Pharmacogenomics & Personalized Medicine: Where Are We …...Precision Medicine in Psychiatry. 7....

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

Rif S. El-Mallakh, MDProfessor and Director

Mood Disorders Research ProgramDepartment of Psychiatry and Behavioral Sciences

University of Louisville School of MedicineLouisville, Kentucky

July 2017 MRC2.CORP.D.00283

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

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Henry A. Nasrallah, MDSydney W. Souers Professor and Chair,

Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO

Editor-in-chiefSchizophrenia Research and Current Psychiatry

© PsychU. All rights reserved.


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 1992.

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).

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Speaker Profiles


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February 2017 MRC2.CORP.X.00129



• 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

Objectives

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Pharmacogenomics in Precision Medicine

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Prendez-Alvarez S and Nemeroff CB. Neurosci Lett. 2016 Oct 13. doi: 10.1016/j.neulet.2016.09.049. [Epub ahead of print.]

Precision Medicine in Psychiatry

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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

• Two important tools of precision medicine are pharmacogenomicsand biomarkers

Environmental Factors

Genetic Variability

Precision Medicine

Clinical Presentation



1. Pharmacogenomics Knowledge Base. PharmGKB FAQs. www.pharmgkb.org/page/faqs. Accessed July 18, 2017.2. Evans WE and Johnson JA. Annu Rev Genomics Hum Genet. 2001;2:9-39.3. Johnson JA et al. Am J Pharmacogenomics. 2001;1:271-281.

• 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 toxicity2

Pharmacogenetics and Pharmacogenomics

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• Much of the early work in pharmacogenetics has focused on the contribution of genetic variability to variations in drug metabolism3



1. Brunton LL et al. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 11th edition (2006); McGraw-Hill.2. Lynch T and Price A. Am Fam Physician. 2007;76:391-396.3. Guengerich FP. Chem Res Toxicol. 2017;30:2-12.4. Ingelman-Sundberg M. Pharmacogenomics J. 2005;5:6-13.

The Cytochrome P450 (CYP450) Family of Enzymes

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Genetic variability in CYP450 enzymes (polymorphisms) influence a patient’s response to a particular drug1

CYP450s are responsible for:

Example:Metabolism of estrogens by

CYP3A43

Example:CYP2D6 metabolizes plant

alkaloids to less toxic compounds4

Production and metabolism of

endogenous compounds2Detoxification of food2 Metabolism of foreign

chemicals2

Example:Drug metabolizing enzymes

contribute to a series of chemical reactions that

increase the water solubility of drugs, allowing for excretion1

CYP450s are an important class of enzymes that catalyze a wide variety of reactions1



Rendic S and Guengerich FP. Chem Res Toxicol. 2015;28:38-42.

• 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

CYP450s and Drug Metabolism

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AKR, aldo-keto reductase; CYP, cytochrome P450; FMO, flavin-containing monooxygenase; MAO, monoamine oxidase.

Enzymes responsible for drug metabolizing reactions

P450 subtype contribution to drug metabolizing reactions

FMO AKR MAO

Other

P450

other

1A2

2C92C19

2D6

3A4

3A5



Drug Metabolism Phenotypes: Cytochrome P450s

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Poor Metabolizers

• Nonfunctional genes1

• Greater risk of adverse effects1

Intermediate Metabolizers

• 1 Functional and 1 nonfunctional1 gene• Increased risk of adverse effects1

Extensive Metabolizers

• 2 Functional wild-type genes1

• Most common phenotype1

Ultra-rapid Metabolizers

• Extra gene copies1,2

• Low response to drug1,2

• Potential risk of high levels of metabolites2

1. El-Mallakh RS et al. Clin Lab Med. 2016;36:507-523.2. Ingelman-Sundberg M and Sim SC. Biochem Biophys Res Commun. 2010;396:90-94.

Phenotypes



1. Lynch T and Price A. Am Fam Physician. 2007;76:391-396.2. Bousman CA et al. BMC Psychiatry, 2017;17:60.3. Ingelman-Sundberg M. Pharmacogenomics J. 2005;5:6-13.

Certain polymorphisms of CYP450 can influence a patient’s response to a particular drug1:• 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 populations2,3:

– The CYP2D6*17 allele, which shows altered substrate affinity, is the most common allele in black Africans, but is absent in Caucasian and Asian populations3

– 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 population5

– 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 allele3

– 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 ethnicities6

Genetic Variability of Cytochrome P450 Drug Metabolism

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4. Clinical Pharmacogenetics Implementation Consortium. Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 update. https://cpicpgx.org/guidelines/guideline-for-tricyclic-antidepressants-and-cyp2d6-and-cyp2c19/. Accessed July 18, 2017.

