Clinical application of pharmacogenomics

Transcription

1 Clinical application of pharmacogenomics Ching-Lung Cheung, PhD Assistant Professor, Department of Pharmacology and Pharmacy, Centre for Genomic Sciences, HKU

2 Survey on pharmacogenomic knowledge Survey on pharmacogenomic knowledge 1. To evaluate pharmacogenomic knowledge among healthcare professionals 2. Hope to promote the knowledge in PGx among healthcare professionals

3 Learning objectives Learning objectives 1. Understanding the role of pharmacists in PGx 2. Understanding the role of PGx in drug development 3. Understand the use of PGx information and how to explain it

4 Role of pharmacists in pharmacogenomics

5 Role of a Pharmacists Role of a Pharmacists Pharmacists enhance patient care and promote wellness. The bottom line is that pharmacists help patients get well: helping people get the best results from their medications. Help outcomes improve and costs decline when involved in patient care. Are accessible, and are someone people can talk to faceto-face without an appointment. Communicate effectively to evaluate factors that may affect a patient s ability to take a medication. Are the medication specialists on the healthcare team. Work in a wide range of healthcare settings and have flexible hours. Are trained in colleges of pharmacy which are centers of academic excellence, scientific research and innovation. Help people live healthier, better lives. Adopted from American Association of Colleges of Pharmacy

6 Pharmacist s responsibility in PGx Pharmacist s responsibility in PGx promoting the optimal use and timing of pharmacogenomic (PGx) tests; interpreting clinical PGx test results; and educating other pharmacists, fellow health care professionals, patients, and the public about the field of PGx. American Society of Health-System Pharmacists (ASHP) Statement on the Pharmacist s Role in Clinical PGx

7 Educating about PGx Educating about PGx Advocating for the rational and routine use of PGx testing Providing test result interpretation and clinical guidance for return of results to providers and patients Optimizing medication therapy based on PGx test results Educating and providing information on the clinical application of PGx to health professionals, patients, and members of the public. Supporting and participating in research, consortia, and networks that guide and accelerate the application of PGx to clinical practice. American Society of Health-System Pharmacists (ASHP) Statement on the Pharmacist s Role in Clinical PGx

8 Pharmacists Functions Pharmacists Functions All pharmacists should have a basic understanding of PGx in order to provide patient care that incorporates PGx recommendations. Elements of a basic understanding of pharmacogenomics should enable pharmacists to perform the following functions: 1. Recommending or scheduling PGx testing to aid in the process of drug and dosage selection. 2. Communicating PGx-specific drug therapy recommendations to the healthcare team American Society of Health-System Pharmacists (ASHP) Statement on the Pharmacist s Role in Clinical PGx

9 Pharmacists Functions Pharmacists Functions 3. Designing a patient-specific drug and dosage regimen based on the patient s PGx profile that also considers the PK and PD properties of the drug. These factors should be combined in the regimen design along with other pertinent patient-specific factors such as comorbidities, other drug therapy, demographics, and laboratory data to optimize patient outcomes. 4. Educating patients, pharmacists, and other healthcare professionals about PGx principles and appropriate indications for clinical PGx testing, including the cost-effective use of PGx testing American Society of Health-System Pharmacists (ASHP) Statement on the Pharmacist s Role in Clinical PGx

10 Role of PGx in drug development

11 How Much They Cost: R&D Spending Per New Drug How Much They Cost: R&D Spending Per New Drug /matthewherper/2013/08/11/ the-cost-of-inventing-a-newdrug-98-companiesranked/#24fa4b5f2f08

12 Drug development process Drug development process LOWEST success rate ** disease hypothesis and target prediction is difficult Human observational study Programme attrition Cost Pre-clinical development Poor predictive accuracy of preclinical studies Clinical development Definitive target validation experiment (the phase III) is the final step

13 Poor predictive accuracy of preclinical studies Intrinsic limitation Poor predictive accuracy of preclinical studies Cell culture Tissue/ organ Animal model Limited insight on whole organ/ animal function Limited insight on whole animal function Animal-human difference; unreliable disease models Low reproducibility Overestimation of effect size High false discovery rate

14 The RCT is the pivotal drug target validation The RCT is the pivotal drug target validation Patients Randomization Intervention Placebo Target affected Target unaffected Outcome Outcome

15 Importance of RCT in drug development Importance of RCT in drug development Experiment in human - Directly transferable Randomized experiment - Avoid of confounding effect Pre-specified efficacy, and safety outcomes, careful sample size determination - Improved statistical power and hence reduced false discovery rate Drawback: Very costly and time consuming

