DRUG DISCOVERY

&
DEVELOPMENT

N.KANAKA DURGA DEVI

KVSR SCOPS, VIJ-10
Introduction

• In the past most drugs have been discovered either by

identifying the active ingredient from traditional
remedies or by serendipitous discovery.
• But now we know diseases are controlled at molecular
and physiological level.
• Also shape of an molecule at atomic level is well
understood.
• Information of Human Genome
History of Drug Discovery :
Pre 1919 1970s 1980s
• Herbal Drugs • Rise of Biotechnology • Commercialization of
• Serendiptious discoveries • Use of IT Drug Discovery
• Combinatorial Chemistry

1920s, 30s 1960s 1990s

• Vitamins • Breakthrough in Etiology • Robotics
• Vaccines • Automation

1940s 1950s
• Antibiotic Era • New technology,
• R&D Boost due to WW2 • Discovery of DNA
 Drug Discovery

In medicine, biotechnology and pharmacology, drug

discovery is the process by which drugs are discovered

The process of drug discovery involves the identification

of candidates, synthesis, characterization, screening,
and assays for therapeutic efficacy.

4
 Focused Areas of Research
Metabolic
Gastrointestinal
Dermatolog
Ophthalmic y

Neurological/ Inflammatory/
Pyschotherapeuti Immune-related
Important DRUG
c
Targets

Infectious Oncology/
Disease Cancer
Microbial/Viral
Cardiovascular/
Musculoskeletal Respiratory
Blood Disorder
5
 Drug Discovery Pathway
Primary Screening
Preclinical Studies
ADME
Discovery Selection of
Efficacy candidate drug
&
Development
Safety
Preformulations
Toxicology Leads
Stability Studies
6
 Drug Discovery Pipeline
Exploratory Research Discovery Development

Proteomics
Diagnostics
Peptide Mass Expression
Fingerprinting Profiling
Fractionate Mass
Protein Spec
Validated
Pathway Targets
Lead Lead
Mapping Pre-clinical Clinical

c t in
Identification Optimization

e
ru te
ur
Protein-

S t P ro
Genotyping protein
Interacti ons H-UHTS Hot M-HTS
Drug L-MTS ADME Human
Genome SNP Leads Candidates PK Trials
Sequencing Discovery Functional Genomics
Primary Secondary Lab & Clinical
Gene Protein Combichem Screening Screening Animal Tests Validation
Expession Localization Synthesis
Compound
Genomics Profiling
Natural
Library
Drug Discovery
Production
Compounds

7
 Drug Discovery Process
Exploratory Drug Discovery Drug Development
Compound library generation

Target Target Lead Clinical

New
Qualification Lead Preclinical
Identification Identification Optimization Development NDA
Validation Development

Drug
Clinical
Assay Discovery Center In vitro & Trials
Development in-vivo &
w/primary & secondary
ADMET Clinical
screening& Pre-ADME monitoring

Functional and ADMET screening assays

becoming more important earlier in the
screening process. 8
Registration:

• The Ministry of health & Family Welfare and the

Ministry of Chemicals & Fertilizers have major role in
regulation of IPM.
• NDA must be submitted to DCGI
• Phase III study reported to CDL, Kolkata
• Package inserted approved by DCI
• Marketing approval from FDA
Market Scenerio:

• ~$800 M spent to bring a new drug to

market.
R&D Share
• $127 Billion spent on Pharma R&D in 2010
• Share of CROs in research operations is 18.8

27%
• World CRO market is 16.3 B (Indian share
$500 M)
Top CROs (By Revenue)

Contract Research Organizations Revenue

Quintiles $2.5 Billion
Pharmaceutical Product Development $1.8 Billion
Covance $1.4 Billion
Charles River Laboratories $1.2 Billion
Parexel $930 Million
Icon $887 Million
Kendle $590 Million
Pharmanet $470 Million
PRA International $410 Million
4G Pharmacovigilance $391 Million
Top CROs (India)

