1. Recent Development in Pharmacogenomics 2011 Personalized Health Care National ConferenceThe Ohio State University Medical CenterColumbus, OhioOctober 6, 2011 Lawrence J. LeskoCenter for Pharmacometrics and Systems PharmacologyUniversity of Florida in Lake Nona
2. What Has Happened? Recent Label Updates New Targeted Therapies Genomic Trends in Research Recent FDA Activities New Education Approaches
3. Burden of Drug Safety: Post-Approval Label Updates Note: 21 drugs withdrawn from market since 2001; 11 drugs had an underlying genetic cause Source: M. Pirmohamed, Wolfson Center for Personalized Medicine (2011)
4. FDA’s Concept of Safety: To Improve B/R Risk predispositionAbacavir, carbamazepine Failure of intended pharmacologyClopidogrel, panitumamab Refinement of doseWarfarin, tetrabenazine Source: Issam Zineh, Genomics Group, Office of Clinical Pharmacology, FDA
5. Risk Predisposition: Causal Pathways and Off-Target Effects Do Not Touch Any of These Wires Safety Biomarkers Like trying to find the one loose wire in this mess of cables
6. PGx Biomarkers to Refine Dose: Tetrabenazine FDA approved – treating chorea associated with Huntington’s DiseaseSubstrate 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
7. Tetrabenazine Strategy: M/S to Integrate Data Totality of EvidenceTwo 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
8. Blueprint For New Label Update of Pimozide BackgroundAntipsychotic indicated for Tourette’s SyndromeFirst approved in 1984: 15 label revisions 2002 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) Drugs@FDA, NDA #017473, 27 Sept 2011
9. Opportunities: Other CYP2D6 Substrate Candidates 58 commonly prescribed drugs undergo metabolism with CYP2D6; 10% are have high risk of QT prolongation and torsade’sAnalgesics, anticonvulsants, antidepressants (SSRIs and TCAs), antiemtics, antihypertensives, antiestrogens (tamoxifen), antineoplastics, antipsychotics, antiretrovirals, antitussives, beta-blockers, cardioactive drugs, H-2 blockers, stimulants and sympathomimetics http://www.mayomedicallaboratories.com; http://www.azcert.org;
10. Leverage Data: Convergence of EMR and Archived Specimens Retrospective assessment of known genetics Discovery of new genetic associations Prospective application of genetics Need: hierarchal level of evidence scale for evaluating clinical utility Clin Pharmacol Ther 2011): 89(3), 379-386
11. Apply Tools: Bioinformatics and Quantitative Clinical Pharmacology Modeling and Clinical Trial Simulation
12. New Targeted Therapies: Biologics Under Development (50%) Therapeutic Category Monoclonal antibodiesInterferonsVaccinesRecombinant proteinsGrowth factorsGene therapiesCell therapiesAntisense N = 901 Source: PhRMA (2011)
14. Potential For Genomics in NDAs and BLAs: Few Targeted Therapies 29% Disease 47% Response None 24% FDA CDER Approvals from Jan-Sept 2010 (N = 21) Medline Search: Disease or Medicine + Genetics or Genomics
15. 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 mutationsTwo targeted therapies No enrollment of biomarker negative subgroupsSensitivity of local assays to detect mutations
16. 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
17. ROI: Drug Saving Ratio to TestCost (20/1) Crizotinib price: $9600/month Copay assistance: $2000/month ALK test price: $250 % of patients with mutation: 5% Vemurafenib price: $9400/month Copay assistance: call company BRAFV600E test price: $150 % of patients with mutation: 50% http://www.medscape.com/viewarticle/748990, http://www.theoncologypharmacist.com http://knol.google.com/k/plx-4032-plexxikon-roche-melanoma-review#
20. 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) 16% 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
26. Hot of the Press 5 October 2011Build out infrastructure to drive and support PMEnable rapid development pathway for TTImprove consistency and clarity to device review process
34. 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)
35. Thank you for your time and attention llesko@cop.ufl.edu
Editor's Notes
XENAZINE is a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington’s disease. (1
