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Brief account of drug discovery by molecular designing approach and drug development.
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DRUG DISCOVERY&
DEVELOPMENT
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• Herbal Drugs• Serendiptious discoveries
1920s, 30s• Vitamins• Vaccines
1940s• Antibiotic Era• R&D Boost due to WW2
1950s• New technology,• Discovery of DNA
1960s• Breakthrough in Etiology
1970s• Rise of Biotechnology• Use of IT
1980s• Commercialization of Drug
Discovery• Combinatorial Chemistry
1990s• Robotics• Automation
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
• ~$800 M spent to bring a new drug to market.
• $127 Billion spent on Pharma R&D in 2010• Share of CROs in research operations is
27%• World CRO market is 16.3 B (Indian share
$500 M)
Market Scenerio:
18.8
R&D Share
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 modulator 4,155
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 7.92 Merck & Co 8.13 Roche 7.84 GlaxoSmithKline 5.75 Sanofi 5.86 Pfizer 9.17 Johnson & Johnson 4.58 Eli Lilly 4.79 AstraZeneca 4.2
10 Takeda 3.411 Bayer 2.312 Bristol-Myers Squibb 3.313 Boehringer Ingelheim 3.114 Amgen 2.815 Novo Nordisk 1.7
Drug Development Cost Break-upR&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
10,000COMPOUNDS
250COMPOUNDS 5 COMPOUNDS
1 FDA APPROVED
DRUG
~6.5 YEARS ~7 YEARS ~1.5 YEARS
DRUG DISCOVERY
PRECLINICAL
CLINICAL TRIALS FDAREVIEW
Drug Discovery & Development-Timeline
Drug Discovery
• Drugs Discovery methods:– Random Screening– Molecular Manipulation– Molecular Designing– Drug Metabolites– Serendipity
Target Selection
• Cellular and Genetic Targets
• Genomics
• Proteomics
• Bioinformatics
Lead Discovery
• Synthesis and Isolation
• Combinatorial Chemistry
• Assay development
• High-Throughput Screening
Medicinal Chemistry
• Library Development
• SAR Studies
• In Silico Screening
• Chemical Synthesis
In Vitro Studies
• Drug Affinity and Selectivity
• Cell Disease Models
• MOA
• Lead Candidate Refinement
In Vivo Studies
• Animal models of Disease States
• Behavioural Studies
• Functional Imaging
• Ex-Vivo Studies
Clinical Trials and
Therapeutics
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target Selection
• Target selection in drug discovery is defined as the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility — is influenced by a complex balance of scientific, medical and strategic considerations.
• Target identification: to identify molecular targets that are involved in disease progression.
• Target validation: to prove that manipulating the molecular target can provide therapeutic benefit for patients.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Target SelectionBiochemical Classes of Drug Targets
G-protein coupled receptors - 45%
enzymes - 28%
hormones and factors - 11%
ion channels - 5%
nuclear receptors - 2%
Techniques for Target Identification
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Cellular & Genetic Targets:Involves the identification of the function of a potential therapeutic drug target and its role in the disease process.
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.
Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Cellular & Genetic Targets:Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease.
Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:The study of genes and their function. Genomics aims to understand the structure of the genome, including the mapping genes and sequencing the DNA.
Seeks to exploit the findings from the sequencing of the human and other genomes to find new drug targets.
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.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Genomics:Drew’s estimates that the number of genes implicated in disease, both those due to defects in single genes and those arising from combinations of genes, is about 1,000
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.
Single Nucleotide Polymorphism (SNP) libraries: are used to compare the genomes from both healthy and sick people and to identify where their genomes vary.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
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 identification.
It is becoming increasingly evident that the complexity of biological systems lies at the level of the proteins, and that genomics alone will not suffice to understand these systems. It is also at the protein level that disease processes become manifest, and at which most (91%) drugs act. 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 Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Proteomics:Proteomics is the systematic high-throughput separation and characterization of proteins within biological systems.