Contract Research Organizations Location

Actimus Biosciences Hyderabad
Advinus Therapeutics Bangalore
Aurigene Discovery technologies Bangalore
Chembiotek Kolkata
GVK Biosciences Hyderabad
Jubilant Organosys Bangalore
Ranbaxy Life Sciences Mumbai
Reliance Life Sciences Mumbai
Suven Life Sciences Hyderabad
Syngene Bangalore
 Most valuable R&D Projects

Rank Product Company Phase Pharmacological class Today's

NPV($mn)
1 Degludec Novo Nordisk Phase III Insulin 5,807
2 Tofacitinib Pfizer Phase III JAK-3 inhibitor 4,953
3 BG-12 Biogen Idec Phase III Fumarate 4,666
4 Incivek J&J Phase IV Hep C protease inhibitor 4,332
5 Relovair Theravance Phase III Corticosteroid 4,241

6 DR Cysteamine Undisclosed Phase III Lysosomal transport 4,155

modulator
7 AMR 101 Undisclosed Phase III Omega-3 fatty acid 4,052
8 Eliquis Bristol Myers Squibb Phase IV Factor Xa inhibitor 3,836
9 Eliquis Pfizer Phase IV Factor Xa inhibitor 3,592
10 Bexssero Novartis Phase IV Meningococcal B vaccine 3,250
Top Companies by R&D Expense:
Sr. No. Company R & D spend($bn),2010
1 Novartis 7.9
2 Merck & Co 8.1
3 Roche 7.8
4 GlaxoSmithKline 5.7
5 Sanofi 5.8
6 Pfizer 9.1
7 Johnson & Johnson 4.5
8 Eli Lilly 4.7
9 AstraZeneca 4.2
10 Takeda 3.4
11 Bayer 2.3
12 Bristol-Myers Squibb 3.3
13 Boehringer Ingelheim 3.1
14 Amgen 2.8
15 Novo Nordisk 1.7
Drug Development Cost Break-up
R&D Function %
Discovery/Basic Research
Synthesis & Extraction 10.0
Biological Screening & testing 14.2
Preclinical Testing
Toxicology & Safety testing 4.5
Pharmaceutical Dosage Formulation 7.3
Clinical Trials
Phase I, II, III 29.1
Phase IV 11.7
Manufacturing & QC 8.3
IND & NDA 4.1
Bioavailability 1.8
Others 9.0
Total 100.0
 DRUG
DISCOVERY
Drug Discovery &
Development-Timeline
PRECLINICAL

CLINICAL TRIALS FDA

10,000 250 REVIEW 1 FDA
COMPOUNDS COMPOUNDS 5 COMPOUNDS APPROVED
DRUG

~6.5 YEARS ~7 YEARS ~1.5 YEARS

Drug Discovery

• Drugs Discovery methods:

– Random Screening
– Molecular Manipulation
– Molecular Designing
– Drug Metabolites
– Serendipity
 Target Lead Medicinal In Vitro In Vivo Clinical
Selection Discovery Chemistry Studies Studies Trials and
Therapeutics
• Cellular and • Synthesis and • Library • Drug Affinity • Animal
Genetic Isolation Development and models of
Targets Selectivity Disease States

• Genomics • Combinatorial • SAR Studies • Cell Disease • Behavioural

Chemistry Models Studies

• Proteomics • Assay • In Silico • MOA • Functional

development Screening Imaging

• Bioinformatics • High- • Chemical • Lead • Ex-Vivo

Throughput Synthesis Candidate Studies
Screening Refinement
 Target Selection
• Target selection in drug discovery is defined as the decision
Cellular & to focus on finding an agent with a particular biological
Genetic Targets action that is anticipated to have therapeutic utility — is
influenced by a complex balance of scientific, medical and
Genomics
strategic considerations.
• Target identification: to identify molecular targets that are
Proteomics involved in disease progression.
• Target validation: to prove that manipulating the molecular
Bioinformatics target can provide therapeutic benefit for patients.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Target Selection
Biochemical Classes of Drug Targets
 G-protein coupled receptors - 45%
Cellular &
Genetic Targets  enzymes - 28%
 hormones and factors - 11%
Genomics  ion channels - 5%
 nuclear receptors - 2%
Proteomics