Dopamine blocker.Control severe tics. 2nd line therapy. PD effect; phenothiazines, TCA and class IA and III antiarrythmics and macrolide antibiotics
Health-care information technology and genotyping technology are both advancing rapidly, creating new opportunitiesfor medical and scientific discovery. The convergence of these two technologies is now facilitating genetic associationstudies of unprecedented size within the context of routine clinical care. As a result, the medical community willsoon be presented with a number of novel opportunities to bring functional genomics to the bedside in the area ofpharmacotherapy. By linking biological material to comprehensive medical records, large multi-institutional biobanksare now poised to advance the field of pharmacogenomics through three distinct mechanisms: (i) retrospectiveassessment of previously known findings in a clinical practice-based setting, (ii) discovery of new associations in hugeobservational cohorts, and (iii) prospective application in a setting capable of providing real-
SLE, RA and MS. HIV, anthrax, TB, viral, hepatitis C
The US Food and Drug Administration (FDA) has approved Vemurafenib (Zelboraf®) for the treatment of BRAF V600 mutation positive metastatic melanoma. The data from a Phase III trial (BRIM3) showed that at 6 months, overall survival for patients treated with Vemurefenib was 84%, with 63% reduction in risk of death compared to chemotherapy (Dacarbazine). Vemurafenib also increased the progression-free survival by 74% compared to chemotherapy. 9 YEARS BENCH TO BEDSIDESomatic mutations.
The US Food and Drug Administration (FDA) has approved Vemurafenib (Zelboraf®) for the treatment of BRAF V600 mutation positive metastatic melanoma. The data from a Phase III trial (BRIM3) showed that at 6 months, overall survival for patients treated with Vemurefenib was 84%, with 63% reduction in risk of death compared to chemotherapy (Dacarbazine). Vemurafenib also increased the progression-free survival by 74% compared to chemotherapy. 9 YEARS BENCH TO BEDSIDESomatic mutations.
"The Abbott ALK FISH test was developed in conjunction with Pfizer and the clinical trials for crizotinib," said Kathryn B. Becker, PhD, director of Abbott Molecular Oncology. "It was configured to work specifically in NSCLC patients, and we have ensured that it is a very high-quality product that is reproducible.“The FDA approved Zelboraf on 17 August 20111 for the treatment of late stage metastatic melanoma. EMA approval is expected soon in 2011. Zelboraf cost will be $9400 per month, $ 56000 for 6 months and $ 112000 for 1 year treatment in line with cost of Yervoy. Sales in 2011 are projected at $150 million and peak sales 3 billion within 5 years of approvals in major markets. Only a single new investigation drug has produced a 81% response rate and extended overall survival by 7 months (range 2-18 months) in a Phase I trials in advanced melanoma. Joint pain, rash, hair loss, fatigue, nausea, and skin sensitivity when exposed to the sun were the most common side effects reported in patients receiving vemurafenib. Due to the fact that about 26% of patients developed the skin-related cancer, cutaneous squamous cell carcinoma (which was managed with surgery), patients treated with vemurafenib should avoid sun exposure.
How does oncologist properly identify subsets of disease and whether or not a patient has a good chance to truly benefit from treatments
Changes in FEV1 With Treatment According to rs37972 Genotype
CF, 2C9 and AD or Huntington’s. Genetically relevant data there but not reported out. SNPedia. Claims For Clinical Genetic Tests: Glimpse Into the Future
What part of 2C19 don’t you understand?
ur knowledge regarding genetic factors that affect drug effectiveness and adverse drug reactions is continuously increasing, and a growing number of pharmacogenetic gene–drug interactions are included in drug labels. Nevertheless, the uptake of this important information into clinical practice has been minimal. The development of concise, evidence-based clinical practice guidelines (CPGs) on pharmacogenetic testing is urgently needed to overcome the barriers hindering clinical implementation by providing guidance on test use and interpretation.
