9/23/2014. Wisconsin Association of Physician Assistants October 10, 2014

Transcription

1 Personalized (Precision) Medicine Wisconsin Association of Physician Assistants October 10, 2014 Disclosures I am an employed by Promega Corporation, a Madison based international biotechnology company Promega does not market any of the products mentioned in this presentation, although we do provide components to some of the manufacturers of these diagnostic assays Ashley G. Anderson Jr., MD, MS Chief Medical Officer Promega Corporation Objectives Promega Corporation Look into the future, and appreciate the growing role, and limitless potential, of molecular diagnostics Understand the term personalized medicine Be motivated to read, learn, and become an early adopter of precision diagnostics Appreciate that these bill be big changes, but they may not come fast. 1

2 Personalized medicine Precision medicine The molecular methods that make personalized medicine possible include testing for variations in genes, gene expression, proteins and metabolites as well as new treatments that target molecular mechanisms. Test results are correlated with clinical factors-such such as disease state, prediction of future disease states, drug response, and treatment prognosis-to help physicians individualize treatment for each patient Personalized Medicine Coalition The tests themselves are not necessarily personalized. They are standardized like most other tests The results from these tests are increasingly more predictive of disease states Certain tests are more predictive of responses to specific therapies The net result is a more precise method of assessing disease and response to therapy Key developments in medicine Sterility Antibiotics Eradication of smallpox, and vaccines for polio, diphtheria, rubella, chicken pox, hep A&B Blood banking and transfusion Insulin Medical imaging advances Heart surgery Minimally invasive surgery 2

3 Physical exam /radiographic studies Blood chemistry Biomarkers A objectively measurable indicator of a biologic state or condition Physical exam Pulse, respiration, blood pressure Clinical chemistry Radiology finding Precision medicine is the identification of more sensitive and specific biomarkers. 3

4 A brief review of the genome Basic DNA structure DNA is composed of 3 billion base pairs, A-T or C-G Short sequences of DNA represent genes, each of which may code for one or more proteins Each gene is located on one of the 23 paired chromosomes The genetic information on an entire genome can be placed on one DVD DNA to RNA to proteins Genes & alleles Gene = A stretch of DNA that codes for a polypeptide or RNA chain that has a function in an organism Gene = A locatable region of genomic sequence, corresponding to a unit of inheritance, which is associated with regulatory regions or other functional sequence regions An allele is an area of variation in a gene responsible for variation in some trait. Everyone has a gene for eye color, but different alleles for the specific color. An allele is a variant of, or within a gene. 4

5 Loci and chromosome regions Locus = It is not a gene, but refers to a map position. A locus is a point in the genome, identified by a marker, which can be mapped by some means. It could, for example, be an anonymous non-coding DNA segment Chromosome region: : a genomic region which has been associated with a specific syndrome or phenotype, particularly when there is a possibility that several genes within it may be involved in the phonotype Genes as biomarkers There are 20,000-25,00025,000 protein encoding genes But it s not all about genetics. Epigenetics-Base pairs, genes are turned on/turned off by epigenetic factors So, is your genetic anatomy your destiny? Only partly. Molecular biomarkers Biomarker that gives an indication of risk Diagnostic biomarkers-make make the diagnosis of a specific disease Prognostic biomarkers-show show progression of disease Therapeutic predictive biomarkers-show show the probable effect of a specific treatment on a patient. Drug development and therapeutics 5

6 Personalized medicine paradigm Future Evidence-based Medicine Genomic Diagnosis paradigm Today Trial and error medicine Current state *Blockbuster drugs targeted at broad patent diagnoses *Approximately 50% or more of patients to not have desired therapeutic outcomes *Significant adverse events Broad Population-based Personalized medicine *Drugs targeted at small patient populations *Genomic profiles determine patient segmentation and therapy Improved therapeutic outcomes with fewer adverse events Diagnostic Targeted Therapeutics Narrow- Patient specific One dose fits all vs. personalized medicine approach Source: Personalized Medicine 2009 Future Medicine, Ltd Warfarin sensitivity Antithrombotic effects of warfarin narrow narrow therapeutic index Molecular diagnostics Genetic analysis 2 Million people are placed on warfarin annually in the US. Some individuals are highly sensitive to warfarin Risk of adverse drug events (bleeding) approaches 9.5%, mostly in the first month of therapy. Cost approaches $18.5M/10,000 patients/5 years Many of these individual have polymorphisms in CYP2C9 and/or VKORC1 genetic loci So we should be testing for these allelic variants, but few institutions are. Why? Cancer Infectious disease 6