Techniques for Target Identification

Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cellular & Genetic Targets:
Involves the identification of the function of a potential therapeutic
Cellular &
drug target and its role in the disease process.
Genetic Targets

Genomics For small-molecule drugs, this step in the process involves

identification of the target receptors or enzymes whereas for some
biologic approaches the focus is at the gene or transcription level.
Proteomics

Drugs usually act on either cellular or genetic chemicals in the body,

Bioinformatics
known as targets, which are believed to be associated with disease.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cellular & Genetic Targets:
Scientists use a variety of techniques to identify
Cellular &
Genetic Targets
and isolate individual targets to learn more about
their functions and how they influence disease.
Genomics

Proteomics Compounds are then identified that have various

interactions with the drug targets that might be
Bioinformatics
helpful in treatment of a specific disease.
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Genomics:
The study of genes and their function. Genomics aims to understand the
structure of the genome, including the mapping genes and sequencing
Cellular &
Genetic Targets the DNA.

Seeks to exploit the findings from the sequencing of the human and other
Genomics
genomes to find new drug targets.

Proteomics
Human Genome consists of a sequence of around 3 billion nucleotides
(the A C G T bases) which in turn probably encode 35,000 – 50,000 genes.
Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Genomics:
Drew’s estimates that the number of genes implicated in disease, both
Cellular &
those due to defects in single genes and those arising from
Genetic Targets combinations of genes, is about 1,000

Genomics Based on 5 or 10 linked proteins per gene, he proposes that the

number of potential drug targets may lie between 5,000 and 10,000.

Proteomics
Single Nucleotide Polymorphism (SNP) libraries: are used to compare
the genomes from both healthy and sick people and to identify where
Bioinformatics
their genomes vary.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Proteomics:
It is the study of the proteome, the complete set of proteins produced by a
species, using the technologies of large – scale protein separation and
Cellular &
Genetic Targets
identification.

It is becoming increasingly evident that the complexity of biological systems lies

Genomics at the level of the proteins, and that genomics alone will not suffice to
understand these systems.

Proteomics It is also at the protein level that disease processes become manifest, and at
which most (91%) drugs act.

Bioinformatics Therefore, the analysis of proteins (including protein-protein, protein-nucleic acid,

and protein ligand interactions) will be utmost importance to target discovery.
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Proteomics:
Proteomics is the systematic high-throughput separation and
Cellular & characterization of proteins within biological systems.
Genetic Targets

Target identification with proteomics is performed by

Genomics comparing the protein expression levels in normal and
diseased tissues.
Proteomics
2D PAGE is used to separate the proteins, which are
Bioinformatics
subsequently identified and fully characterized with
LC-MS/MS.
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Bioinformatics:
Bioinformatics is a branch of molecular biology that involves extensive analysis of
biological data using computers, for the purpose of enhancing biological research.
Cellular &
Genetic Targets
It plays a key role in various stages of the drug discovery process including
Genomics  target identification
 computer screening of chemical compounds and
Proteomics  pharmacogenomics

Bioinformatics

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Bioinformatics:
Bioinformatics methods are used to transform the raw sequence into
Cellular &
meaningful information (eg. genes and their encoded proteins) and to
Genetic Targets compare whole genomes (disease vs. not).

