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The Role of Pharmacogenetics in Safety Assessment

The Role of Pharmacogenetics in Safety Assessment. Michael Mosteller, Arlene R. Hughes, Sara H. Hughes, and Matthew R. Nelson. 32 nd Midwest Biopharmaceutical Statistics Workshop Ball State University, May 19, 2009. What is Pharmacogenetics? Some Basic Genetics.

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The Role of Pharmacogenetics in Safety Assessment

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  1. The Role of Pharmacogenetics in Safety Assessment Michael Mosteller, Arlene R. Hughes, Sara H. Hughes, and Matthew R. Nelson 32nd Midwest Biopharmaceutical Statistics Workshop Ball State University, May 19, 2009

  2. What is Pharmacogenetics?Some Basic Genetics U.S. Department of Energy Genome Research Programs: genomics.energy.gov Available at: www.ornl.gov/sci/techresources/Human_Genome/publicat/primer2001/primer11.pdf • Single Nucleotide Polymorphism (SNP) • A single nucleotide polymorphism (SNP) with two sequences that differ at a single position: ATCGC and ATTGC • Allele - Any of two or more alternative DNA sequence patterns that occur at a given location in the genome. • For the SNP above, the possible alleles would be: C and T • Genotype - The alleles present in a particular person at a particular location in the genome. • For the above SNP, the possible genotypes are: C/C, C/T, or T/T • Genetic Markers – Locations in the genome at which people have differing DNA sequences. • Can be used as genetic landmarks (SNPs are an example) • Phenotype – A general term that refers to any non-genetic feature of an organism.

  3. What is Pharmacogenetics?Some Historic Highlights • 1950’s - Drug responses linked to known genetic deficiencies • G6PD deficiency + primaquine = hemolysis • “Pharmacogenetics” proposed in 1959 • 1980’s - Dawn of the molecular genetics/genomics era • The number of genetic markers increased dramatically • “Pharmacogenomics” coined in 1986 • 1990’s - Human Genome Project and the SNP Consortium • More (and more) genetic markers • 2000’s-The HapMap Project • Over 3 million SNPs studied in 270 individuals of European, African, Japanese and Chinese ancestry • 2000’s-Advances in DNA Microarray Genotyping Chips • Rapid, relatively inexpensive, genome-wide genotyping of ~1 million SNPswith commonly occurring alleles. The stage is set to explore the possibilities of pharmacogenetics.

  4. What is Pharmacogenetics?Definition & Essence of a Pharmacogenetic Analysis DNA RNA PROTEIN PHENOTYPE The endpoint can be continuous… …or binary. P = 2 x 10-22 % of Patients with Bilirubin Change > 2 mg/dl 6,7 7,7 6,6 UGT1A1 Genotype (Danoff et al., The Pharmacogenomics Journal (2004) 4, 49–53) 6,6 6,7 7,7 UGT1A1 Genotype (rs3064744) (Adapted from Danoff et al., The Pharmacogenomics Journal (2004) 4, 49–53) • Pharmacogenetics: The study of the influence of genetics (variations in DNA sequence) on drug response. • Statistical Bottom Line:Does a genotype (or allele)have a significant effect on how an individual responds to a drug? Enzymes Cell Surface Receptors Antibodies Medicine ResponseAdverse Reaction Symptoms Abnormal Lab Values

  5. Drug Safety: Key Role in Personalized Medicine • The Vision of Personalized Medicine: • The right medicine to the right patient at the right dose • Optimize the benefit/risk ratio fortheindividual • Reducing safety risk is critical • Lots of collaborative activity…

  6. Drug Safety: A Special Focus for FDA Phase 1 ― SAEC Membership ( 11 ) Spanish DILI EUDRAGENE DILIGEN Top 5 SAEs External Collaborators/Contributors SAE C onsortium • Numerous initiatives to improve drug safety • International Serious Adverse Events Consortium (SAEC) • Formed in 2007, with strategic and scientific support from FDA • Initial projects:Drug induced liver injuryStevens Johnson Syndrome • Future projects underconsideration include: • QT Prolongation • Hypersensitivity Rxn • Rhabdomyolosis • Edema • Renal Failure

  7. A Safety Pharmacogenetics Success Story • HLA-B*5701 status predicts susceptibility to hypersensitivity reaction to abacavir sulfate. • Good uptake into clinical practice; referenced in US product label:

