osu lesko 6 oct final
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Recent Development in Pharmacogenomics
2011 Personalized Health Care National ConferenceThe Ohio State University Medical CenterColumbus, OhioOctober 6, 2011Lawrence J. LeskoCenter for Pharmacometrics and Systems PharmacologyUniversity of Florida in Lake Nona
What Has Happened?
1. Recent Label Updates2. New Targeted Therapies3. Genomic Trends in
Research4. Recent FDA Activities5. New Education
Approaches
Burden of Drug Safety: Post-Approval Label Updates
Setting ADR RateNumber of Patients
Primary Care 25.1% 1150
Inpatient 14.7% 3675
Hospital Admissions
6.5% 18820
ER Visits 2.5% ?
Source: M. Pirmohamed, Wolfson Center for Personalized Medicine (2011)
Note: 21 drugs withdrawn from market since 2001; 11 drugs had an underlying genetic cause
FDA’s Concept of Safety: To Improve B/R
1. Risk predispositionAbacavir, carbamazepine
2. Failure of intended pharmacologyClopidogrel, panitumamab
3. Refinement of doseWarfarin, tetrabenazine
Source: Issam Zineh, Genomics Group, Office of Clinical Pharmacology, FDA
Risk Predisposition: Causal Pathways and Off-Target Effects
Do Not Touch Any of These
Wires
Safety Biomarker
s
Like trying to find the one loose
wire in this mess of cables
PGx Biomarkers to Refine Dose: Tetrabenazine
FDA approved – treating chorea associated with Huntington’s Disease
Substrate for CYP2D6 – sponsor conducted DDI study in HV with 2D6 inhibitor, paroxetine. Observed 2.4 to 9X increase in AUC for parent and active metabolites. High exposure = QTc increase, depression, suicidality
Dose for CYP2D6 genotypes– derived from PK/PD and exposure with paroxetine: using M/S to estimate lower doses for PMs; no actual clinical studies
Tetrabenazine Strategy: M/S to Integrate Data
Totality of Evidence
Two D/R studies to evaluate QT prolongation50 mg SD AUC 8 msec increase100 mg MD + paroxetine AUC > 50 mg SDConstructed PK/PD relationshipAssume: AUC with paroxetine = AUC in CYP2D6 PMM/S: predict doses among CYP2D6 genotypes
Blueprint For New Label Update of Pimozide
Drugs@FDA, NDA #017473, 27 Sept 2011
Background
Antipsychotic indicated for Tourette’s Syndrome
First approved in 1984: 15 label revisions2002 label warning: DDIs with additive QT prolongationMetabolism: CYP 3A4 and 2D6Contraindications: strong 2D6 inhibitors (paroxetine)CYP2D6 PMs: 150% higher AUC, 62% greater CmaxGenotyping: doses > 4 mg/day (usual=1-2 mg/day)Titration: no earlier than 14 days (usual=every 2 days)
Opportunities: Other CYP2D6 Substrate Candidates
58 commonly prescribed drugs undergo metabolism with CYP2D6; 10% are have high risk of QT prolongation and torsade’s
Analgesics, anticonvulsants, antidepressants (SSRIs and TCAs), antiemtics, antihypertensives, antiestrogens (tamoxifen), antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants and sympathomimeticshttp://www.mayomedicallaboratories.com; http://www.azcert.org;
Leverage Data: Convergence of EMR and Archived Specimens
Clin Pharmacol Ther 2011): 89(3), 379-386
1. Retrospective assessment of known genetics
2. Discovery of new genetic associations3. Prospective application of genetics
Need: hierarchal level of evidence scale for evaluating clinical utility
Apply Tools: Bioinformatics and Quantitative Clinical Pharmacology
Modeling and Clinical Trial Simulation
New Targeted Therapies: Biologics Under Development (50%)
Source: PhRMA (2011)
N = 901
Therapeutic Category
Monoclonal antibodiesInterferonsVaccinesRecombinant proteinsGrowth factorsGene therapiesCell therapiesAntisense
Key Components: Disease Biology and Right Target
Potential For Genomics in NDAs and BLAs: Few Targeted Therapies
