Pharmacogenomics & Personalized Medicine: Where Are We Now & Where Are We Going?

Transcription

1 Pharmacogenomics & Personalized Medicine: Where Are We Now & Where Are We Going? Rif S. El-Mallakh, MD Professor and Director Mood Disorders Research Program Department of Psychiatry and Behavioral Sciences University of Louisville School of Medicine Louisville, Kentucky Henry A. Nasrallah, MD Sydney W. Souers Professor and Chair, Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO Editor-in-chief Schizophrenia Research and Current Psychiatry Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. July 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

2 Speaker Profiles Rif El-Mallakh, MD Position: Dr. El-Mallakh is Professor and Director of the Mood Disorders Research Program in the Department of Psychiatry and Behavioral Sciences at the University of Louisville School of Medicine in Louisville, Kentucky. For the past 25 years, Dr. El-Mallakh has focused his research on the pathophysiology of bipolar illness. Dr. El-Mallakh has authored or coauthored over 250 peer-reviewed articles and 2 books. Education: Dr. El-Mallakh received his MD degree from the University of Illinois. He completed a medical internship and an adult psychiatry residency at the University of Connecticut. He spent 3 years as a clinical research fellow at the National Institute of Mental Health (NIMH) and joined the faculty of the Department of Psychiatry at the University of Louisville in Henry A. Nasrallah, MD Position: Dr. Nasrallah is the Sydney W. Souers Professor and Chair of the Department of Psychiatry and Behavioral Neuroscience at Saint Louis University (St. Louis, MO), and he is the Editor-in-Chief of Schizophrenia Research and Current Psychiatry. Education: Dr. Nasrallah earned his MD degree from the American University of Beirut, School of Medicine (Beirut, Lebanon). He completed a psychiatry residency at the University of Rochester Medical Center (Rochester, NY) and a neuroscience research fellowship at the National Institutes of Health (National Institute of Mental Health) Laboratory of Clinical Psychopharmacology (Washington, DC). 2

3 This program was developed with the support of Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. The speakers are compensated contractors of Otsuka Pharmaceutical Development & Commercialization, Inc. 3 advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.

4 PsychU Virtual Forum Rules of Engagement: Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck, LLC. have entered into collaboration with OPEN MINDS, to explore new ways of bringing/increasing awareness around serious mental illness. OPDC/Lundbeck s interaction with OPEN MINDS is through PsychU, an online, non-branded portal dedicated to providing information and resources on important disease state and care delivery topics related to mental illness. One of the methods employed for the sharing of information will be the hosting of virtual fora. Virtual fora conducted by OPDC/Lundbeck are based on the following parameters: When conducting medical dialogue, whether by presentation or debate, OPDC/Lundbeck and/or its paid consultants aim to provide the viewer with information that is accurate, not misleading, scientifically rigorous, and does not promote OPDC/Lundbeck products. No continuing medical education (CME) credits are available for any PsychU program. OPDC/Lundbeck and/or their paid consultants do not expect to be able to answer every question or comment during a PsychU Virtual Forum; however, they will do their best to address important topics and themes that arise. OPDC/Lundbeck and/or their paid consultants are not able to provide clinical advice or answer questions relating to specific patient s condition. Otsuka and Lundbeck employees and contractors should not participate in this program (e.g., submit questions or comments) unless they have received express approval to do so from Otsuka Legal Affairs. OPDC/Lundbeck operate in a highly regulated and scrutinized industry. Therefore, we may not be able to discuss every issue or topic that you are interested in, but we will do our best to communicate openly and directly. The lack of response to certain questions or comments should not be taken as an agreement with the view posed or an admission of any kind. February 2017 MRC2.CORP.X

5 Objectives Define precision medicine and its potential benefits in patient care Review the history and basics of pharmacogenetics and pharmacogenomics Discuss the role of biomarkers in precision medicine Explore current developments in the use of pharmacogenomics and precision medicine in the psychiatric clinic Address gaps in understanding and barriers to the successful implementation of precision medicine 5

6 Pharmacogenomics in Precision Medicine 6

7 Precision Medicine in Psychiatry Precision Medicine: proposes tailoring health care to the individual by integrating data from their genetic makeup, epigenetic modifications, other biomarkers, clinical symptoms, and environmental exposures Goal: combine early diagnosis, targeted therapies, and more accurate prediction of disease susceptibility to reduce morbidity and mortality of psychiatric conditions Environmental Factors Genetic Variability Two important tools of precision medicine are pharmacogenomics and biomarkers Precision Medicine Clinical Presentation Prendez-Alvarez S and Nemeroff CB. Neurosci Lett Oct 13. doi: /j.neulet [Epub ahead of print.] 7

