Implementation of Pharmacogenomics in Clinical Medicine in the USA

Transcription

1 Implementation of Pharmacogenomics in Clinical Medicine in the USA Dan M. Roden, MD Senior Vice President for Personalized Medicine Vanderbilt University Medical Center, Nashville, TN

2 The vision "Here's my sequence... New Yorker, 2000 Francis Collins, NEJM 9/16/2009

3 US pharmacogenomic implementation sites Pre-emp4ve Point of care

4 US pharmacogenomic implementation sites Pre-emptive Reactive

5 The vision PREDICT Pharmacogenomic Resource for Enhanced Decisions In Care and Treatment "Here's my sequence... New Yorker, 2000

6 The vision PREDICT Pharmacogenomic Resource for Enhanced Decisions In Care and Treatment "Here's my sequence... New Yorker, Select popula-ons of pa-ents who are at high risk for receiving a drug with a pharmacogene-c story. 2. Genotype them preemp-vely on a pla?orm that assays many pharmacogene-c variants. 3. Store the genotypes, develop the informa-cs tools to provide point-of-care advice. Track outcomes.

7 A Case for Prospective Genotyping Identifying a high risk group 52,942 Vanderbilt Medical Home patients followed for up to 5 years. How many patients received drug(s) that have a recognized pharmacogenetic story? Number of PGx Meds % received 1 med within 5 years Number of PaJents Estimated number of severe adverse events mitigated : 383 Schildcrout et al, CPT 2012

8 Selection of PREDICT Drug-Gene Interactions Evidence Review Guidance: Professional Socie?es, FDA Review and Approval by P&T Committees Implementation including automated decision support Replication in Vanderbilt population (BioVU)

9 Selection of PREDICT Drug-Gene Interactions Evidence Review Guidance: Professional Societies, FDA Review and Approval by P&T Committees Implementation including automated decision support ReplicaCon in Vanderbilt populacon (BioVU)

10 Clopidogrel label revision March 2010 identifies a high risk group

11 Clopidogrel label revision March 2010 identifies a high risk group

12 Genetic data, prediction, and actionability

13 % with death, MI, or stroke CYP2C19 loss of function variants à decreased anti-platelet effect 12 carriers 12.1% 9 8.0% 6 3 non-carriers N=1459, P= days on therapy Hulot et al., 2006 Mega et al., 2009

14 % with death, MI, or stroke CYP2C19 loss of function variants à decreased anti-platelet effect 12 3 carriers non-carriers 6 potentially avert one N=1459, P= days on therapy 12.1% Number needed to 9 genotype to adverse cardiac outcome: % Hulot et al., 2006 Mega et al., 2009

15 % with death, MI, or stroke Clopidogrel adverse events associated with CYP2C19 status in BioVU From clinical trials From the EHR 12 carriers 12.1% Normal metabolizers 9 8.0% 6 3 non-carriers N=1459, P=0.01 Carriers N=807, P= days on therapy Mega et al., 2009 Delaney et al. Clin Pharm Ther. 2012

16 The future is here

17 The future is here

18 cdskb.org a joint project of emerge and IGNITE to share Clinical Decision Support elements

19 CYP2C19 genotypes in 13,423 patients at Vanderbilt University Hospital heterozygous (19.4%) homozygous (2.7%) no variant (*2, *3, *4, *6, *8)

20 CYP2C19 genotypes in 13,423 patients at Vanderbilt University Hospital heterozygous (19.4%) gnomad non-synonymous variants (*2, *3, *4, *6, *8) homozygous (2.7%) 9 with MAF>1% in at least one populacon no variant splice variants (e.g. *2) clinically important

21 Frequency of actionable genotypes in the first 10,000 PREDICT patients At least one high risk variant At least one actionable variant No actionable variants

22 Frequency of actionable genotypes in the first 10,000 PREDICT patients At least one high risk variant 91% At least one actionable variant No actionable variants