Genomics Can compare the entire genome of pathogenic and non-pathogenic

strains of a microbe and identify genes/proteins associated with
pathogenism
Proteomics
Using gene expression micro arrays and gene chip technologies, a
single device can be used to evaluate and compare the expression of
Bioinformatics
up to 20000 genes of healthy and diseased individuals at once

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Lead Discovery:
• Identification of small molecule modulators of
Synthesis and
Isolation protein function
Combinatorial
• The process of transforming these into high-
Chemistry content lead series.
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Synthesis and Isolation:
• Separation of mixture
Synthesis and
Isolation • Separation of impurities
Combinatorial • In vitro chemical synthesis
Chemistry
• Biosynthetic intermediate
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Combinatorial Chemistry:
Rapid synthesis of or computer simulation of
Synthesis and
Isolation large no. of different but structurally related
molecules
Combinatorial
Chemistry • Search new leads
Assay • Optimization of target affinity & selectivity.
Development
• ADME properties
High
Throughput
Screening
• Reduce toxicity and eliminate side effects
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Assay Development
• Used for measuring the activity of a drug.
Synthesis and
Isolation • Discriminate between compounds.
Combinatorial
• Evaluate:
Chemistry
• Expressed protein targets.
Assay
Development
• Enzyme/ substrate interactions.
High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 High throughput screening:
• Screening of drug target against selection of
Synthesis and
Isolation chemicals.
Combinatorial
• Identification of highly target specific
Chemistry compounds.
Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 High throughput screening:
Synthesis and
Isolation

Combinatorial
Chemistry

Assay
Development

High
Throughput
Screening

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Medicinal Chemistry:
• It’s a discipline at the intersection of synthetic
Library organic chemistry and parmacology.
Development
• Focuses on small organic molecules (and not on
SAR Studies biologics and inorganic compounds)
• Used in
In Silico
Screening • Drug discovery (hits)
• Lead optimization (hit to lead)
Chemical
Synthesis • Process chemistry and development
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Library Development:
• Collection of stored chemicals along with
Library
Development associated database.
• Assists in High Throughput Screening
SAR Studies
• Helps in screening of drug target (hit)
In Silico
Screening • Based on organic chemistry
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 SAR Studies:
• Helps identify pharmacophore
Library
Development • The pharmacophore is the precise section
SAR Studies
of the molecule that is responsible for
biological activity
In Silico
Screening • Enables to prepare more active compound
Chemical • Allow elimination of excessive functionality
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 SAR Studies:
Library
Development

SAR Studies

In Silico
Screening

Chemical Morphine Molecule

Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In silico screening:
• Computer simulated screening of chemicals
Library
Development • Helps in finding structures that are most likely
to bind to drug target.
SAR Studies
• Filter enormous Chemical space
In Silico
Screening
• Economic than HTS
Chemical
Synthesis

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Chemical Synthesis:
• Involve production of lead compound in
Library
Development suitable quantity and quality to allow large
scale animal and eventual, extensive human
SAR Studies
clinical trials
In Silico • Optimization of chemical route for bulk
Screening
industrial production.
Chemical
Synthesis
• Suitable drug formulation
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 In Vitro Studies:
• (In glass) studies using component of organism i.e. test tube
Drug Affinity experiments
and Selectivity • Examples-
Cell Disease
• Cells derived from multicellular organisms
Models • Subcellular components (Ribosomes, mitochondria)
• Cellular/ subcellular extracts (wheat germ, reticulocyte
MOA extract)
• Purified molecules (DNA,RNA)
Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In Vitro Studies:
Advantages:
Drug Affinity • Studies can be completed in short period of time.
and Selectivity
• Reduces risk in post clinical trials
Cell Disease • permits an enormous level of simplification of the system
Models
• investigator can focus on a small number of components

MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Drug affinity and selectivity
• Drug affinity is the ability of drug to bind to its biological
Drug Affinity target (receptor, enzyme, transport system, etc.)
and Selectivity

Cell Disease
• Selectivity- Drug should bind to specific receptor site on the
Models cell (eg. Aspirin)

MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Cell disease models
• Isogenic human disease models- are a family of cells that are
Drug Affinity selected or engineered to accurately model the genetics of a specific
and Selectivity patient population, in vitro