FDA CDER Approvals from Jan-Sept 2010 (N = 21)
47%
24%
29%
DiseaseResponseNone
Medline Search: Disease or Medicine + Genetics or Genomics
Translational Successes: Bench to Bedside in 9 Years
Crizotinib (anaplastic lymphoma kinase inhibitor) is approved for advanced NSCLC that expresses the ALK enzyme (5% of patients). All patients must be screened by to identify “responders”. The test is called Vysis ALK break apart FISH test (validated in trial)
2 single arm studies (n=255) with background therapy
Objective response rates: 50-61%60% of NSCLC have 1 of 10 genomic mutations
Two targeted therapiesNo enrollment of biomarker negative subgroupsSensitivity of local assays to detect mutations
Translational Successes: Vemurafenib
Vemurafenib (serine-threonine kinase inhibitor) is approved for metastatic melanoma with BRAFV600E mutation (23-60%). All patients must be screened by a FDA approved test (Cobas 4800 V600 mutation test) to select “responders” (validated in registration trials) 2 single arm studies in naïve (n=337) and prior
treatment (n=132)Objective response rates: 48-52%
ORR standard therapy: 5.5%No enrollment of biomarker negative subgroupsSensitivity of local assays to detect mutations
ROI: Drug Saving Ratio to TestCost (20/1)
Crizotinib price: $9600/monthCopay assistance: $2000/monthALK test price: $250 % of patients with mutation: 5%
http://www.medscape.com/viewarticle/748990, http://www.theoncologypharmacist.com http://knol.google.com/k/plx-4032-plexxikon-roche-melanoma-review#
Vemurafenib price: $9400/monthCopay assistance: call companyBRAFV600E test price: $150% of patients with mutation: 50%
Targeted Cancer Therapies: Growing List
Medicine Target Indication
Crizotinib ALK NSCLC
Vemurafenib BRAF Metastatic Melanoma
Trastuzumab HER2 Breast Cancer
Rituximab CD20 NHL
Gefitinib EGFR NSCLC
Imatinib KIT GIST
Erlotinib EGFR NSCLC
Cetuximab KRAS Colorectal Cancer
Panitumamab KRAS Colorectal Cancer
Bevacizumab VEGF Colorectal Cancer
Trends in Research: GWAS
Holmes et al, BMJ (2011):343:d4953
Asthma Genotype: Step Forward But Not Overwhelming
After 4-8 wks of inhaled glucocorticoids in 4 replication populations (n=936)
Poorest response associated with mutant T allele of the GLCCI1 (OR=2.4 for poor response)
A functional GLCCI1 variant associated with substantial decreases in response to inhaled
glucocorticoids in asthma patients (accounts for ~ 7% of response variability)
Tantisira et al, N Engl J Med (2011); 365:1173-1183
16%
DTC Genetic Testing: Big Issue Is Claims
Stepped up oversight of genetic testing companies
Implicit desire to formally review and approve tests
Concern related to not providing interpretation
Also sidestepping physician involvement Allows patients to interpret on their own
(SNPedia)
1. Carrier status for recessive disease (CF)2. PGx status for CYP gene variants (CYPs)3. Serious disease with genetic component
(AD)
Recent FDA Activities: Major Reorganization
…..clinical pharmacology, pediatrics, personalized medicine, translational medicine, industry and academic experience…..
Hot of the Press
5 October 2011
Build out infrastructure to drive and support PM
Enable rapid development pathway for TT
Improve consistency and clarity to device review process
Recent FDA Guidances
February 2011
DNA Collection
Non-Approved Tests
Evidence
Education: What Part of 2C19 Don’t You Understand?
Guidelines Would Help
Clinical Pharmacogenetics Implementation Consortium
Future Is Promising for PM
“The thing always happens that you really believe in; and the belief in a thing makes it happen.”
Frank Lloyd Wright, US Architect (1869-1959)