  8. Steps Leading to Full Clinical Implementation of a Safety Pharmacogenetics Association • From Marker Discovery to Clinical Implementation • Discovery of the statistical association • Confirmation of the statistical association • Proposal of a biological hypothesis • Demonstration of clinical utility • Demonstration of generalizability among ethnically diverse patients • Provision of a pharmacogenetic marker test • Demonstration that cost effectiveness is likely • Incorporation of pharmacogenetic information in product label • Education of patients, physicians, regulators, and payers

  9. Abacavir Hypersensitivity Reaction • Abacavir (ABC): Effective HIV medicine • Hypersensitivity reaction (HSR) in 2-9% • Symptoms: Fever, rash, malaise, GI symptoms • Symptoms resolve with permanent discontinuation • Rechallenge can result in a life-threatening or fatal reaction • Effective clinical management program developed • Pharmacogenetics program initiated to improve benefit/risk • Candidate genes (PK and immune) • Genome Scan

  10. Discover An Association • CNA30027, a retrospective case/control study in 100 HSR Cases, 200 Controls • 2001: Unprecedented results seenin an interim analysis of CNA30027 • Association later refined to HLA-B*5701 Based on data in Hetherington, et al., Lancet 2002; 359: 1121–22.

  11. Confirm the Association • Dr. Simon Mallal was also conducting PGx research on ABC HSR • 2001: Mallal et al., independently identified the association between HLA-B*5701 and ABC HSR • Therefore, association was seen in two independent sample sets • Results from a later report: * Martin, et. al, PNAS 2004; 101:4180-4185.

  12. Reasonable Biological Hypothesis Abacavir Aldehyde (ABC Metabolite) B*5701 Biological mechanism not critical for prediction purposes, but… Bolsters evidence provided by other findings Naisbitt DJ, Pirmohamed M, Park BK, Current Allergy and Asthma Reports 2003;3:22-29

  13. Show Clinical Utility is Likely GenotypeResult ABC Hypersensitivity Present Absent True Positive False Positive 17 4 B*5701+ • HSR, screening: 1/227 = 0.4% 227 1 226 True Negative FalseNegative B*5701- • HSR, no screening: 18/248 = 7.3% 248 18 230 Total • No universal criterion for utility • One criterion: AE incidence reduction • Using retrospective data… What if HLA-B*5701+ patients were screened out? • Based on these results Martin et al. (2004) concludedHLA-B*5701 could be useful in reducing HSR incidence

  14. Demonstration of Clinical Utility in a Prospective, Randomized Clinical Trial: PREDICT-1 PREDICT-1: Large, prospective GSK clinical study to assess the utility of HLA-B*5701 screening Compare HSR incidence in Standard ofCare Arm and HLA-B*5701 Screening Arm ABC-containing regimen with HSR monitoring according to Standard of Care (~900) ABC Naïve Subjects(~1800) Exclude Subjects who are B*5701 positive Randomize (1:1) ABC-containing regimen Prospective HLA-B*5701Screening (~900) Enroll Subjects who are B*5701 negative Hughes S, Hughes A and Brothers C et al. PREDICT-1 (CNA106030): The first powered, prospective trial of pharmacogenetic screening to reduce drug adverse events. Pharmaceutical Statistics 2007

  15. PREDICT-1: The First Pharmacogenetic Study of its Kind

  16. PREDICT-1: Primary Study Endpoints • Co-primary endpoints comparisons between study arms of: • Incidence of clinically-suspected ABC HSR • Incidence of immunologically-confirmed ABC HSR • Major symptoms of clinically-suspected hypersensitivity Hetherington S, et al. Clin Ther 2001; 23: 1603-14

  17. PREDICT-1 Incorporated Skin Patch Testing: A tool to refine HSR phenotype Adhesive surface • Research tool used to identify patients with immune-mediated ABC HSR • Requires prior ABC exposure • Phenotype refinement without need for rechallenge 1% abacavir Petrolatum control 10% abacavir Excipient control Phillips et al. AIDS 2002 and 2005 Phillips et al. IAS 2007 Abstract MOPEB001 24-hour reading (48 hour reading)

  18. PREDICT-1: Design & Analysis Details • Sample size of 1806 provided ≥90% power to detect • 50% reduction in clinically suspected HSRs • 80% reduction in immunologically confirmed HSRs • Power for immunologically confirmed HSR endpoint >99%; power for clinically suspected HSR endpoint = 90%  overall study power approx. 90% (>0.99 x 0.90) • Closed test approach for analysis of co-primary nested endpoints (immunologically confirmed HSRs are a subset of clinically suspected HSRs) • if significant reduction in immunologically confirmed HSRs then test for reduction in clinically suspected HSR endpoint • HSR rates compared between study arms using logistic regression, adjusting for randomisation strata and other prognostic factors