Cell Disease
Models • Stem cell disease models-Adult or embryonic stem cells carrying
or induced to carry defective genes can be investigated in vitro to
understand latent molecular mechanisms and disease characteristics
MOA

Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Lead Candidate refinement
• Optimizing chemical hits for clinical trial is commonly referred
Drug Affinity to as lead optimization
and Selectivity • The refinement in structure is necessary in order to improve
Cell Disease
• Potency
Models • Oral Availability
• Selectivity
MOA
• pharmacokinetic properties
• safety (ADME properties)
Lead Candidate
Refinement

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 In vivo studies
• Its experimentation using a whole, living
Animal models of
Disease States organism.
• Gives information about,
Behavioural
Studies • Metabolic profile
Functional • Toxicology
Imaging
• Drug interaction
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Animal models of disease states
• Test conditions involving induced disease or
Animal models of
Disease States injury similar to human conditions.
• Must be equivalent in mechanism of cause.
Behavioural
Studies • Can predict human toxicity in 71% of the cases.
Functional • Eg. SCID mice-HIV
Imaging
NOD mice- Diabetes
Ex-Vivo Studies
Danio rerio- Gene function
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Behavioural Studies
• Tools to investigate behavioural results of drugs.
Animal models of • Used to observe depression and mental disorders.
Disease States
• However self esteem and suicidality are hard to induce.
Behavioural • Example:
Studies
• Despair based- Forced swimming/ Tail suspension
Functional
Imaging • Reward based
• Anxiety Based
Ex-Vivo Studies

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Functional Imaging:
• Method of detecting or measuring changes
Animal models of
Disease States in metabolism, blood flow, regional chemical
Behavioural
composition, and absorption.
Studies • Tracers or probes used.
Functional
Imaging
• Modalities Used-
• MRI
Ex-Vivo Studies
• CT-Scan
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Ex-Vivo Studies:
• Experimentation on tissue in an artificial
Animal models of
Disease States environment outside the organism with the
Behavioural
minimum alteration of natural conditions.
Studies • Counters ethical issues.
Functional
Imaging
• Examples:
• Measurement of tissue properties
Ex-Vivo Studies
• Realistic models for surgery
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Clinical trials:
• Set of procedures in medical research and
Phase-I drug development to study the safety and
efficacy of new drug.
Phase-II
• Essential to get marketing approval from
Phase-III
regulatory authorities.
• May require upto 7 years.
Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase 0:
• Recent designation, also known as human micro-dosing
studies.
Phase-I
• First in human trials, conducted to study exploratory
investigational new drug.
Phase-II
• Designed to to speed up the development of promising drugs.
• Concerned with-
Phase-III
• Preliminary data on the drug’s pharmacodynamics and
pharmacokinetics
Phase-IV • Efficacy of pre-clinical studies.

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase I:
• Clinical Pharmacologic Evaluation
Phase-I • First stage of testing in human subjects.
• 20-50 Healthy Volunteers
Phase-II
• Concerned With:
Phase-III – Human Toxicity.
– Tolerated Dosage Range
Phase-IV – Pharma-cology/dynamics
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase I:
Types of Phase-I Trials
Phase-I • SAD (Single Ascending Dose)
• MAD (Multiple Ascending Dose)
Phase-II
• Food effect

Phase-III

Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 Phase II:
• Controlled Clinical Evaluation.
Phase-I • 50-300 Patients
• Controlled Single Blind Technique
Phase-II
• Concerned With:
Phase-III
– Safety
– Efficacy
Phase-IV
– Drug Toxicity
– Drug Interaction
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase III:
• Extended Clinical Trials.
Phase-I • Most expensive & time consuming.
• 250-1000 Patients.
Phase-II
• Controlled Double Blind Technique.
Phase-III
• Concerned With:
– Safety, Efficacy
Phase-IV – Comparison with other Drugs
– Package Insert
Target Selection Lead Medicinal In Vitro In Vivo Clinical
Discovery Chemistry Studies Studies Trials
 Phase IV:
• Post Marketing Surveillance.
Phase-I • Designed to detect any rare or long-term
adverse effects.
Phase-II • Adverse Drug Reaction Monitoring.
• Pharmacovigilance.
Phase-III

