The Role of Pharmacogenetics in Safety Assessment

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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
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What is Pharmacogenetics?Some Basic Genetics

• 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.

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What is Pharmacogenetics?Some Historic Highlights

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

The stage is set to explore the possibilities of
pharmacogenetics.
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What is Pharmacogenetics?Definition Essence of
a Pharmacogenetic Analysis

• Pharmacogenetics The study of the influence of
  genetics (variations in DNA sequence) on drug
  response.
• Statistical Bottom LineDoes 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
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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 for the
  individual
• Reducing safety risk is critical
• Lots of collaborative activity

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Drug Safety A Special Focus for FDA

• Numerous initiatives to improve drug safety
• International Serious Adverse Events Consortium
  (SAEC)
• Formed in 2007, with strategic and scientific
  support from FDA
• Initial projectsDrug induced liver
  injuryStevens Johnson Syndrome
• Future projects underconsideration include
• QT Prolongation
• Hypersensitivity Rxn
• Rhabdomyolosis
• Edema
• Renal Failure

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A Safety Pharmacogenetics Success Story

• HLA-B5701 status predicts susceptibility to
  hypersensitivity reaction to abacavir sulfate.
• Good uptake into clinical practice referenced in
  US product label

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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

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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

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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-B5701

Based on data in Hetherington, et al., Lancet
2002 359 112122.
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Confirm the Association

• Dr. Simon Mallal was also conducting PGx research
  on ABC HSR
• 2001 Mallal et al., independently identified the
  association between HLA-B5701 and ABC HSR
• Therefore, association was seen in two
  independent sample sets
• Results from a later report

Western Australian HIV Cohort Study Western Australian HIV Cohort Study Western Australian HIV Cohort Study
HSR No HSR
B5701 17 4
B5701- 1 226
Sensitivity94 Specificity98
Martin, et. al, PNAS 2004 1014180-4185.
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Reasonable Biological Hypothesis

• 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 2003322-29
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Show Clinical Utility is Likely

• No universal criterion for utility
• One criterion AE incidence reduction
• Using retrospective data

• What if HLA-B5701 patients were screened out?

• Based on these results Martin et al. (2004)
  concludedHLA-B5701 could be useful in reducing
  HSR incidence

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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-B5701 screening
• Compare HSR incidence in Standard ofCare Arm and
  HLA-B5701 Screening Arm

ABC-containing regimen with HSR monitoring
according to Standard of Care (900)
ABC Naïve Subjects(1800)
Exclude Subjects who are B5701 positive
Randomize (11)
ABC-containing regimen Prospective HLA-B5701
Screening (900)
Enroll Subjects who are B5701 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
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PREDICT-1 The First Pharmacogenetic Study of
its Kind
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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
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PREDICT-1 Incorporated Skin Patch Testing A
tool to refine HSR phenotype
Adhesive surface
1 abacavir
Petrolatum control
10 abacavir
Excipient control

• Research tool used to identify patients with
  immune-mediated ABC HSR
• Requires prior ABC exposure
• Phenotype refinement without need for rechallenge

Phillips et al. AIDS 2002 and 2005 Phillips et
al. IAS 2007 Abstract MOPEB001
24-hour reading
(48 hour reading)
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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
  gt99 power for clinically suspected HSR endpoint
  90
• ? overall study power approx. 90 (gt0.99 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

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PREDICT-1 Key Results Comparing HSR Rates in PGx
Screening Arm versus Standard of Care Arm
Prospective Screen Evaluable N802 Standard of Care Evaluable N842
Immunologically Confirmed HSR 0/802 (0) 23/842 (2.7)
Statistical Results Exact Odds Ratio1 (95CI) 0.03 (0.00, 0.18) P-value plt0.0001 Exact Odds Ratio1 (95CI) 0.03 (0.00, 0.18) P-value plt0.0001
Evaluable N803 Evaluable N847
Clinically Suspected HSR 27/803 (3.4) 66/847 (7.8)
Model Based Proportions 2 3.3 7.9
Statistical Results Odds Ratio1 (95CI) 0.40 (0.25, 0.62) P-value plt0.0001 Odds Ratio1 (95CI) 0.40 (0.25, 0.62) P-value plt0.0001

• 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

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PREDICT-1 Key Results Test Characteristics for
Predicting Immunologically Confirmed HSR
Immunologically Confirmed HSR No Immunologically Confirmed HSR Total
HLA-B5701 Positive 23 25 48
HLA-B5701 Negative 0 794 794
Total 23 819 842

• 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

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PREDICT-1 Key Results Covariate Assessment
Model Covariates Immunologically Confirmed HSR Clinically Suspected HSR
Prospective Screen Arm vs. Standard of Care Arm p lt 0.0001 p lt 0.0001
White vs. Non-White p 0.11 p 0.02
ART Naive vs. ART Experienced p 0.66 p 0.26
Introduction of NNRTI (Yes vs. No) p 0.57 p 0.001
Concurrent PI Use (Yes vs. No) p 0.91 p 0.009

• Clinically suspected HSR was influenced by
  several covariates
• Refined phenotype (patch test confirmed HSR) was
  independent of these covariates

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The SHAPE Study Are Findings Relevant only to
Caucasians?
M Saag, et al. Clinical Infectious Diseases
2008 461111-1118.
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SHAPE Study Key Results Frequency of HLA-B5701
by Patient Subgroups
Percentage of Subjects with HLA-B5701 (95 CI)
100

• For clinically suspected HSR, the frequency of
  HLA-B5701 was lower in Black subjects
• For immunologically confirmed HSR, all case
  individuals carried the HLA-B5701 allele,
  regardless of race
• The utility of HLA-B5701 appears to generalize
  to US Black patients

80
60
40
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Clinically SuspectedCases
AbacavirTolerantControls
ImmunologicallyConfirmedCases
(Adapted from M Saag, et al. Clinical
Infectious Diseases 2008 461111-1118.)
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Develop / Access an Assay for Pharmacogenetic
Marker Detection

• In general, development of laboratory based
  assays or test kits may be needed
• For HLA-B5701
• HLA typing was widely available for tissue typing
  purposes
• Several centralized clinical laboratories now
  offer HLA-B5701 evaluation for abacavir
  hypersensitivity

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Evaluate Cost Effectiveness

• A Cost Effectiveness Analysis of HLA-B5701
  Screening
• Results depend on realistic assumptions
• Usually, achieving a healthcare benefit comes
  with a cost
• However, under many scenarios, screening with
  HLA-B5701 was predicted to reduce HSRs and
  average cost of care (referred to as a
  Dominant outcome)

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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-B5701 key messages are
• Discontinue abacavir permanently if HSR cannot be
  ruled out, regardless of the HLA-B5701 result.
• HLA-B5701 testing should never be performed
  diagnostically to support a decision to
  rechallenge with abacavir.
• HLA-B5701 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.

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Challenges for Safety Pharmacogenetics

• Association of HLA-B5701 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

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Questions and Discussion