Disclosure. Gaps in Knowledge, Competence, Performance, or Patient Outcomes 7/10/2018. Overview. Precision Medicine: Outlive Your Family History

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1 Precision Medicine: Outlive Your Family History Disclosure I have commercial relationships with: Willard H. Dere MD FACP Professor of Internal Medicine June 21, 2018 Shareholder: Amgen, BioMarin, Eli Lilly Former employee: Amgen and Eli Lilly Board of Directors: BioMarin, Mersana Therapeutics, Radius Health, Seres Therapeutics Gaps in Knowledge, Competence, Performance, or Patient Outcomes Gaps in Knowledge, Competence, Performance, or Patient Outcomes Gap: Desired Result: Gap: Desired Result: Role of socio economic, genetic, and environmental influences on overall health are underestimated. Education about the potential ways in which genetic determinants of health can assist a physician in stratifying patients according to risk and implement early prevention or treatment interventions. Pharmacogenomics, resulting in substantial variability in drug levels and response, is not wellappreciated as relevant for appropriate use of medicines. Understand the potential value of pharmacogenomic testing for use of selected medicines. Gaps in Knowledge, Competence, Performance, or Patient Outcomes Gap: The role of genetics in identifying value drug targets is not wellappreciated. Desired Result: Understand the value of identifying gene variants that are thought to cause human disease and which may be valuable in drug discovery. Overview Overview of Health Determinants and Current Shortcomings Utah: UPDB, role of family history in identifying disease causing genes Precision Medicine: All of Us cohort and the multiple facets impacting human health Precision and Public Health: pathway to Precision Public Health Practical applications Pharmacogenomics Genetics and Risk stratification New therapies 1

2 Importance of Behavioral, Genetic, and Social Determinants of Health Schroeder, n engl j med 357;12 september 20, 2007 Where is the Value in Health Care Today? >75% of all U.S. Health Care Spending is Spent on Preventable Conditions ~30% of all U.S. Health Care Spending is Spent on Unnecessary Services Our therapeutic interventions do not provide a uniformly positive benefit risk profile What about efficacy? In randomized controlled clinical trials, 20% to 75% of enrolled participants do not respond to the active treatment. Adverse drug reactions account for up to 100,000 deaths annually in the US, and are the 6 th leading cause of hospitalizations. Spear, et al. Trends Mol Medicine 7: ,

3 Why Precision Medicine? Deeper understanding of genetics and biology: Human Genome Project, NGS, role of epigenetics and environment on phenotypic expression of disease and health Lack of efficacy or effectiveness of current interventions High risk of adverse reactions, particularly in certain patient subsets Inappropriate use of interventions Utah s Gift to the World AN OPPORTUNITY FOR UTAH TO ALLEVIATE GLOBAL SUFFERING THROUGH FAMILIES AND GENETIC SCIENCE Outlive Your Family History: How Utah Innovations Are Advancing Precision Medicine What is the Utah Population Database? World s largest medical genealogy archive founded by Utah leaders for the common good President Gordon B. Hinckley Utah Genealogical Society Governor Scott Matheson There are 100+ Million Unique Lives in the Utah Population Database. Use of the Utah Population Database is regulated by the Resource for Genetic Epidemiology that must approve all research projects with the help of the LDS Church. RESPONSIBLY STEWARDING UPDB DATA ZERO BREACHES How Genetic Discovery Alleviates Suffering Turning Discoveries into Preventions, Treatments and Cures He has his grandfather s nose, his mother s eyes, and his father s heart disease. 3

4 Personalized Health at the University of Utah The Right Patient should get the Right Intervention at the Right Time for the Right Cost. Why now? Precision Medicine Cohort: Overview and Data Flow The Genomic Testing Landscape is Growing Rapidly Differing views about PM Increasing number of genetic tests Across lifespan (preconception to adults) Across continuum (prevention treatment) Whole genome sequencing as tool in clinical and public health practice Increasing public awareness and interest Proliferation of direct to consumer genetic tests Adoption by some healthcare systems Precision Medicine Initiative (AllofUs) NIH Genetic Testing Registry Search January 25, 2018: tests, conditions, genes, and 509 labs 4

5 A Crucial Public Health Role is to Ensure Population Health Benefits of Genomics and Precision Medicine Khoury MJ, JAMA, Identifying applications that are supported by evidence for their use Assessing the population health impact of genomics and precision medicine o Quantifying burden of preventable disease o Assessing Impact of interventions in terms of lives saved, disease prevented or detected earlier o Quantifying and modeling healthcare costs and savings o Assessing barriers and facilitators to implementation o Documenting and addressing health disparities o Assessing Laboratory practice CDC Evidence based Classification of Genomics and Precision Medicine Applications Tiers Dotson WD, et al. Clin Pharmacol Ther Supported by a base of synthesized evidence for implementation in practice Synthesized evidence is insufficient to support routine implementation in practice; may provide information for informed decision making Evidence based recommendations against use, or no relevant synthesized evidence identified; not ready for routine implementation in practice Examples Newborn screening Many pharmacogenomic tests Direct to consumer personal genomic tests Evidence based Genomic Tests Are Available in Practice and Can Save Lives Now! 68 Tier 1 tests, more than half are cancer related 107 Tier 2 tests, many pharmacogenomics Information on guidelines, programs, publications and tools can be searched using the Public Health Genomics Knowledge Base (PHGKB) Intended uses across the lifespan include screening, diagnosis, treatment, prognosis and risk assessment Weekly Update reaches ~70,000 subscribers Selected Tier 1 Genomic Applications Beyond Newborn Screening Hereditary Breast and Ovarian Cancer (BRCA1/2) Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Familial Hypercholesterolemia Collectively Affect ~2 Million People in US and Most Don t know it. Familial Hypercholesterolemia is Common and Undertreated in the United States Prevalence of documented statin and self reported lipid lowering medication use Young and uninsured patients are at the highest risk for under treatment We do an experiment in clinical pharmacology in every patient to whom we give a medicine Bucholz, EM et al. Circulation (in press) 5

