyrogens)

Low Viruses Viruses Allergens BSE, TSE, prions,virus

No. of Products approved

34 11 2 14NONE>15 in Develop

NONE>60 in Development

From various published sourcesAbove information from various published sources

Transgenic Biopharmaceuticals in Clinicals

Transgenic Biopharmaceuticals in ClinicalsPlant-derived Biopharmaceuticals Animal-derived Biopharmaceuticals

ProductCompany

(Host used)Stage Product Company (Host

used) Stage

Anticaries antibody Monsanto (Corn) Phase III Antithrombin-

IIIApproved in EU

Phase-III US GTC

(Goat)

scFv (non-Hodgkin)

Large Scale Biology(Tobaco)

Phase III C1-esterase inhibitor

Phase-III On Fast Track

Pharming(Rabbits)

Gastric LipaseMeristem

Therapeutics(Corn)

Phase II -1-antitrypsin Phase-II complete PPL

therapeutic

Newcastle Disease Poultry

Vaccine

DOW Agriscience (Non-nicotine

Tobacco)

Approved in USA

ABX-IL-8 MAB

Phase-IIAbgenix(Mice)

Antitumor antibody

Monsanto (Corn)

Phase I MDX-CD4 MAB Phase-II Medarex

(Mice)

Anti-HSV antibody

Epicyte & Monsanto

(Corn & Soybean)Phase I MM-093 Phase-I Merimack

TGEV vaccineProdiGene

(Corn)Phase I Factor-IX Phase-I HemoCare

(Pigs)

PHARMING OF PHARMING OF FARMACEUTICALSFARMACEUTICALS

Company Plant used Product Indication Clinical Stage Meristem Therapeutics Maize Gastric lipase Cystic fibrosis Phase 2

Maize Lactoferrin Gastrointestinal disorders Phase 1

Planet Biotechnology Corn slgA Prevention of tooth decay Phase 2

Tobacco ICAM1 receptor for common cold Phase 1

Prodigene Maize Lt-B vaccine Traveller's diarrhoea Phase 2

LSBC (in Ch.11 Tobacco scFv Non-Hodgkin's Lymphoma Phase 3

Tobacco Vaccine Feline Parvovirus Phase 3

Arizona State Univ. Potato Vaccine E.Coli Phase 1

Potato Vaccine Hepatitis "B" Phase 1

Potato / Tobacco Vaccine Norwark virus Phase 1

Ventria Biosciences Rice Lactoferrin Undisclosed Undisclosed

Rice Lysozyme Undisclosed Undisclosed

Biolex Lemna Interferon Alpha Hepatitis "B" & "C" & CML Phase 1

Cobento Biotech AS Aribidopsis Intrinsic Factor Vitamin B12 deficiency Phase 2 / 3

Dow Agrisciences Non nicotine tobacco Vaccine Newcastle disease -Poultry USDA Approved Protalix Glucocerebrosidase Gaucher's disease Phase 1

D.Yusibov and others Spinach Vaccine Rabies Phase 2

Epicyte / Monsanto Maize Antibody Cancer Phase 3

PHARMING OF PHARMING OF FARMACEUTICALSFARMACEUTICALS

LIFESTOCK AS LIFESTOCK AS BIOREACTORSBIOREACTORS

      Rabbit     Pig     Sheep     Goat    

Gestation time, months     1     4     5     5    

Age at sexual maturity (months)     5     6     8     8    

Induced lactation in prepubertal founder females     –     –     9     9    

Natural lactation in founder females     7     16     18     18    

Induced lactation in prepubertal daughters     –     –     22     22    

Natural lactation in daughters     15     28     31     31    

Number of offspring     8     10     1–2     1–2    

Annual milk yield, l     5(a) 300(b) 500     800    

Raw recombinant protein per female per year, kg     0.02     1.5     2.5     4    

[a]Average total production from 2–3 lactations per year. [b]Average total production from 2 lactations per year.

INDIA SHOULD MOVE INDIA SHOULD MOVE TOWARDS ALTERNATIVE TOWARDS ALTERNATIVE

PLATFORMSPLATFORMS• 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

HOW PRODUCTS PORTFOLIO COULD BE CREATED?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

CONCLUDING REMARKSCONCLUDING 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.

Radical Re-designing of Indian R&D necessary to make a global impactRadical Re-designing of Indian R&D necessary to make a global impact

Multifaceted International R&D has a big basket requiring very large investment

Multifaceted International R&D has a big basket requiring very large investment

Thank youThank youSources of all pictures gratefully acknowledged