7 Sequencing the human genome Next gen sequencing Began in The sequence of last chromosome was published in Nature in Goal was to determine the sequence of chemical base pairs that make up human DNA, and identify and map all the genes Human Genome Project (HGP) = $3 Billion dollar project Celera Corporation, using some data from the HGP, sequenced the genome for $300M with commercial aspirations, which caused controversy Very slow, painstaking, expensive Definition: Developed approximately 5 years ago Low cost sequencing-approaching the $1000 genome Very rapid results at significant cost reductions Ion Torrent Illumina (Solexa) sequencing Exome sequencing-looking only at the protein encoding genes in the genome Select for the subset of genes that encode proteins (180,000), or 1% of the genome or 30 million base pairs Mutations in these are much more likely to have severe consequences Next generation sequencing Next generation sequencing 7

8 The $1000 dollar genome Genome Wide Association Study (GWAS) Collect genomic information Analyze information for common genetic variants (alleles) in different individuals to see if they are associated with a trait. Perform SNP analysis to determine the SNPs associated with the disease. SNP= sequence variation within population consisting of a single nucleotide (A,T,C or G) different in individuals First GWA study was performed in 2005, for macular degeneration. Found 2 SNPs with altered allele frequency as contrasted with controls. Genetic testing Carrier screening-screens screens for one copy of a gene mutation Pre-implantation genetic diagnosis (PGD) Avoids selective pregnancy termination Sex discrimination? Ethical issues? Forensic testing Crime Paternity 8

9 Prenatal genomic screening (PGS) Circulating fetal DNA (cfdna) fragments are harvested from the maternal blood stream Costs range from $200-$2500 $2500 (or more) Multiple companies, notably Sequenom, Illumina Illumina s Verifi test has false positive rate of only 0.03% What are the implications of a diagnosis, and how might this impact parent s decisions False positive rates for detection of trisomies 21 and 18 were significantly less than other methods of screening (0.03%) (Test is very specific) Use of cfdna detected all cases of aneuploidy (100% sensitivity) DNA Deletions in chromosome 22 associated with DeGeorge Synd Molecular diagnostics Genetic analysis Cancer Infectious disease 9

10 Breast cancer Myriad Bracanalysis assay for BRCA1 and BRCA2 gene mutations Patients with either mutation have up to an 87% chance of developing breast cancer, and a 44% chance of developing ovarian cancer prior to age 70 Benefits: Increased surveillance for test positive individuals Earlier diagnosis and treatment Cost = $ Competitors tried to offer for less resulting in legal action ultimately confirming Myriad s right to own genes Phenotype to phenotype + genotype Enhanced customization for specific individuals and tumors Companion diagnostics Herceptin (trastuzumab) Companion diagnostics are assays (a test or measurement) intended to assist physicians in making treatment decisions for their patients. They do so by elucidating the efficacy and/or safety of a specific drug or class of drugs for a targeted patient group or sub- groups. Types of diagnostics Test developed after drug comes to market Test developed in conjunction with drug Monoclonal antibody that interferes with the Her2/neu receptor HercepTest Approved by FDA in 2010 as companion diagnostic Identify tumors with over expression of HER2 protein Immunohistochemistry test Dako Corporation manufactures test, while Genentech manufactures the therapeutic Numerous other companies now have companion diagnostic assays for HER2 (Ventana, LTI, Abbott, Biogenex) 10

