MS523.L21.Pharmacogenomics.Q2.22.pptx

Lecture: Pharmacogenomics Presenter: Dr. Darl Swartz Course: Human Genetics MS523 Date: 12/5/22 12/12/ Dr. Darl Ray. Swartz 1 Objectives: 1. Describe how genomics can be leveraged for drug development and clinical trials. 2. Explain how experiments of nature (natural variants) have and can be us...

Lecture: Pharmacogenomics Presenter: Dr. Darl Swartz Course: Human Genetics MS523 Date: 12/5/22 12/12/ Dr. Darl Ray. Swartz 1 Objectives: 1. Describe how genomics can be leveraged for drug development and clinical trials. 2. Explain how experiments of nature (natural variants) have and can be used for drug discovery. 3. Give retrospective and prospective examples of drug-gene pairs. 4. Distinguish between pharmacokinetics and pharmacodynamics. 5. Explain how pharmacogenetics is applied to decipher adverse drug reactions mediated through variants involved in pharmacokinetics and pharmacodynamics. 6. Describe how you would find pharmacokinetic and pharmacodynamic information about a drug. 12/12/2 Dr. Darl Ray. Swartz 2 Outline: I. PGx II. PGx in Drug Discovery III. PharmGKB 12/12/2 Dr. Darl Ray. Swartz 3 Pharmacogenomics 12/12/2 Dr. Darl Ray. Swartz 4 Pharmacogenomics A) Current drug development cost about 60$ billion per year with a success rate of about 5% for new (first in class) drugs 1) Phase I trials > Safety and dosage > 70% success rate 2) Phase II trials > Efficacy and side effects > 33% success rate > most first in class fail here 3) Phase III trials > Efficacy and monitoring for adverse reactions > 25 – 30% success rate 4) Phase IV trials > Safety and efficacy in large scale clinical trials 5) Use of PGx from target to approval improved success rate about 2-fold over not using PGx 12/12/2 Dr. Darl Ray. Swartz 5 Pharmacogenomics B) Use of genetic/genomic data to: 1) Define proteins/genes for drug targeting 2) Identify genes involved in drug metabolism (absorption, cell uptake, cell activation, inactivation, excretion) 3) Identify variants involved in modified drug metabolism (too slow or too rapid) 4) Identify variants in target proteins that do not respond or respond differently 12/12/2 Dr. Darl Ray. Swartz 6 Pharmacogenomics C) Explains large investment of Pharma in obtaining genomic data through collaborations with hospitals or countries with nationalized medicine 1) Regeneron and Geisinger 2) Amgen and DeCode 3) GSK and UC-Berkeley and UCSF/23andMe collaboration/UK BioBank/The Broad Institute as well as AI (NIVIA/Cerebras) 4) And many more 12/12/2 Dr. Darl Ray. Swartz 7 Pharmacogenomics D) NIH/NHGRI/NICHD (via HHS) developed PharmGKB as a pharmacogenomics knowledge resource E) An important component of personalized medicine but not routinely used in the clinic on the front side 1) Let’s do the experiment on the patient to figure out the dosage or switch to a different medicine rather than use genetic information! F) Historically used post drug development to determine drug metabolism and differences in efficacy within a population and now used on the front (development) side G) Highly leveraged for drug therapy for cancers in conjunction with AI for personalized cancer treatment 1) Multiple drugs to target different pathways 12/12/2 Dr. Darl Ray. Swartz 8 PGx in Drug Discovery 12/12/2 Dr. Darl Ray. Swartz 9 PGx in Drug Discovery A) Plenge, R.M., E.M. Scolnick, and D. Altshuler, 2013, Validating therapeutic targets through human genetics, Nature Reviews Drug Discovery 12:581 1) Gives retrospective and prospective view on genomics in drug discovery B) Historically involved leveraging “experiment of nature” in human medicine 1) Human variants that cause disease 2) Can be dominant (gain) or recessive (loss) with gene-dosage effects (a) Dosage effects (incomplete dominance) gives range of phenotype and thus a dose-response curve 3) Can explain drug effect if gene/protein 12/12/2 not known – retrospective Dr. Darl Ray. Swartz 10 PGx in Drug Discovery C) Experiments of nature have advantages as a pre-clinical model compared to other models 12/12/2 Dr. Darl Ray. Swartz 11 PGx in Drug Discovery D) Retrospective examples 1) Thiazolidinediones and Type 2 diabetes (a) Discovered via compound screening using hypoglycemic activity in a mouse model in 1988 (b) Increases insulin sensitivity in peripheral tissues (c) Discovered that it acts as a ligand to activate PPARG > increase fat and downstream target of PGC1-alpha (mitochondrial biogenesis) 12/12/2 Dr. Darl Ray. Swartz 12 PGx in Drug Discovery D) Retrospective examples 2) SGLT2 (sodium glucose transporter 2) inhibitors (a) Phlorizin (glucoside) known for over 100 years to cause renal glucosouria and was modified to enhance metabolism giving current approved drugs of Farxiga, Invokana, and Jardiance (b) Transporter discovered in the 90s and is only expressed in the initial segments of the proximal convoluted tubule (c) Biology explains the mechanism and few off target 12/12/2 Dr. Darl Ray. Swartz responses to the drug 13 PGx in Drug Discovery E) Prospective examples 1) CFTR gene (a) Drugs developed to modify the ER/Golgi processing of specific variant proteins (ivacaftor) 2) PCSK9 targeted drugs and lowering of LDL levels > coronary artery disease (a) Gene codes for proprotein convertase subtilisin/kexin type 9 – a serum protease involved in processing of the LDL receptor (i) Natures experiments show that gain of function mutations result in hypercholesterolemia while loss of function result in hypocholesterolemia (b) Several peptide and large molecule (antibodies) approved or in development to inhibit the activity of the protease 3) Regeneron has several large molecule drugs (antibodies or binding proteins) that target cytokines and other factors to inhibit function 12/12/2 Dr. Darl Ray. Swartz 14 PGx in Drug Discovery F) Current approach is to use genomic/phenomic data to identify target proteins then refine for drug development 1) Search data bases for gain or loss of function human variants (a) Homozygotes for loss of function (i) Focus on screening in populations with high consanguinity 12/12/2 Dr. Darl Ray. Swartz 15 PGx in Drug Discovery F) Current approach is to use genomic/phenomic data to identify target proteins then refine 2) GWAS and other data to identify target proteins/genes linked to diseases (a) Mostly exome sequence data (b) More recently GETex data (c) Use of Mendelian randomization in epidemiological studies (i) Genotype or gene expression (mRNA) as an instrumental variable (d) Recent paper by a founder of Mendelian randomization of gene expression data pointed out that: (i) TPO gene is highly expressed in the thyroid gland and may be involved in thyroid disease  Gene codes for thyroid peroxidase (ii) RPS26 gene is expressed in all tissues and not likely involved in thyroid disease  Gene codes for a protein of the 40s subunit of ribosomes (iii) REALLY!!!! Maybe these epidemiologist should take some courses 12/12/2 Dr. Darl Ray. Swartz other than statistics – all authors are statisticians!!!!!!!!!!!!!!!!!!! 16 PGx in Drug Discovery F) Current approach is to use genomic/phenomic data to identify target proteins then refine 2) GWAS and other data to identify target proteins/genes linked to diseases (c) Use of Mendelian randomization in epidemiological studies 12/12/2 Dr. Darl Ray. Swartz 17 PGx in Drug Discovery F) Current approach is to use genomic/phenomic data to identify target proteins then refine 3) Refine region to find gene and further characterize genome/phenome relationship 4) Determine molecular mechanisms of variant (a) Mostly focus on inhibition of target via drug than activation as easier to design inhibitory drugs (b) Look for loss of function mutations for inhibitory target to assess clinical adverse effects (excess dosage/inhibition effects) (c) Multiple omics and big data analysis to infer mechanisms 5) Test experimentally using in vitro and animal models 6) Leverage genomics in clinical trials for selection of participants 12/12/2 Dr. Darl Ray. Swartz 18 PGx in Drug Discovery G) More recent approach is to use CRISPR to screen for protein function in cell models 1) Focus on “non-house” keeping/essential genes and develop a panel of 3,000 – 5,000 target proteins 2) Test in cell culture models to see biological role of protein 3) Used in recent discovery of protein essential for HBV protein production (as well as other infectious diseases) (a) Used a liver cell model with HBV sequence inserted in the genome (b) Found targets that reduced HBV antigen production and a drug that modifies it (i) Proteins involved in adding a poly-A tail to the transcripts (ii) Drug is specific