6 Mysterious deaths in children Post tonsillectomy / adenoidectomy Two children, recently emigrated from Lebanon Prescribed codeine in customary doses for post op pain Clinical effect: respiratory death from obstructive sleep apnea Why? Codeine Metabolism Pathway Racoosin JA et al. N Engl J Med 2013;368: Cytochrome P450 (CYP) A family of microsomal drug metabolizing enzymes involved in the metabolism of numerous chemically diverse, endogenous and exogenous compounds Usually they function as a terminal oxidase in a multi component electron transfer chain They catalyze many reactions, including: Aromatic (warfarin) Side chain hydroxylation Dealkylation (tamoxifen) Deamination and others Phenytoin First synthesized in 1908 in Germany Approved in Europe in 1937 for antiseizure activity Approved by FDA in Phenytoin TDM Studied since 1950 s Well accepted therapeutic range: mg/l 50% response rate >10 mg/l 80% response rate >15 mg/l; little additional improvement >20 mg/l Seizures can precipitate at >35 mg/l 1981 study (Koch Wester) of patients on 300mg/d 29% in therapeutic range 60% sub therapeutic 11% toxic Phenytoin High pharmacokinetic variability Substrate of CYP2C9 Drug drug interactions common High (>90%) protein binding Extensive metabolism Elimination kinetics can shift from first order to zero order Polypharmacy common Many automated commercial assays available CPIC guideline published in

7 CPIC Phenytoin Guideline CYP450 genetic variation and metabolism TDM is recommended! Ultra rapid metabolizer (UM): multiple copies of normal alleles, promoter variants Normal/ Extensive metabolizer (EM): 2 normal alleles Intermediate metabolizer (IM): 1 decreased function, 1 no function allele Poor metabolizer (PM): 2 no function alleles CYP2C9 PGx Can predict CYP2C9 phenotype Relatively simple gene; many testing options Many common loss of function alleles Allele Caucasian African American Middle Eastern South / Central Asian *2 12.6% 2.3% 13.2% 10.7% *3 7.1% 1.2% 9.3% 10.2% * % 0.07% 0 * % 0 0 *8 0.14% 6.7% 0.5% 0.1% * % 1.4% 0 0.1% Phenytoin TDM at the UU, 2017 Age 0 96 yrs (average 53 yrs) Total number of patients tested ~1000 Range of concentrations wide Negative: 23% (<0.5 mg/l) Therapeutic: 45% of positives Supra therapeutic: 11% (high 58.5 mg/l) Sub therapeutic: 41% of positives No CYP2C9 or HLA B:1502 testing Global Impact of Cardiovascular Disease ~ 17.3 MILLION deaths annually worldwide Annual cost of disease: ~ $863 BILLION LEADING CAUSE of morbidity and mortality worldwide ~ 47,000 fatalities per day High Cholesterol Is a Major Contributor to Cardiovascular Disease Nikolai N. Anitschkow ( ) 7

8 Statins Have a Proven Record of Reducing Cardiovascular Mortality Millions of Patients Cannot Control Their LDL C Goal With Available Treatments 2011 High Cholesterol Market US/EU5/Japan Proportion Alive Simvastatin Placebo Years Since Randomization 265 Million: High Cholesterol Population 95 Million: Drug Treated 45 Million: High Risk* 17 Million: Over 30% Patients Above LDL C Goal Lancet. 1994; 344 (1385). LDL C = low density lipoprotein cholesterol *Coronary heart disease/coronary heart disease risk equivalent or high risk statin intolerant PCSK9, a Protein That Inhibits LDL Cholesterol Clearance Human Genetics Has Helped Us Understand PCSK9 Biology Gain in function genetic mutation High LDL C Loss in function genetic mutation Low LDL C Monoclonal antibody Inhibits PCSK9 Inhibition of PCSK9 results in Lower Cholesterol (LDL C) MoAB blocks PCSK9 LDL R = LDL receptor 8

9 Genetic Revolution The Right Care for the Right Patient At risk for XX: frequent screenings recommended At risk for XX: new drug therapy recommended Alternative SMN2 Messenger RNA (mrna) Splicing as a Target for Small Molecule Therapies 9