16 PGx role in drug development PGx role in drug development 1. Identification of drug target 2. Alternatives to RCT 3. Avoidance of severe adverse drug reaction 4. Facilitate the new drug approval

17 Identification of drug target

18 Genetics of common diseases: OP Genetics of common diseases: OP RANKL SOST RANKL: Denosumab SOST: Romosozumab An important tool for therapeutic target identification Cheung CL et al., (2010) Nat Rev Rheumat

19 Romosozumab (AMG 785): Phase II, increase 11.3% in BMD at the LS, vs. 7.1% teriparatide in 12 mths: - Variant effect size r 2 < 1% Denosumab Hong Kong

20 Alternatives to RCT

21 The RCT is the pivotal drug target validation The RCT is the pivotal drug target validation Patients Randomization Intervention Placebo Target affected Target unaffected Outcome Outcome

22 Mendelian Randomization: An alternative to RCT Mendelian Randomization (MR): An alternative to RCT Patients Randomization using genotype Target genotype aa Target genotype Aa Target genotype AA Target modified Target modified a bit Target unmodeified Outcome Outcome Outcome

23 Concepts of MR Concepts of MR Allele per se is a randomizer: owing to random assortment of alleles at meiosis Genotype is functionally relevant to the drug target (or at least a susceptibility locus of the drug target) Genotype affects drug target function and hence affects clinical outcome Causality can be inferred by MR, and provides stronger evidence before expensive trial

24 Assumptions of MR Assumptions of MR Genetic variant (instrument) Exposure Outcome Unmeasured confounders Three assumptions: (1) the genetic marker is associated with the exposure; (2) the genetic marker is independent of the outcome given the exposure and all confounders (measured and unmeasured) of the exposureoutcome association, and (3) the genetic marker is independent of factors (measured and unmeasured) that confound the exposure-outcome relationship.

25 Example of MR statin Example of MR statin HMGCR inhibitor: Statin Patients Randomization using genotype HMGCR (rs12916) Target genotype aa LDL-levels Target genotype Aa LDL-levels Target genotype AA LDL-levels Risk of CHD Risk of CHD Risk of CHD 3-hydroxy- 3-methylglutaryl-coenzyme A reductase (HMGCR) HMGCR (rs12916): LDL-C reduced by 0.07mmol/L CHD risk reduction by 6% Ference et al., J Am Coll Cardiol 2012

26 Importance of MR Importance of MR Using this approach, study found that HDL is not causally related to CVD risk Using MR can identify if a biomarker or a molecule is causally related to a disease outcome Is it a drug target or therapeutic agent

27 Avoidance of ADR: will be discussed

28 Facilitate the new drug approval

29 Bucindolol (gencaro) story Bucindolol (gencaro) story Bucindolol is a non-selective beta blocker with activity at both the β1 and β2 receptor subtypes. It also has activity at the α1 receptor, which confers a mild vasodilative effect, and indirectly at the α2c receptor, which serves to reduce the release of norepinephrine from sympathetic nerve terminals (sympatholytic effect). In 1995, a Phase 3 clinical trial was initiated

30 Bucindolol (gencaro) story Bucindolol (gencaro) story It was originally evaluated for the treatment of heart failure, and when the primary endpoint of the Phase 3 trial did not reach statistical significance the original sponsor (Incara) abandoned development in 1999.?? In 2013, the Company s GencaroTM Investigational New Drug (IND) application for atrial fibrillation (AF) has been accepted by the U.S. (FDA) and is now active (i.e. re-activation of the investigation)

31 Bucindolol (gencaro) story Bucindolol (gencaro) story A subsequent analysis by the academic researchers who ran the trial concluded that certain patients (with genetic marker in the receptors involved in sympathetic stimulation of the heart) have greater benefit from the drug than previously realized. In 2008, ARCA Biopharma submitted an new drug application (NDA) for bucindolol that included the genetic information. In 2009, in a Complete Response Letter, FDA asked for additional, prospectively derived data in the genetically defined subpopulation.

32 Bucindolol (gencaro) story Bucindolol (gencaro) story β1 receptor polymorphism: Arg homozygous JCHF. 2013;1(4):

33 Role of PGx in clinical application

34 PharmGKB PharmGKB

35 Clinical guideline Clinical guideline We encourage reviewing the primary literature and using one s clinical judgment rather than relying solely on recommendations. Lee DH, (2011) Archives Int Med For the 99.9% of healthcare professional who don t adequately review primary literature, a peer-reviewed group of experts review and recommendations would be better.