Phase-IV

Target Selection Lead Medicinal In Vitro In Vivo Clinical

Discovery Chemistry Studies Studies Trials
 DRUG
DISCOVERY
Drug Discovery &
Development-Timeline
PRECLINICAL

CLINICAL TRIALS FDA

10,000 250 REVIEW 1 FDA
COMPOUNDS COMPOUNDS 5 COMPOUNDS APPROVED
DRUG

~6.5 YEARS ~7 YEARS ~1.5 YEARS

Gene Therapy

• Technique for correcting

defective genes.
• It is the process of inserting
genes into cells to treat
diseases.
• Gene therapy is used to correct
a deficient phenotype.
Gene Therapy-Approaches

Germline Gene Therapy

 Sperm or eggs, are modified by the introduction of functional genes, which are
integrated into their genomes.

 Change would be heritable and would be passed on to later generations.

Somatic Gene Therapy

 The therapeutic genes are transferred
Into the somatic cells of a patient.

 Change will not be inherited by the

Gene Therapy- Types

Ex Vivo Gene Therapy

 Transfer of therapeutic genes in cultured cells which are then reintroduced into
patient.

Eg: Therapy for ADA Deficiency

In Vivo Gene Therapy

 The direct delivery of genes into the cells of a particular tissue is referred to as in
vivo gene therapy.

Eg: Therapy for Cystic fibrosis

Gene Therapy- Vectors

• Viruses
Retroviruses
Adenoviruses
Adeno-associated viruses
Herpes Simplex viruses
• Pure DNA Constructs
• Lipoplexes
• DNA Molecular Conjugates
• Human Artificial Chromosome
Gene Therapy- Limitations

• Short lived nature of gene therapy

• Immune response
• Problems with viral vectors
• Multigene disorders
Recent Developments

• Nanotechnology + gene therapy yielded treatment to

torpedo cancer
• Results of world's first gene therapy for inherited
blindness show sight improvement
• New Method of Gene Therapy Alters Immune Cells for
Treatment of Advanced Melanoma
• Dual Gene Therapy Suppresses Lung Cancer in Preclinical
Test
Orphan Drugs:

• An orphan drug is a pharmaceutical agent that has been

developed specifically to treat a rare medical condition, the
condition itself being referred to as an orphan disease.
• National Organization for Rare
Disorders

• European Organization for Rare

Diseases
Advantages:

• Tax incentives.
• Enhanced patent protection and marketing rights.
• Clinical research financial subsidization.
• Rise in research and developmen.
• Crown Corporation.
Orphan Drugs Act:

• 4th January 1983

• 6000 Orphan Diseases
• Unprofitable Drug Development
• Affecting < 2,00,000 Persons
• Orphan Drug Status to 1,090
Drugs Tourette Syndrome
• 1985 Amendment- Marketing An Orphan Disease

Exclusivity
FDA Orphan Drug Approvals:

% Share

19 2
Big Pharma
Small Biopharma
43
Established
Biopharma
Small & Medium
17 Pharma
Academic Institutes
19
Rare Diseases & Orphan Drugs:

Sr. Disease Cause Orphan Drug

1. Gaucher’s Disease Glucocerbrosidase Enzyme Miglustat

2. Fabry’s Disease Galactosidase Enyme Galsidase β

3. Mucopolysaccharidosis Lysosomal Enzyme Laronidase

4. Tourette’s Syndrome Motor Tics Lamotrizine

5. Crohn’s Syndrome Unknown Infliximab

6. Wilson Disease Copper Deposition Trientine

7. SCID Adenosine Deaminase Enzyme Pegadimase