11 HER2 Oncotype DX Tests surgical samples from breast CA patients for 21 genes to predict probability of recurrence. Genomic Health-Redwood City, CA Marketing began in Jan 2004 Predicts likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer, and has been shown to predict the likelihood of recurrence in ductal carcinoma in situ Cologuard test for colon cancer Madison based molecular diagnostics company Multi-target target test performed on stool samples KRAS mutations Aberrant NDRG4 and BMP3 methylation B-actin Hemoglobin immunoassay Approved by FDA in August % sensitivity to detection of colon CA, 42% sensitivity to detection of pre-cancerous polyps. 66% sensitivity for polyps greater than 2 cm in size 87% specificity (true negative results) How much will it cost? Cologuard How much is that cost spread over a population? What will be the net effect on population health? Does it do a good enough job of detecting adenomas? Does that matter? Should it replace colonoscopy? If not, how should it be used? 11

12 Erbitux (cetuximab) Biobanks Indicated for certain head and neck cancers, along with some types of metastatic colorectal carcinoma Tumors with KRAS mutation negative gene (wild type), along with positive EGFR Companion diagnostic: Therascreen for KRAS, along with Dako EGFR assay Therascreen detects seven somatic mutations of the human KRAS oncogene, using DNA extracted from FFPE slides from colon cancer tissues. Repositories for human biological samples In many cases, known therapeutic courses, with known results, can be studied along with molecular characterization of diseases Used in genome wide association studies Importantly, specimens can be shared across laboratories and disciplines Discovery of many more SNPs associated with diseases Retrieving DNA from slides DNA can be recovered from pathology slides that are fixed in formalin & embedded in paraffin (FFPE slides = formalin fixed, paraffin embedded slides. Molecular Diagnostics Genetic analysis Implication #1: Tissue can be harvested anywhere, and DNA can be recovered from the sample at a later date. Implication #2:= There are billions of slides from patients who were treated for various conditions, and in many cases, we know the outcomes! Cancer Infectious disease 12

13 Identifying bacteria Traditional methods = culture and gram stains Subjective analysis, sometimes difficult to grow bacteria New methods involve sequencing of bacteria (and viruses) for identification purposes Point of care testing The Cephied GeneXpert Sample to answer box, that can be operated with minimal training Very rapid assessment of MRSA & c. difficile (66 minutes or less) Flu virus from 1918 was sequenced from victim s tissues Standard technologies include PCR and microarrays, but mass spectrometry has also been used Point of care testing HPV testing FDA Considerations Over 80% of women are infected with HPV between ages of Duration is usually less than 1 year, with spontaneous resolution Over 100 HPV types, but certain types are more pathologic (16,18,45). Vast majority of women with high-risk HPV types do not develop cancer HPV can t be cultured there there is are molecular tests Digene HC2 High-risk HPV DNA Test (Qiagen) Cervista HPV HR Test (Hologic)* (Uses Invader technology developed in Madison at Third Wave) Cobas 4800 HPV Test (Roche) Implications for surveillance and treatment phenotype of cells vs. HPV status. Plenty of controversy, but bottom line is that co-testing can result in increased screening intervals. Vaccines for prevention of high-risk HPV Development of head and neck cancers- Increasing incidence of HPV related head and neck carcinoma. Why? Better prognosis The primary role of the FDA is to keep our population safe Most molecular tests are laboratory developed tests (LDTs). The FDA does not regulate LDTs they are regulated under the Clinical Laboratory Improvement Act (CLIA). But ultimately, the FDA does have authority over them. The industry is huge compared to the FDA. How can the FDA keep up with the scientific advances in molecular medicine? Should they? 13

14 23 and Me Summary Medicine is changing rapidly there is an explosion of research in the area of molecular diagnostics and targeted therapeutics The way we look at diseases will change dramatically over the next decade The rate of change will be tremendous, and we will need to work hard to keep up with new scientific developments Hang on tight and enjoy the ride! 14

15 Thank you! Ashley G. Anderson Jr, MD, MS Chief Medical Officer Promega Corporation 2800 Woods Hollow Road Madison, WI