8 Pharmacogenetics and Pharmacogenomics According to the Pharmacogenomics Knowledge Base (PharmGKB.org) 1 : Pharmacogenetics: how variation in a single gene influences an individual s response to a single drug Pharmacogenomics: how all genes influence an individual s response to drugs Both have the potential to identify patients genetically predisposed to not respond to therapy or to develop unacceptable toxicity 2 Much of the early work in pharmacogenetics has focused on the contribution of genetic variability to variations in drug metabolism 3 1. Pharmacogenomics Knowledge Base. PharmGKB FAQs. Accessed July 18, Evans WE and Johnson JA. Annu Rev Genomics Hum Genet. 2001;2: Johnson JA et al. Am J Pharmacogenomics. 2001;1:

9 The Cytochrome P450 (CYP450) Family of Enzymes CYP450s are an important class of enzymes that catalyze a wide variety of reactions 1 CYP450s are responsible for: Production and metabolism of Detoxification of food 2 Metabolism of foreign endogenous compounds 2 chemicals 2 Example: Metabolism of estrogens by CYP3A4 3 Example: CYP2D6 metabolizes plant alkaloids to less toxic compounds 4 Example: Drug metabolizing enzymes contribute to a series of chemical reactions that increase the water solubility of drugs, allowing for excretion 1 Genetic variability in CYP450 enzymes (polymorphisms) influence a patient s response to a particular drug 1 1. Brunton LL et al. Goodman and Gillman s The Pharmacological Basis of Therapeutics. 11 th edition (2006); McGraw-Hill. 2. Lynch T and Price A. Am Fam Physician. 2007;76: Guengerich FP. Chem Res Toxicol. 2017;30: Ingelman-Sundberg M. Pharmacogenomics J. 2005;5:

10 CYP450s and Drug Metabolism CYP450s are responsible for 96% of reactions involved in the metabolism of drugs (marketed and under development): 75% of those reactions are carried out by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 Enzymes responsible for drug metabolizing reactions FMO AKR MAO Other P450 subtype contribution to drug metabolizing reactions 3A5 other 3A4 1A2 P450 2D6 2C19 2C9 AKR, aldo-keto reductase; CYP, cytochrome P450; FMO, flavin-containing monooxygenase; MAO, monoamine oxidase. Rendic S and Guengerich FP. Chem Res Toxicol. 2015;28:

11 Drug Metabolism Phenotypes: Cytochrome P450s Poor Metabolizers Intermediate Metabolizers Nonfunctional genes 1 Greater risk of adverse effects 1 1 Functional and 1 nonfunctional 1 gene Increased risk of adverse effects 1 Phenotypes Extensive Metabolizers 2 Functional wild-type genes 1 Most common phenotype 1 Ultra-rapid Metabolizers Extra gene copies 1,2 Low response to drug 1,2 Potential risk of high levels of metabolites 2 1. El-Mallakh RS et al. Clin Lab Med. 2016;36: Ingelman-Sundberg M and Sim SC. Biochem Biophys Res Commun. 2010;396:

12 Genetic Variability of Cytochrome P450 Drug Metabolism Certain polymorphisms of CYP450 can influence a patient s response to a particular drug 1 : There is large variation in the representation of different alleles in different ethnic populations, which can be viewed as a reflection of foods available for those populations 2,3 : The CYP2D6*17 allele, which shows altered substrate affinity, is the most common allele in black Africans, but is absent in Caucasian and Asian populations 3 The CYP2D6 intermediate metabolizer phenotype is nearly twice as prevalent in African Americans (~13%) than in Caucasians (7%) 4 Ethiopians have a higher frequency of gene duplication (resulting in ultra-rapid metabolism) of CYP2D6 (up to 29%) than the general population 5 51% of Asians have the CYP2D6*10 allele, which generates an unstable enzyme and contributes to an intermediate metabolizer phenotype, while only 1-2% of Caucasians have this allele 3 African Americans are 1.5- to 2.1-fold more likely to have only 1 functional copy of CYP2D6 (poor / intermediate metabolizer) and 1.4- to 3.4-fold higher to have 3 or more copies of CYP2D6 (ultra-rapid metabolizer) compared with other ethnicities 6 CYP, cytochrome P Lynch T and Price A. Am Fam Physician. 2007;76: Bousman CA et al. BMC Psychiatry, 2017;17: Ingelman-Sundberg M. Pharmacogenomics J. 2005;5: Clinical Pharmacogenetics Implementation Consortium. Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 update. and-cyp2c19/. Accessed July 18, Aklillu E et al. Pharmacogenetics. 2002;12: Beoris M et al. Pharmacogenet Genomics. 2016;26:

13 Drug Target and Pharmacogenomics Genetic variations related to disease susceptibility tend to be a much more powerful predictor of response compared with the CYP450 genotype Examples Serotonin transporter Variants associated with poorer response to antidepressants in MDD BDNF Polymorphism associated with more severe depressive illness Catechol-O-methyltransferase Variant associated with poor response to antidepressants Dopamine receptors Variants associated with schizophrenia and antipsychotic response BDNF, brain-derived neurotropic factor; CYP450, cytochrome 450; MDD, major depressive disorder. El-Mallakh RS. Clin Lab Med. 2016;36:

14 SERT: short vs long form A 44-base-pair deletion in the promoter region leads to decreased expression of SERT Normal Quantity of SERT transcription Wild-type promoter region SERT protein coding region transcription Reduced Quantity of SERT Short form promoter region SERT protein coding region SERT, serotonin transporter. Luddington NS et al. Prim Care Companion J Clin Psychiatry, 2009;11(3):

15 The Short-form SERT Allele Patients heterozygous or homozygous for the short-form SERT gene may have: An increased chance of developing depression following significant life adversity* 1 A decreased response to SSRI treatment 1 A slower response to SSRI treatment 2 : In a double-blind, placebo-controlled study in depressed patients aged 60 years (n = 176): Patients with 1 or 2 copies of the short-form allele had a significantly decreased response to an SSRI at week 1 (1.6% vs 16.7%) and week 2 (9.1% vs 34.6%) ǂ There was no difference in response between genotypes by week 8 Patients with bipolar disease who were homozygous for the short-form SERT were more likely to have a history of rapid cycling 1 : Short-form allele was associated with an increased risk of antidepressant-induced mania in patients with bipolar disease 1 Some evidence suggests that identifying the short-form allele in patients can be used to guide treatment decisions 1 *Demonstrated in multiple longitudinal studies. Response measured as Clinical Global Impression Scale - Improvement score of 2. ǂCompared with patients homozygous for the long-form allele. SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor. 1. Luddington NS et al. Prim Care Companion J Clin Psychiatry, 2009;11(3): Durham LK et al. Psychopharmacology (Berl.). 2004;174:

16 DISCUSSION 16

17 Current Progress and Advances in Precision Psychiatry 17

18 Polling Question How often do you use pharmacogenomic testing to guide treatment decisions in your practice? A. Never B. Rarely C. Sometimes D. All the time 18

19 The Potential Impact of Pharmacogenetic Testing In a study that examined whether variations in metabolic capacity translate into clinically important parameters (predisposition to AEs or to be a nonresponder): Genotype was determined in patients at clinical extremes (ie, those with AEs or nonresponders): The poor metabolizer frequency in patients with AEs (n = 28) was 4-fold that of the country s population The ultra-rapid metabolizer frequency in nonresponders (n = 16) was ~5-fold that of the country s population Other studies have demonstrated an increased hospitalization rate in poor metabolizers treated with antidepressants and antipsychotics and an increase in the development of AEs * *Compared with extensive metabolizers. AE, adverse effect. Rau T et al. Clin Pharmacol Ther. 2004;75:

20 The Potential Impact of Pharmacogenomic Testing Gene-by-gene testing has shown limited clinical utility 1 In an analysis of 3 studies * utilizing combinatorial pharmacogenomic test results to inform medication changes for patients with treatment-resistant depression (N = 258), compared to unguided treatment, pharmacogenomic-guided treatment resulted in 2 : A 2.3-fold increase in the odds of clinical response (P = 0.004) A 53% greater improvement in depressive symptoms (P = ) A 1.7-fold relative improvement in response (P = 0.01) A NNT for 1 clinical response above that seen in the unguided group of 6.07 Phenotypes ascribed to any of the single genes failed to predict clinical outcomes Clinical utility analysis: medication decision congruent with testing guidance were reported to save significantly in medication costs 3 Proved especially effective at reducing costs in the primary care setting *8-10 weeks in duration. CYP, cytochrome P450; HRT2A, serotonin receptor 2A; NNT, number needed to treat; SLC6A4, serotonin transporter. 1. Benitez J et al. Appl Transl Genom. 2015,5: Altar CA et al. Mol Neuropsychiatry. 2015;1: Brown LC et al. Clin Ther. 2017;39: e1. 4. Hall-Flavin DK et al. Transl Psychiatry. 2012;2:e172. Genotype 4 CYP2D6, CYPC19, CYP1A2 HRT2A SLC6A4 algorithm Prescribing recommendations 20

21 Biomarkers in Precision Medicine Biomarker: a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Molecular, histologic, radiographic, or physiologic characteristics are types of biomarkers. A biomarker is not an assessment of how a patient feels, functions, or survives 1 While other medical fields utilize clinical examination in combination with biological tests and quantitative measurements, psychiatric diagnosis often relies solely on clinical examination 2 The FDA-NIH Biomarker Working Group divides biomarkers by clinical use into 7 classes 1 : Diagnostic Monitoring Pharmacodynamic / response Predictive Prognostic Safety Susceptibility / risk FDA, Food and Drug Administration; NIH, National Institutes of Health. 1. Food and Drug Administration-National Institutes of Health Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource Accessed July 18, Frye MA, Transl Psychiatry, 2015;5:e

22 Biomarkers in Psychiatry: Current Developments Beyond pharmacogenetics, there are no biomarkers qualified by the FDA for use in psychiatry 1,2 Examples of Biomarkers Under Investigation or In Use in the Psychiatric Clinic Class Diagnostic Monitoring Pharmacodynamic Predictive Prognostic Safety Susceptibility / risk 1. am/biomarkerqualificationprogram/ucm htm. Accessed July 18, Accessed July 18, Young JJ et al, Front Pscyhiatry. 2016;7: Woodruff DB et al. ADHD Atten Def Hyp Disord. 2011;3: Example in Psychiatry Increased blood levels of inflammatory markers (ie, CRP, IL-6, and TNFα) were significantly associated with atypical depression as compared to typical/melancholic depression 3 Measurement of cellular membrane potential may help diagnose ADHD 4 and bipolar disorder 5 Blood concentrations of an addictive drug can be used to monitor abstinence and compliance in patients prone to substance abuse 6 Serum BDNF levels are decreased in untreated MDD patients and treatment with antidepressant medications can restore these levels 7 REM latency was reported to predict response to treatment with certain antidepressants 7 Patients with MDD and high blood CRP levels corresponded to a better response to a TCA than an SSRI 8 Individuals with a copy of the short-form of the SERT promoter polymorphism exhibited more depression and suicidality in relation to stressful life events than did individuals homozygous for the long allele 7 In older patients ( 60 years) with MDD, lower evening cortisol levels predicted poorer course at 2 year follow-up 9 Currently in use: CYP2D6 poor metabolizers have higher than expected plasma concentrations of TCAs when given usual doses 2 Polymorphisms and variable number tandem repeat regions in the serotonin transporter gene were associated with development of MDD 7 BDNF, brain-derived neurotrophic factor; CRP, C-reactive protein; CYP, cytochrome p450; IL-6, interleukin 6; FDA, Food and Drug Administration; MDD, major depressive disorder; REM, rapid eye movements; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TNFα, tumor necrosis factor α. 5. Woodruff DV et al. Ann Clin Psychiatry. 2012;24(2): FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver Spring (MD) Prendez-Alvarez S et al. Neurosci Lett Oct 13. doi: /j.neulet [Epub ahead of print.] 8. Uher R et al. Am J Psychiatry. 2014;171: Kabia FM et al. Psychoneuroendocrinology. 2016;63:

23 Clinical Tools in Psychiatry Current clinical assessment of psychiatric disorders is predominantly restricted to evaluating mental and behavioral signs and symptoms 1 Physical Assessments Which Can Be Useful in Diagnosis of Psychiatric Conditions Presence of Cognitive Impairment Severe cognitive deficits across multiple domains are present in schizophrenia, bipolar disorder, and major depression 1 Test Batteries for memory, attention, visuospatial skills, and executive function can aid in diagnosis 1 Monitoring of cognitive impairment can be clinically useful, ie, in diagnosis, assessment of illness severity, and to monitor response to treatment 2 Presence of Neurological Soft Signs (NSS): One meta-analysis found that NSS scores decreased with remission of psychopathological symptoms of schizophrenia 3 This decrease is less pronounced in patients with non-remitting schizophrenia 3 Presence of Comorbidities: Physical illnesses can be markers for subsequent psychological disturbances 4 Mental health problems can be markers of later physical pathologies 4 1. Nasrallah HA. Curr Psychiatr. 2013;13: Nasrallah HA. Curr Psychiatr. 2008;7: Bachmann S et al. Front Psychiatry. 2014;5: Anisman H and Hayley S. J Psychiatry Neurosci. 2012;37:

24 DISCUSSION 24

25 Polling Question For those who answered never or rarely : What prevents you from implementing pharmacogenomic or biomarker testing? A. Reimbursement considerations B. Lack of sufficient knowledge C. Need for more clinical trial evidence D. Lack of standardization E. I currently use such testing in my practice 25

26 Barriers to Successful Implementation of Precision Medicine 26

27 Gaps in Understanding Difficulty interpreting how multiple genetic risk factors coalesce to affect disease risk 1 Heterogenous nature of most psychiatric disease 2 : Use of sophisticated clinical approaches to subdivide psychiatric syndromes into groups that exhibit a more homogenous response may aid in identification of pharmacogenomic targets for investigation 2 According to a survey of psychiatrists, ¾ of respondents agreed that genotyping results should be accompanied by psychoeducation such as genetic counseling 3 : There is a need for physician training on how to interpret and convey complex genetic results 4 Most tools have been developed based on Caucasian populations 5 : Design of tests can lead to false phenotyping in minority populations 5 Sparsity of data concerning clinical effectiveness: Few randomized controlled trials 6 Limited analysis of utility and cost effectiveness 5 1. Gandal MJ et al. Nat Neurosci. 2016;19: de Leon J. Acta Neuropsychiatr. 2014;26: Thompson C et al. Psychiatry Res. 2015;226: Perlis RH, World Psychiatry. 2016;15: Bousman CA et al. BMC Psychiatry. 2017;17: Luzum JA et al. Clin Pharmacol Ther Jan 16. doi: /cpt.630. [Epub ahead of print]. 27

28 Barriers to Implementation Lack of infrastructure and standardization 1 Clinician inexperience 1 Scarcity of clear and consistent recommendations for testing: As of mid-2017, the CPIC had published pharmacogenetic guidelines for 33 drugs, the majority of which relate to metabolism 2 : 12 guidelines have been released for drugs with psychiatric indications, 6 of which relate to metabolism of tricyclic antidepressants Lack of prospective randomized clinical trials for approach validation 1 Cost and reimbursement considerations 1 : Coverage is variable and reimbursement policies may change over time CPIC, Clinical Pharmacogenetics Implementation Consortium. 1. Luzum JA et al. Clin Pharmacol Ther Jan 16. doi: /cpt.630. [Epub ahead of print]. 2. Clinical Pharmacogenetics Implementation Consortium. Guidelines. Accessed July 18,

29 QUESTIONS 29

30 CLOSING 30

31 Upcoming Virtual Fora* Event Speaker(s) Date Time HEDIS Behavioral Health Measures: An Update From NCQA Junqing Liu, PhD, MSW Emily Morden, MSW Lauren Niles, MPH Tuesday, August 15, :00 pm 1:00 pm EST Suicide Affects Everyone: The Role of the Health Care Professional in Suicide Prevention Christine Moutier, MD Thursday, September 14, :00 pm 1:00 pm EST Innovations in The Criminal Justice System for Individuals with Mental Illness Lawrence G. Brown, JD Dean Barker Thursday, September 28, :00 pm 12:30 pm EST *Register for these programs at 31

32 Pharmacogenomics & Personalized Medicine: Where Are We Now & Where Are We Going? Rif S. El-Mallakh, MD Professor and Director Mood Disorders Research Program Department of Psychiatry and Behavioral Sciences University of Louisville School of Medicine Louisville, Kentucky Henry A. Nasrallah, MD Sydney W. Souers Professor and Chair, Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO Editor-in-chief Schizophrenia Research and Current Psychiatry Otsuka Pharmaceutical Development & Commercialization, Inc Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. July 2017 MRC2.CORP.D advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.