23 Patient Notification of Drug Sensitivities

24 Once clinicians get a genotype, do they act on it? Poor Metabolizer Rate Adjusted HR 58% 8.1 (5.4,12.1) Intermediate Metabolizer 33% 5.0 (4.0,6.3) Non-Actionable 8% Ref Peterson, CPT 2016

25 One predictor of switching Cardiologists with >40 subjects genotyped Peterson et al., 2016

26 Major adverse cardiovascular events (MACE) by genotype in the IGNITE network Cavalleri et al., 2017

27 (European) evidence shows PGx improves outcomes Randomized Controlled Trial of PGx vs. Standard of Care Notarangelo et al. JACC 2018

28 Percutaneous Coronary Intervention after recent Acute Coronary Syndrome N=5270 randomize Delayed Genotyping CYP2C19*2, *3, *17 at 1 year Prospective genotyping CYP2C19*2, *3, and *17 Tailor PCI randomize clopidogrel 75 mg/d No CYP2C19*2 and/or *3 CYP2C19*2 and/or *3 clopidogrel 75 mg/d ticagralor 90 mg bid Primary endpoint Major cardiovascular events over1 yr Secondary outcome Major bleeding Primary analysis ~1675 patients with *2/*3 alleles: clopidogrel vs ticagrelor

29 The case of the CETP inhibitor dalcetrapib Schwartz et al, dal-outcomes group, NEJM, 2012

30 A genetic predictor of response to the CETP inhibitor dalcetrapib? dal-outcomes genetic substudy, n=5,749 Supporting evidence from dal-plaque-2 (n=386) changes in CRP and cholesterol efflux studies CETP x ACDY9 mice fed atherogenic dets Tardif et al., 2015

31 Effect of ADCY9 rs genotype on Major Adverse Cardiovascular Events during CETP inhibitor therapy evacetrapib dalcetrapib Nissen et al., 2018

32 The dal-gene trial Recent Acute Coronary Syndrome N=~35,000 genotyping AA ADCY9 genotype N=6000 AG, GG ADCY9 genotypes N=29,000 randomize Dalcetrapib 600 mg/d Placebo Not randomized Major CV events over ~30 months

33 Finding solutions on a national scale: the Precision Medicine Initiative I want the country that eliminated polio and mapped the human genome to lead a new era of medicine - PRESIDENT BARACK OBAMA State of the Union Address, Jan. 20, 2015

34 Major building blocks of the program DATA AND RESEARCH CENTER (DRC) Big data capture, cleaning, curation, & sharing in secure environment Vanderbilt, Verily, Broad Institute BIOBANK Repository for processing, storing, & sharing biosamples (35+M vials) Mayo Clinic PARTICIPANT CENTER Direct volunteer participant enrollment, digital engagement innovation, & consumer health technologies Scripps Research Institute (with multiple partners) PARTICIPANT TECHNOLOGY SYSTEMS CENTER Web & phone-based platforms for participants Vibrent Health HEALTH CARE PROVIDER ORGS (HPOs) Clinical & scientific expertise network, enrollment & retention of participants 30+ regional med centers, FQHCs, VA, future awards to grow network 34 COMMUNICATIONS & ENGAGEMENT Comms, marketing, & design expertise; Engagement coordination & community partners network Wondros, HCM, 4 community partner orgs, future awards to grow network

35 Enrollment began May 7, ,305 consented 61,650 fully enrolled

36 One view of truly personalizing medicine 57yo with DM2, FHx heart disease, échol admitted for chest pain, receives stent Cath, more stents In-stent thrombosis, restent Recath, stent Plavix x 1 year minimum. ASA life long. In-stent thrombosis, restent 9 th admission, 5 th intervention, 9 th stent CYP2C19*2/*2 clopidogrel poor metabolizer January clopidogrel started April December Switched to prasugrel

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38 What happens when we implement? Process outcomes Peterson et al., 2016