Translation of Personalized Medicine into the Clinic: Difficult but not Impossible

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Translation of Personalized Medicine into the
Clinic Difficult but not Impossible
Predict-1 HIV Test and HCV test

• Simon Mallal
• Professor Director
• Institute for Immunology Infectious Diseases
  Murdoch University
• Royal Perth Hospital
• Western Australia

Univation 4 November 2010
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Potential of Personalized Medicine
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Very Few Translate.....
Widespread Clinical Application
Pharmacogenomic Associations
Lost in Translation
Time
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T1?T4 The Translational Paradigm

• Step 1 A discovery with a potential
  application
• Step 2 Generation of high-level clinical
  evidence
• Basic science supports biological
  plausibility
• Step 3 Delivery of research to the clinic
• Quality assurance, valid, efficient
  and
• inexpensive lab testing and lab
• report easy to interpret

Step 4 Evaluation of test in real
clinical practice
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HLA-B5701 Abacavir
Lancet March 2, 2002
Lancet March 30, 2002
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ABACAVIR CLINICAL ROADMAP
Abacavir causes abacavir hypersensitivity (ABC
HSR) in 5-8 1998
Two independent groups publish strong association
between ABC HSR and HLA-B5701 in predominantly
Caucasian populations
2002 2002 2004
2002-2008 2000-2005 2008
2008
Apparent low sensitivity of HLA-B5701 in
non-white populations questions generalizability
Clarity added to the false positive clinical
diagnosis of ABC HSR, observational studies
Patch testing is a highly specific for true ABC
HSR
Randomised clinic trial using patch testing
confirms utility of HLA-B5701 and case-control
study shows generalizability across ethnicity
Widespread uptake into clinic in developed world,
incorporation into treatment guidelines, test
reimbursed
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Mechanism of Positive Patch Test in Patients
Previously Systemically Exposed
Phillips et al AIDS 200216223, Phillips et al
AIDS 200519979.
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First Randomised Study to Examine Utility of
Pharmacogenetic Test to Decrease toxicity
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Incorporation of HLA-B5701 Testing into
Treatment Guidelines
Preferred Preferred Preferred
NNRTI EFV ABC/3TC (for HLA-B5701 negative patients) or TDF/FTC
PI FPV/r BID LPV/r BID ATV/r ABC/3TC (for HLA-B5701 negative patients) or TDF/FTC
DHHS Guidelines http//aidsinfo.nih.gov/ContentF
iles/AdultandAdolescentGL.pdf Jan 2008. IAS
Guidelines JAMA 2008300(5)555-70
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Phillips E, Mallal S, Current Opinion in
Molecular Therapeutics 200911231-42
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Laboratory Translation
Cost Turn-around-time Feasibility
High resolution HLA B typing High (gt500 USD) Long (2 weeks or more) Not feasible unless specialty laboratory
PCR-based techniques Moderate (lt100 USD) Moderate (lt2 week) Feasible for labs with molecular technologies
B17-monoclonal Flow Cytometry Low (lt50 USD) Low (mandated by need for fresh cells) For labs doing CD4/8
Phillips and Mallal, Mol Diag Ther 200913(1)
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Ongoing quality assurance program mediated by
APHIA (formerly ASEATTA) MDiviney_at_arcbs.redcro
ss.org.au
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(Genome-wide) association studies Spontaneous
clearance of Hepatitis C
IL28B encodes interferon lambda (cytokine with
antiviral activity) OR 2.3-3.1
Thomas et al. Nature. 2009461798-801. Rauch A,
et al. Gastroenterology 2010 Jan 7.
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NSVR/SVR No Sustained Viral Response
/Sustained Viral Response CHC/SC Chronic
Hepatitis C /Spontaneous Clearer
Association of HLA-C genotype with Hepatitis C
clearance with and without therapy
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Genotype Positive Predictive Value
IL28GG 66
IL28GX 64
HLA-C  C2C2 63
HLA-C C2X 54
IL28Gx / HLA-C C2C2 80
Prediction of failure to clear Hepatitis C on
therapy with PegIFN/R
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Services

• Our key areas of clinical and research expertise
  lie in chronic immunologically mediated and
  infectious diseases
• Viral sequencing (particularly HIV and HCV), HLA
  and other genotyping
• Human pathogen immunobiology and genetics
  (sequencing, Roche FLX)
• Shaping of viral evolution by the host immune
  system
• Cellular immunology (flow cytometry, fluorescent
  microscopy, ELISA test)
• Biological statistics (bioinformatics, statistics
  and software development)
• Robotics, automation, high throughput assays
• Drug hypersensitivity
• Vaccine development
• Personalised Medicine
• Clinical translation

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Acknowledgements
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Back-up Slides
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Number Needed to Test...
Phillips E. Pharmacogenomics 201011973-987
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Laboratory Aspects are Critical

• IP- freedom to operate
• development of simple, inexpensive,
• robust,
• yes/no laboratory tests
• and associated reagents (eg monoclonal
  antibodies)
• rapid and simple report and interpretation
• global distribution and commercialization of
  allele specific test
• quality assurance of allele specific test
• reimbursement of test

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Evolutionary Processes
Legal
Medical
Commercial
Technical
Cultural
Biological
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The Future?

• What Can Be Predicted
• Human Behavior
• Instincts (modifiable risks from past)
• Migration to resource rich areas
• Huddle
• Attend to danger
• Trust empiricism (slow)
• Needs / Addictions
• Conflict / Shifting Alliances
• Altruism
• Motivators
• Power of diversity
• Pathogen Behavior
• Existing
• Resistance, Virulence Factors
• Newly Emerging

• What Cannot
• Shifts in environment
• Fundamental
• (history no longer a guide)
• Food security
• Globalization
• -Commerce
• -Free flow of information
• -Diffusion of power
• Next?
• Geopolitical alliances
• Discoveries
• Tools
• Agents
• Small molecules
• Biologics, siRNA etc

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