Target identification with proteomics is performed by comparing the protein expression levels in normal and diseased tissues.
2D PAGE is used to separate the proteins, which are subsequently identified and fully characterized with LC-MS/MS.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Bioinformatics:Bioinformatics is a branch of molecular biology that involves extensive analysis of biological data using computers, for the purpose of enhancing biological research.
It plays a key role in various stages of the drug discovery process including
target identification
computer screening of chemical compounds and
pharmacogenomics
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Cellular & Genetic Targets
Genomics
Proteomics
Bioinformatics
Bioinformatics:Bioinformatics methods are used to transform the raw sequence into meaningful information (eg. genes and their encoded proteins) and to compare whole genomes (disease vs. not). Can compare the entire genome of pathogenic and non-pathogenic strains of a microbe and identify genes/proteins associated with pathogenism Using gene expression micro arrays and gene chip technologies, a single device can be used to evaluate and compare the expression of up to 20000 genes of healthy and diseased individuals at once
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Lead Discovery:
• Identification of small molecule modulators of protein function
• The process of transforming these into high-content lead series.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Synthesis and Isolation:• Separation of mixture• Separation of impurities• In vitro chemical synthesis• Biosynthetic intermediate
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Combinatorial Chemistry:Rapid synthesis of or computer simulation of
large no. of different but structurally related molecules
• Search new leads• Optimization of target affinity & selectivity.• ADME properties• Reduce toxicity and eliminate side effects
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
Assay Development• Used for measuring the activity of a drug.• Discriminate between compounds.• Evaluate:• Expressed protein targets.• Enzyme/ substrate interactions.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
High throughput screening:• Screening of drug target against selection of
chemicals.• Identification of highly target specific
compounds.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Synthesis and Isolation
Combinatorial Chemistry
Assay Development
High Throughput Screening
High throughput screening:
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Medicinal Chemistry:
• It’s a discipline at the intersection of synthetic organic chemistry and parmacology.
• Focuses on small organic molecules (and not on biologics and inorganic compounds)
• Used in• Drug discovery (hits)• Lead optimization (hit to lead)• Process chemistry and development
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Library Development:• Collection of stored chemicals along with
associated database.• Assists in High Throughput Screening• Helps in screening of drug target (hit)• Based on organic chemistry
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
SAR Studies:• Helps identify pharmacophore• The pharmacophore is the precise section
of the molecule that is responsible for biological activity
• Enables to prepare more active compound• Allow elimination of excessive functionality
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
SAR Studies:
Morphine Molecule
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
In silico screening:• Computer simulated screening of chemicals• Helps in finding structures that are most likely
to bind to drug target.• Filter enormous Chemical space• Economic than HTS
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Library Development
SAR Studies
In Silico Screening
Chemical Synthesis
Chemical Synthesis:• Involve production of lead compound in
suitable quantity and quality to allow large scale animal and eventual, extensive human clinical trials
• Optimization of chemical route for bulk industrial production.
• Suitable drug formulation
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
In Vitro Studies:
• (In glass) studies using component of organism i.e. test tube experiments
• Examples-• Cells derived from multicellular organisms• Subcellular components (Ribosomes, mitochondria)• Cellular/ subcellular extracts (wheat germ, reticulocyte
extract)• Purified molecules (DNA,RNA)
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
In Vitro Studies:
Advantages:• Studies can be completed in short period of time.• Reduces risk in post clinical trials • permits an enormous level of simplification of the system • investigator can focus on a small number of components
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
Drug affinity and selectivity• Drug affinity is the ability of drug to bind to its biological
target (receptor, enzyme, transport system, etc.)