5. Aklillu E et al. Pharmacogenetics. 2002;12:375-383.6. Beoris M et al. Pharmacogenet Genomics. 2016;26:96-99.

CYP, cytochrome P450.



• 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;36:507-523.

Drug Target and Pharmacogenomics

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SERT, serotonin transporter.Luddington NS et al. Prim Care Companion J Clin Psychiatry, 2009;11(3):93-102.

SERT: “short” vs “long form”

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• A 44-base-pair deletion in the promoter region leads to decreased expression of SERT

“Wild-type” promoter region SERT protein coding region

“Short form” promoter region SERT protein coding region

transcription

transcription

Normal Quantity of SERT

Reduced Quantity of SERT



*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):93-102.2. Durham LK et al. Psychopharmacology (Berl.). 2004;174:525-529.

The “Short-form” SERT Allele

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• 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 treatment1– A slower response to SSRI treatment2:

• 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 cycling1:

• “Short-form” allele was associated with an increased risk of antidepressant-induced mania in patients with bipolar disease1

• Some evidence suggests that identifying the “short-form” allele in patients can be used to guide treatment decisions1



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DISCUSSION



Current Progress and Advances in Precision

Psychiatry

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How often do you use pharmacogenomic testing to guide treatment decisions in your practice?

A. NeverB. RarelyC. SometimesD. All the time

Polling Question

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*Compared with extensive metabolizers.

AE, adverse effect.Rau T et al. Clin Pharmacol Ther. 2004;75:386-393.

• 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*

The Potential Impact of Pharmacogenetic Testing

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*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. 2015,5:47-49.2. Altar CA et al. Mol Neuropsychiatry. 2015;1:145-155.3. Brown LC et al. Clin Ther. 2017;39:592-602.e1.4. Hall-Flavin DK et al. Transl Psychiatry. 2012;2:e172.

• Gene-by-gene testing has shown limited clinical utility1

• 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 in2:• A 2.3-fold increase in the odds of clinical response (P = 0.004)• A 53% greater improvement in depressive symptoms (P = 0.0002)• 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 costs3

• Proved especially effective at reducing costs in the primary care setting

The Potential Impact of Pharmacogenomic Testing

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Prescribing recommendations

HRT2A

CYP2D6, CYPC19, CYP1A2

SLC6A4

Genotype4

algorithm



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 2016.

www.ncbi.nlm.nih.gov/books/NBK326791/. Accessed July 18, 2017.2. Frye MA, Transl Psychiatry, 2015;5:e689.

• While other medical fields utilize clinical examination in combination with biological tests and quantitative measurements, psychiatric diagnosis often relies solely on clinical examination2

Biomarkers in Precision Medicine

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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 survives1

• The FDA-NIH Biomarker Working Group divides biomarkers by clinical use into 7 classes1:

– Diagnostic– Monitoring– Pharmacodynamic / response– Predictive– Prognostic– Safety– Susceptibility / risk



1. www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/ucm535383.htm. Accessed July 18, 2017.

2. www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm. Accessed July 18, 2017.

3. Young JJ et al, Front Pscyhiatry. 2016;7:72.4. Woodruff DB et al. ADHD Atten Def Hyp Disord. 2011;3:265-269.

• Beyond pharmacogenetics, there are no biomarkers qualified by the FDA for use in psychiatry1,2

Biomarkers in Psychiatry: Current Developments

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Class Example in Psychiatry

Diagnostic• Increased blood levels of inflammatory markers (ie, CRP, IL-6, and TNFα) were significantly associated with atypical

depression as compared to typical/melancholic depression3

• Measurement of cellular membrane potential may help diagnose ADHD4 and bipolar disorder5

Monitoring • Blood concentrations of an addictive drug can be used to monitor abstinence and compliance in patients prone to substance abuse6

Pharmacodynamic • Serum BDNF levels are decreased in untreated MDD patients and treatment with antidepressant medications can restore these levels7

Predictive • REM latency was reported to predict response to treatment with certain antidepressants7

• Patients with MDD and high blood CRP levels corresponded to a better response to a TCA than an SSRI8

Prognostic• 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 allele7

• In older patients (≥60 years) with MDD, lower evening cortisol levels predicted poorer course at 2 year follow-up9

Safety • Currently in use: CYP2D6 poor metabolizers have higher than expected plasma concentrations of TCAs when given usual doses2

Susceptibility / risk • Polymorphisms and variable number tandem repeat regions in the serotonin transporter gene were associated with development of MDD7

Examples of Biomarkers Under Investigation or In Use in the Psychiatric Clinic

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):135-139.6. FDA-NIH Biomarker Working Group. BEST (Biomarkers, EndpointS, and other Tools) Resource [Internet]. Silver

Spring (MD). 2016.7. Prendez-Alvarez S et al. Neurosci Lett. 2016 Oct 13. doi: 10.1016/j.neulet.2016.09.049. [Epub ahead of print.]8. Uher R et al. Am J Psychiatry. 2014;171:1278-1286.9. Kabia FM et al. Psychoneuroendocrinology. 2016;63:320-326.