  19. PREDICT-1 Key Results: Comparing HSR Rates in PGx Screening Arm versus Standard of Care Arm [1] Odds ratio adjusted for actual strata of race, ART status, introduction of NNRTI and concurrent PI use. [2] Model-based proportions calculated using parameter estimates and subject characteristics in the overall population. ART = Antiretroviral therapy NNRTI = Non-nucleoside reverse transcriptase inhibitor PI = Protease inhibitor

  20. PREDICT-1 Key Results: Test Characteristics for Predicting Immunologically Confirmed HSR Specificity: 794/819 = 96.9% 95% CI (95.5%, 98.0%) Sensitivity: 23/23 = 100% 95% CI (85.2%, 100.0%) PPV: 23/48 = 47.9% 95% CI (33.3%, 62.8%) NPV: 794/794 = 100% 95% CI (99.5%, 100.0%) Calculated using the Standard of Care arm data only

  21. PREDICT-1 Key Results: Covariate Assessment • Clinically suspected HSR was influenced by several covariates • Refined phenotype (patch test confirmed HSR) was independent of these covariates

  22. The SHAPE Study: Are Findings Relevant only to Caucasians? M Saag, et al. Clinical Infectious Diseases 2008; 46:1111-1118.

  23. SHAPE Study Key Results: Frequency of HLA-B*5701 by Patient Subgroups 100% 100% 44% 14% 4% 1% WhiteCS-HSR n=130 WhiteIC-HSR n=42 BlackCS-HSR n=69 WhiteControl n=202 BlackIC-HSR n=5 BlackControl n=206 Percentage of Subjects with HLA-B*5701 (95% CI) 100 • For clinically suspected HSR, the frequency of HLA-B*5701 was lower in Black subjects • For immunologically confirmed HSR, all case individuals carried the HLA-B*5701 allele, regardless of race • The utility of HLA-B*5701 appears to generalize to US Black patients 80 60 40 20 Clinically SuspectedCases ImmunologicallyConfirmedCases AbacavirTolerantControls (Adapted from: M Saag, et al. Clinical Infectious Diseases 2008; 46:1111-1118.)

  24. Develop / Access an Assay for Pharmacogenetic Marker Detection Lai-Goldman & Faruki, Genetics in Medicine 2008; 10: 874-78. • In general, development of laboratory based assays or test kits may be needed • For HLA-B*5701: • HLA typing was widely available for tissue typing purposes • Several centralized clinical laboratories now offer HLA-B*5701 evaluation for abacavir hypersensitivity

  25. Evaluate Cost Effectiveness Hughes, DA, et al., Pharmacogenetics 2004, 14:1–8 • A Cost Effectiveness Analysis of HLA-B*5701 Screening • Results depend on realistic assumptions • Usually, achieving a healthcare benefit comes with a cost • However, under many scenarios, screening with HLA-B*5701was predicted to reduce HSRs and average cost of care (referred to as a “Dominant” outcome)

  26. Educate & Inform Patients, Physicians, Regulators, and Payers • Benefits & limitations of using the pharmacogenetic marker • How to order the marker assay • How to interpret the assay results • For HLA-B*5701 key messages are: • Discontinue abacavir permanently if HSR cannot be ruled out, regardless of the HLA-B*5701 result. • HLA-B*5701 testing should never be performed diagnostically to support a decision to rechallenge with abacavir. • HLA-B*5701 testing must not be used as a screening test after someone has started treatment with abacavir. If a hypersensitivity reaction is suspected abacavir must be immediately and permanently discontinued.

  27. Challenges for Safety Pharmacogenetics • Association of HLA-B*5701 with abacavir hypersensitivity effectively illustrates the potential of pharmacogenetics to improve drug safety, however… • There are many challenges for safety pharmacogenetics: • Limited sample sizes in early clinical development • Very low rates of some serious adverse events • Monitoring safety of newly approved drugs • Acquiring DNA samples from cases • Accurate diagnosis of adverse drug reactions in the presence of symptoms from other causes • Finding causal markers that occur with low frequency • Finding multiple genetic markers contributing to risk of an adverse drug reaction

  28. Questions and Discussion

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