36 PharmGKB PharmGKB

37 CPIC CPIC Clinical pharmacogenetics implementation consortium 33 CPIC guidelines available

38 ADR ADR ADR: An adverse reaction is a response to a medicinal product which is noxious and unintend. (European Medicines Agency, 2010) Classification: ABCDE Type A: Augmented, predictable, dosedependent, common Type B: Bizarre, unpredicted, idiosyncratic, non-dose-dependent, rare Type C (chronic)/ D (delayed) /E (end-oftreatment)

39 Precision medicine of warfarin usage

40 PGx of type A ADR: Warfarin PGx of type A ADR: Warfarin Warfarin: 1-1.5% of the population (EU) Dose (mg) range per day: Fold variability: 40 Major bleeding incidence: 2.6 per 100 person-years

41 PGx of warfarin PGx of warfarin >30 genes have been implicated in warfarin treatment Variants in CYP2C9 and VKORC1 are robustly associated with warfarin treatment outcomes International normalized ratio (INR) Bleeding events Maintenance dose Jonas and McLeod, 2009

42 Metabolism of warfarin Metabolism of warfarin

43 SNPs of CYP2C9 and VKORC1 in warfarin dose SNPs of CYP2C9 and VKORC1 in warfarin dose VKORC1, -1639G>A polymorphism: Explain 20-35% of variance in warfarin dosage Jonas and McLeod, 2009

44 Is the genetic marker clinically useful? Is the genetic marker clinically useful? A multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism.

45 TTR and INR TTR and INR International Normalized Ratio Time in Therapeutic Range Genotype-guided group: Increased the TTR by approximately 7% (the primary outcome) Reduced over-anticoagulation (INR>4.0) by 69%

46 Time to reach therapeutic INR and stable dose Time to reach therapeutic INR and stable dose Time to Reach Therapeutic INR Time to Reach Stable Dose HR 1.43 (95% CI 1.17, 1.76) P<0.001 HR 1.40 (95% CI 1.12, 1.74) P<0.001 Genotype-guided group: Reduced the time required to reach therapeutic INR by about 28% Improved the time required to reach stable dose by 25%

47 CPIC guideline on warfarin dosing CPIC guideline on warfarin dosing

48 Initiation dose algorithm Initiation dose algorithm The modified version of the IWPC maintenance dose algorithm predicting weekly dose is as follows: Loading dose will be calculated based on the predicted maintenance dose.

49 Clinical question? Clinical question? 1. Would you recommend your patient to have genetic screening before using warfarin? 2. If your patient carries CYP2C9*2, what will you do? 3. How will you explain to the patient or doctor about this PGx result? What is CYP2C9 and VKORC1? Why we need to screen these two genes before using warfarin? What is the advantage compared to the convention approach?

50 Clinical interpretation Clinical interpretation (ANSWER) 1. Up to you indeed, but trial proved that genotypeguided dose is better than conventional approach 2. Predict the dose based on existing algorithm 3. Recommended answer: CYP2C9 drug metabolizing enzyme (PK); VKORC1 is the target of warfarin (PD) Variations in these two genes have been shown to be PGx markers of warfarin, involved in PK and PD, tailor-made dosing Potentially fewer ADR, quicker therapeutic dose, cost-effective?!

51 Precision medicine of hyperthyroidism

52 Genetics of Graves disease Genetics of Graves disease Simmonds MJ (2013) Nat Rev Endo

53 Clinical management of hyperthyroidism Clinical management of hyperthyroidism Antithyroid drug Adapted from NIH website Surgical removal I-131

54 Antithyroid drug Antithyroid drug The thiourea antithyroid drugs (ATDs): Carbimazole (CMZ)/ methimazole (MMI) Propylthiouracil (PTU) have been used >50 years % of patients prescribed ATD develop agranulocytosis Sing Cheung (2017) Pharmacoepi and Drug Saf

55 Risk estimate of drug induced agranulocytosis Risk estimate of drug associated with agranulocytosis The most common associated drug groups were antithyroid drugs (41.9%) in Hong Kong Sing Cheung (2017) Pharmacoepi and Drug Saf

56 ATD induced agranulocytosis ATD induced agranulocytosis Idiosyncratic Severe adverse drug reaction (e.g. SJS/TEN) have a strong genetic basis Genome-wide association study to identify the susceptibility genetic variation of ATDinduced agranulocytosis

57 10 HA hospitals participated 10 HA hospitals participated TMH PMH KWH UCH CMC QEH QMH AKung RH TWEH PYNEH