to the unique enzyme that adds the poly-A to the transcript 12/12/2 Dr. Darl Ray. Swartz 19 II. PharmGKB 12/12 20 II. PharmGKB A) Classical pharmacogenetics focuses on genes involved in pharmacokinetic mechanisms and pharmacodynamic mechanisms 1) Pharmacokinteics > genes involved in drug metabolism 2) Pharmacodynamics >variants involved in drug action (i.e. target proteins) B) Initial studies focused on DNA sequence analysis to find variants then develop assays 1) PCR-based assays that assess common variants 2) Targeted sequencing of multiple variants of interest C) Slowly becoming more prevalent in routine clinical application but suffers from 1) Complexity of assays 2) Inconsistent/non-interpretable data presentation 3) Cost D) Variants associated with altered pharmacokinetic and pharmacodynamic interactions can result in adverse drug response (ADR) 12/12 1) ADR = an appreciably harmful or unpleasant reaction resulting from an 21 II. PharmGKB E) Pharmacokinetics variants 1) Drug activation and inactivation within the body/cells (a) Variants range from poor metabolizers to ultrarapid metabolizers (b) Knowledge of variant can inform dosage and/or response 2) Drug clearance/excretion from body/cells by conjugation and/or transport 12/12 22 II. PharmGKB E) Pharmacokinetics variants 3) Main genes of interest are: 12/12 (a) Cytochrome P450 (CYPXXX)enzymes involved in molecule oxidation (i) At least 58 different genes in humans (ii) Variants can be loss of function to hyperactive (b) Dihydropyridine dehydrogenase (DPYD) involved in pyrimidine metabolism (i) Cancer drug metabolism (c) Thiopurine S-methytransferase (TPMT) involved in thiopurine metabolism (i) Immunosuppressant drug metabolism (d) Organic acid carriers (OATs or SLCO- Solute Carrier Organic) as membrane uniporters (i) Transport of various drugs in and out of the cell 23 II. PharmGKB E) Pharmacokinetics variants 3) Main genes of interest are: 12/12 24 II. PharmGKB F) Pharmacodynamic variants 1) Loss of function variants for target proteins (a) VKOR for vitamin K activation in relation to warfarin treatment (anticlotting) (b) CFTR can be activated by ivacftor in some CFTR variants responsible for cystic fibrosis 12/12 25 II. PharmGKB F) Pharmacodynamic variants 2) Gain of function variants for target proteins that result in malignant hyperthermia (a) RYR1 gene (ER calcium channel) activated (opened) by certain anesthetics (i) Induces calcium overload in skeletal muscle (b) CACNA1S (Voltage-dependent calcium channel/aka Dihydropyridine receptor) (i) Again, calcium overload of skeletal muscle 12/12 26 II. PharmGKB F) Pharmacodynamic variants 3) Both gain or loss of function for HCV treatment by interferons (a) IFNL3 (interferon lambda 3) gene 4) HLA (human leukocyte antigen) variants involved in antigen presentation associated with hypersensitivity of many drugs (a) Essentially develop immune response to drug through potentially multiple mechanism 12/12 27 II. PharmGKB G) Probably many more out there that have not been genomically characterized but anticipate more as genomics is used to investigate ADRs H) Currently >280 prescription drugs with FDA genetic testing labeling but currently a low level of testing is done (4 – 10% in a somewhat recent study) I) Example data from clinical trial on WGS of patients showing high frequency of variants of pharmacological relevance 1) Seems like this is a no-brainer to implement instead of trial 12/12 and error with patient (do the 28 II. PharmGKB J) PharmGKB knowledge resource 1) Annotate genetic variants and gene-drug-disease relationships via literature review 2) Summarize important pharmacogenomic genes, associations between genetic variants and drugs, and drug pathways 3) Curate FDA drug labels containing pharmacogenomic information 4) Enable consortia examining important questions in pharmacogenomics K) Example of drugs that require genetic testing for abemaciclib L) Example of pharmacodynamics with SGLT2 M)Example of pharmacodynamics with RYR1 12/12 29 Copyright Notice All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subject to copyright protection, and may be restricted from further dissemination, retention or copying. Disclosure I have no financial relationship with a commercial entity producing health-care related products and/or services.