Presence of Cognitive Impairment Severe cognitive deficits across multiple domains are present in schizophrenia, bipolar

disorder, and major depression1

Test Batteries for memory, attention, visuospatial skills, and executive function can aid in diagnosis1

Monitoring of cognitive impairment can be clinically useful, ie, in diagnosis, assessment of illness severity, and to monitor response to treatment2

Presence of Neurological “Soft Signs” (NSS): One meta-analysis found that NSS scores decreased with remission of

psychopathological symptoms of schizophrenia3

This decrease is less pronounced in patients with non-remitting schizophrenia3

Presence of Comorbidities: Physical illnesses can be markers for subsequent psychological disturbances4

Mental health problems can be markers of later physical pathologies4

1. Nasrallah HA. Curr Psychiatr. 2013;13:8-9.2. Nasrallah HA. Curr Psychiatr. 2008;7:16-17.

Clinical Tools in Psychiatry

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• Current clinical assessment of psychiatric disorders is predominantly restricted to evaluating mental and behavioral signs and symptoms1

Physical Assessments Which Can Be Useful in Diagnosis of Psychiatric Conditions

3. Bachmann S et al. Front Psychiatry. 2014;5:185.4. Anisman H and Hayley S. J Psychiatry Neurosci. 2012;37:221-223.



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DISCUSSION



For those who answered “never” or “rarely”: What prevents you from implementing pharmacogenomic or biomarker testing?

A. Reimbursement considerationsB. Lack of sufficient knowledgeC. Need for more clinical trial evidenceD. Lack of standardizationE. I currently use such testing in my practice

Polling Question

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Barriers to Successful Implementation of Precision

Medicine

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1. Gandal MJ et al. Nat Neurosci. 2016;19:1397-1407.2. de Leon J. Acta Neuropsychiatr. 2014;26:327-333.3. Thompson C et al. Psychiatry Res. 2015;226:68-72.4. Perlis RH, World Psychiatry. 2016;15:228-235.5. Bousman CA et al. BMC Psychiatry. 2017;17:60.6. Luzum JA et al. Clin Pharmacol Ther. 2017 Jan 16. doi: 10.1002/cpt.630. [Epub ahead of print].

• Difficulty interpreting how multiple genetic risk factors coalesce to affect disease risk1

• Heterogenous nature of most psychiatric disease2:– 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 investigation2

• According to a survey of psychiatrists, ¾ of respondents agreed that genotyping results should be accompanied by psychoeducation such as genetic counseling3:

– There is a need for physician training on how to interpret and convey complex genetic results4

• Most tools have been developed based on Caucasian populations5:– Design of tests can lead to “false phenotyping” in minority populations5

• Sparsity of data concerning clinical effectiveness:– Few randomized controlled trials6

– Limited analysis of utility and cost effectiveness5

Gaps in Understanding

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CPIC, Clinical Pharmacogenetics Implementation Consortium.1. Luzum JA et al. Clin Pharmacol Ther. 2017 Jan 16. doi: 10.1002/cpt.630. [Epub ahead of print].2. Clinical Pharmacogenetics Implementation Consortium. Guidelines. https://cpicpgx.org/guidelines/. Accessed July 18, 2017.

• Lack of infrastructure and standardization1

• Clinician inexperience1

• 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 metabolism2:• 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 validation1

• Cost and reimbursement considerations1:– Coverage is variable and reimbursement policies may change over time

Barriers to Implementation

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QUESTIONS



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CLOSING



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© 2017 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD

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

Rif S. El-Mallakh, MDProfessor and Director

Mood Disorders Research ProgramDepartment of Psychiatry and Behavioral Sciences

University of Louisville School of MedicineLouisville, Kentucky

July 2017 MRC2.CORP.D.00283

Otsuka Pharmaceutical Development & Commercialization, Inc. Lundbeck, LLC.

32

Henry A. Nasrallah, MDSydney W. Souers Professor and Chair,

Department of Psychiatry and Behavioral Neuroscience, Saint Louis University, St. Louis, MO

Editor-in-chiefSchizophrenia Research and Current Psychiatry

Pharmacogenomics & Personalized Medicine: Where Are We …...Precision Medicine in Psychiatry. 7....

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