• Selectivity- Drug should bind to specific receptor site on the cell (eg. Aspirin)
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
• Isogenic human disease models- are a family of cells that are selected or engineered to accurately model the genetics of a specific patient population, in vitro
• 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
Cell disease models
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Drug Affinity and Selectivity
Cell Disease Models
MOA
Lead Candidate Refinement
• Optimizing chemical hits for clinical trial is commonly referred to as lead optimization
• The refinement in structure is necessary in order to improve • Potency• Oral Availability• Selectivity• pharmacokinetic properties• safety (ADME properties)
Lead Candidate refinement
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
In vivo studies
• Its experimentation using a whole, living organism.
• Gives information about,• Metabolic profile• Toxicology• Drug interaction
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Animal models of disease states• Test conditions involving induced disease or
injury similar to human conditions.• Must be equivalent in mechanism of cause.• Can predict human toxicity in 71% of the cases.• Eg. SCID mice-HIV
NOD mice- DiabetesDanio rerio- Gene function
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Behavioural Studies• Tools to investigate behavioural results of drugs.• Used to observe depression and mental disorders.• However self esteem and suicidality are hard to induce.• Example:
• Despair based- Forced swimming/ Tail suspension• Reward based• Anxiety Based
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Functional Imaging:• Method of detecting or measuring changes
in metabolism, blood flow, regional chemical composition, and absorption.
• Tracers or probes used.• Modalities Used-• MRI• CT-Scan
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Animal models of Disease States
Behavioural Studies
Functional Imaging
Ex-Vivo Studies
Ex-Vivo Studies:• Experimentation on tissue in an artificial
environment outside the organism with the minimum alteration of natural conditions.
• Counters ethical issues.• Examples:• Measurement of tissue properties• Realistic models for surgery
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Clinical trials:• Set of procedures in medical research and
drug development to study the safety and efficacy of new drug.
• Essential to get marketing approval from regulatory authorities.
• May require upto 7 years.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase 0:• Recent designation, also known as human micro-dosing
studies.• First in human trials, conducted to study exploratory
investigational new drug.• Designed to to speed up the development of promising drugs.• Concerned with-
• Preliminary data on the drug’s pharmacodynamics and pharmacokinetics
• Efficacy of pre-clinical studies.
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:• Clinical Pharmacologic Evaluation• First stage of testing in human subjects.• 20-50 Healthy Volunteers• Concerned With:– Human Toxicity.– Tolerated Dosage Range– Pharma-cology/dynamics
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase I:Types of Phase-I Trials• SAD (Single Ascending Dose)• MAD (Multiple Ascending Dose)• Food effect
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase II:• Controlled Clinical Evaluation.• 50-300 Patients• Controlled Single Blind Technique• Concerned With:
– Safety– Efficacy– Drug Toxicity– Drug Interaction
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase III:• Extended Clinical Trials.• Most expensive & time consuming.• 250-1000 Patients.• Controlled Double Blind Technique.• Concerned With:
– Safety, Efficacy– Comparison with other Drugs– Package Insert
Target Selection Lead Discovery
Medicinal Chemistry
In Vitro Studies
In Vivo Studies
Clinical Trials
Phase-I
Phase-II
Phase-III
Phase-IV
Phase IV:• Post Marketing Surveillance.• Designed to detect any rare or long-term
adverse effects.• Adverse Drug Reaction Monitoring.• Pharmacovigilance.
10,000COMPOUNDS
250COMPOUNDS 5 COMPOUNDS
1 FDA APPROVED
DRUG
~6.5 YEARS ~7 YEARS ~1.5 YEARS
DRUG DISCOVERY
PRECLINICAL
CLINICAL TRIALS FDAREVIEW
Drug Discovery & Development-Timeline
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 patient's offspring or later generations.
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
• VirusesRetrovirusesAdenovirusesAdeno-associated virusesHerpes 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 RareDisorders
• European Organization for RareDiseases
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• 1985 Amendment- Marketing
Exclusivity
Tourette SyndromeAn Orphan Disease
FDA Orphan Drug Approvals:
43
19
17
19 2
% Share
Big PharmaSmall BiopharmaEstablished BiopharmaSmall & Medium PharmaAcademic Institutes
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