Sales Trainer for PGXL Laboratories 502-836-3361 Kim Dolan Sales Trainer for PGXL Laboratories 502-836-3361

The Human Genome © 2009 - 2014 PGXL Laboratories

Human Genome Research Initiative “As important a breakthrough as understanding human anatomy” Francis Collins, Director National Institutes of Health Goals Determine the sequence of chemical pairs that make up Human DNA Identify and map the 25,000 genes and 3.1 million base pairs of the human genome from a physical and functional standpoint Understand genes and how they work to understand how diseases are caused and how best to cure them Switch from reacting to a disease to prevention

Evolution of Pharmacogenetics PGXL Founders Are Pioneers in the Field 1988 – International Human Genome Initiative (HGRI) launched 1989 – Dr. Roland Valdes launches post-PhD Molecular Clinical Chemistry program 1993 – Dr. Francis Collins assumes leadership of HGRI 1997 – Dr. Valdes and Dr. Mark Linder publish seminal pharmacogenetics paper Continued…

Evolution of Pharmacogenetics PGXL Founders Are Pioneers in the Field 2001 – PGXL Laboratories is first CLIA-certified pharmacogenetics specialist in U.S. 2004 – Human genome sequenced and published 2010 – Drs. Valdes and Linder publish guidelines for operating a pharmacogenetics laboratory …Continued

Pharmacogenetics Why It Matters There can be wide variability in patient response to commonly prescribed medications Genetics is estimated to account for 20-95% of the variability in drug effects Adverse Drug Reactions (ADRs) are the 6th leading cause of death A review of drugs most commonly associated with ADRs found that 57% (16 of 27) were metabolized by a gene with a known genetic polymorphism

Current Situation/Implications 57% of meds in top 20 list causing ADRs are linked to a genetic variation 20-90% variability in patient response to medications can be explained by genetics >120 drugs have FDA box warnings related to genetics Lazarou et al. JAMA 1998; 279:1200-1205; Phillips KA et al JAMA 2001;286:2270-2279; Kalow W et al. Pharmacogenetics 1998;8:283-289

Pharmacogenetics Same Diagnosis, Same Medications, Different Outcomes Typical Clinic Day N=30 No Variance Normal Response Variance Risk Decreased Variance Lack of Efficacy Variance High Risk

Pharmacogenetics The Study of How Our Genes Affect Our Response to Drugs Every human has a genetic code that is unique to them There is no perfect version of the code; we all have variants Variances in genes responsible for drug metabolism, transport and uptake/binding can: Be of no consequence to the drug’s safety and efficacy Render a medication useless Result in a medication causing serious adverse reactions

Incidence of Genetic Variants Important to Drug Selection and Drug Dose % of Extensive Metabolizers % of Intermediate Metabolizers % of Poor Metabolizers % of Ultra-Rapid Metabolizers VARIANTS 2D6 53% 35% 10% 2% 47% 2C19 36% 32% 4% 28% 64% 2C9 57% 40% 3% NA 43% VKOR >70% 3A4 87% 12% 1% N/A 13% 3A5 18% 81% 99% SLC6A4 25% 50% 75% 1. Pharmacogenetics Knowledge Base Implementation: www.pharmgkb.org Property of PGxl Laboratories

Leading ADRs resulting in hospitalizations Drug group/drug No (%) of cases Individual drugs Adverse reactions NSAIDs 363 (29.6) Aspirin (218), diclofenac (52), ibuprofen (34), rofecoxib (33), celecoxib (8), ketoprofen (6) naproxen (5) GI bleeding, peptic ulceration, haemorrhagic cerebrovascular accident, renal impairment, wheezing, rash Diuretics 334 (27.3) Furosemide (128), bendroflumethiazide (103), bumetanide (43), spironolactone (37), amiloride (19), metolazone (11), indapamide (6) Renal impairment, hypotension, electrolyte disturbances, gout Warfarin 129 (10.5) — GI bleeding, haematuria, high INR, haematoma ACE inhibitors/All receptor antagonists 94 (7.7) Ramipril (28), enalaparil (25), captopril (12), lisinopril (9), irbesartan (6), losartan (5), perindopril (4) Renal impairment, hypotension, electrolyte disturbance, angioedema Antidepressants 87 (7.1) Fluoxetine (17), paroxetine (14), amitriptyline (13), citalopram (9), lithium (8), venlafaxine (8) dosulepin (7) Confusion, hypotension, constipation, GI bleed, hyponataemia β blockers 83 (6.8) Atenolol (69), propranolol (6), sotalol (3), bisoprolol (2), metoprolol (2), carvedilol (1) Bradycardia, heart block, hypotension, wheezing Opiates 73 (6.0) Morphine (20), dihydrocodeine (20), co-codamol (8), tramadol (8), co-dydramol (6), fentanyl (5) Constipation, vomiting, confusion, urinary retention Digoxin 36 (2.9) Symptomatic toxic digoxin levels Prednisolone 31 (2.5) Gastritis, GI bleeding, hyperglycaemia, osteoporotic fracture Clopidogrel 29 (2.4) GI bleeding Pirmohamed et al. BMJ 2004;329(7456):15–9.

State-of-the-Art -- 2014 Cardiovascular Behavioral Health Benefits of Molecular PGx Guided Therapy Decision Making Behavioral Health Treatment Resistant Depression Schizophrenia Cardiovascular Anti-Platelet Activation Anti-Coagulation Pain Management Opioids Patient Improvement Cost Savings Patient Satisfaction & Compliance Risk Reduction

CIPHER™ strength of evidence CV Antiplatelet therapy Anticoagulation management Hyperlipidemia Hypertension/arrhythmia Pain Opioids NSAIDs Muscle relaxants Behavioral Health Treatment-resistant depression (TRD) Psychosis ADHD Internal Med/GP Antithrombotic therapies CV health (arrhythmia, lipids, stroke) Chronic pain management Type II diabetes management GU health Antimicrobials Multidrug sensitivity Oncology (under development) Colorectal cancer (KRAS, BRAF, Lynch) Breast cancer (tamoxifen) Lung Cancer (EGFR, etc) Property of PGxl Laboratories

Personalized Medicine Program PM Program Core Team Creation PGxl & Client Project Planning Meeting Schedule Design Program Launch and Support Program Track and Modify Program