58 Manhattan plot Manhattan plot Peak = significant signal Cheung CL et al. (2016) Clin Pharmacol Ther

59 Regional association plot of GWAS Near the HLA genes Cheung CL et al. (2016) Clin Pharmacol Ther

60 ATD induced agranulocytosis: Results ATD induced agranulocytosis: Results The presence of the rs is associated with increased risk of ATD-induced agranulocytosis (OR~37-52) rs is a marker of HLA-B* HLA-B* is associated with CMZ/MMIinduced agranulocytosis (OR=265.5) Cheung CL et al. (2016) Clin Pharmacol Ther

61 # needed to screen to prevent one case # needed to screen to prevent one case 211 patients need to be screened to prevent one case

62 Is it clinically useful? Is it clinically useful? The prediction accuracy of HLA-B*38:02:01: The sensitivity and specificity in predicting CMZ/MMI-induced agranulocytosis was 94.7% (95% CI: %) and 93.2% (95% CI: %) The positive and negative predictive values were 0.07 and The posterior probability of having agranulocytosis after screening was 7.3% for the HLA-B*38:02:01 carrier and 0.028% for HLA-B*38:02:01 non-carrier. Cheung CL et al. (2016) Clin Pharmacol Ther

63 Clinical question? Clinical question? 1. Would you recommend your patient to have genetic screening before using carbimazole? 2. If your patient carries HLA-B*38:02, would you use carbimazole in your patient? 3. How will you explain to your patient about this PGx result? What is HLA? What is the risk in developing agranulocytosis? Whats the consequence of taking carbimazole?

64 Clinical interpretation Clinical interpretation (ANSWER) 1. Up to you indeed, but literature suggests that people carry HLA-B*38:02 will increase chance of having carbimazole-induced agranulocytosis 2. No guideline, safeguard No~ use PTU; otherwise the patient is advised to be careful of infection related symptoms, such as fever, sore throat 3. Recommended answer: HLA: antigen presentation; autoimmunity; 7% Have a HIGHER chance of having agranulocytosis, a potentially lethal ADR

65 Free screening service Free screening service Acknowledgement: SK Yee Medical Foundation

66 Thyrotoxic periodic paralysis Thyrotoxic periodic paralysis (TPP) TPP is a complication of thyrotoxicosis Acute condition acute flaccid paralysis Due to hypokalemia Untreated TPP is life-threatening, due to respiratory muscle paralysis or cardiac arrhythmia In Chinese, TPP occurs in up to 13% of male thyrotoxic patients

67 Regional association plot of TPP GWAS Regional association plot of TPP GWAS Mutation of KCNJ2 gene leads to Andersen-Tawil syndrome, which is characterised with periodic paralysis Cheung CL et al. (2012) Nat Genet

68 Association result of TPP GWAS Association result of TPP GWAS rs is associated with TPP with an OR of 3.8 (95% CI: ) Other 3 genetic variations are markers of rs Cheung CL et al. (2012) Nat Genet

69 Is it clinically useful? Is it clinically useful? AUC: 0.73 (95% CI: ) Sensitivity of 57.9% (95% CI %) Specificity of 79.3% (95% CI %) TPP has a prevalence of 13% (1:8 ratio) among male Graves disease patients: Carrier: post-test probability of 29.4% (approximately 1:3) Non-carrier: post-test probability of 7.33% (1:14 ratio). Cheung CL et al. (2012) Nat Genet

70 Precision medicine of hyperthyroidism Precision medicine of hyperthyroidism Antithyroid drug Adapted from NIH website Genetics is important Thyrotoxic periodic paralysis

71 Metabolic phenotype

72 Metabolic phenotype Metabolic phenotype Metabolic phenotype: determined by the drug metabolizing enzyme activity Affected by genetic variation

73 Metabolic phenotype Metabolic phenotype

74 CYP2D6 functionality table CYP2D6 functionality table

75 Take home message

76 Learning objectives Learning objectives 1. Understanding the role of pharmacists in PGx 2. Understanding the role of PGx in drug development 3. Understand the use of PGx information and how to explain it

77 Next Seminar Next seminar 18 Mar (Sat) 14:30-15:30 OR Mar (Wed) 19:30-20:30

78 AppointMed Mobile APP AppointMed Mobile APP A FREE mobile APP of PGx PGx database Regularly update Clinical recommendation from FDA and Clinical Pharmacogenetics Implementation Consortium (CPIC) Supported by HKU KE Fund

79 Thank you Thank you Q and A Comments?