drug discovery webinar presentation - genomenon - july 2019€¦ · the promise of genomics in drug...
TRANSCRIPT
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Drug Discoveryin the
Age of Genomics
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www.genomenon.com | [email protected] | @genomenon
Mark Kiel, MD PhDFounder and Chief Science Officer, GenomenonMolecular Genetic PathologyUniversity of Michigan, Ann Arbor
Alex Joyner, PhD Senior Field Application Scientist, GenomenonBiomedical Sciences & BioinformaticsUniversity of California, San Diego
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1. WHY use Genomics?• Core Benefits and Applications of Genomics
2. HOW should we go about it?• Practical Considerations for Use of Genomic Data
3. WHAT are some Examples?• Representative Case Studies
Outline
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DRUG DISCOVERY IN THE AGE OF GENOMICS
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Core Benefits and Applications of Genomics
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“[G]enetically supported targets could double the success rate in
clinical development”
5 Nat Genet. 2015 Aug;47(8):856-60.
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GENOMICS EMPOWERS PHARMA TO:
•Optimize Pre-Clinical Therapeutic Targets
• Reduce R&D Costs
•Maximize Success of Clinical Trials
• Expedite FDA Approval
• Decrease Time To Market
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• Understand the biomolecular basis of disease
• Identify new pathways in complex disease
• Provide a molecular starting point for targeted therapy
• Discover biomarkers in disease populations• Disease-Causing• Response-Modifying• Response-Monitoring
OPTIMIZE PRE-CLINICAL TARGETS
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1950 - 1970 Phenotypic Screening
1970 - 1990 Putative Protein Target
1990 - 2003 EST Studies
2003 - 2013 GWAS Studies
2013 - now NGS Studies
8 Nat Rev Drug Discovery 2018 March; 17(3):183-196
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• Focus on High-Yield Candidates
• Decrease Failure Rate
• Save on Opportunity Costs
REDUCE R&D COSTS
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“The cost to develop new therapeutics has increased significantly over the past 30-40
years, while the success rate has remained unchanged.”
“Many therapeutic failures occur after large investment.”
10 J Transl Med. 2016; 14:105.
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• Use Genomic Markers as Inclusion/Exclusion Criteria
• Ensure a More Homogenous Patient Cohort
• Establish a Molecular Companion Diagnostic
• Increase Drug Response Rate
• Add Statistical Power to the Study
MAXIMIZE SUCCESS OF CLINICAL TRIALS
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12 https://www.q2labsolutions.com/companion-diagnostics
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• Provide Supporting Data for Biomarker Candidacy
• Establish Objectivity with Genetic Evidence
• Support Understanding of Pharmacogenomics
• Proactively Strengthen Initial Submission
EXPEDITE FDA APPROVAL
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14 The future of the drug approval process Linda Honaker; figure Rebecca Clements.
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• More Efficient Product Development
• More Innovative Clinical Trial Design
• e.g. n-of-1 trials
• Out-Compete Competitors
DECREASE TIME TO MARKET
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Practical Considerations for Use of Genomic Data
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SELECTING THE RIGHT OMIC DATA
1. Single Nucleotide Variants and Indels
2. Structural Alterations – Copy Number Variants
3. Structural Alterations – Fusion Genes
4. Transcriptome – Gene Expression
5. Epigenetic Change – Methylation Marks
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A GENETIC WORKFLOW MODEL
1. Determine Study Parameters
2. Design Cohort Composition and Inclusion Criteria
3. Perform Sequencing/Array Experiment
4. Analyze NGS Data
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PRIMARY & SECONDARY ANALYSIS
DNA to Data
chr GeneATGCBAMFASTQ VCF
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TERTIARY ANALYSIS
Variant Interpretation - The Evidence Triad (ACMG/AMP)
PUBLISHED LITERATURE
PREDICTIVEMODELS
POPULATIONDATA
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TERTIARY ANALYSIS
External Curated Data Sources
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QUATERNARY ANALYSIS
Cohort Analysis - Putting it all together at the population level
AGGREGATE ANNOTATE ASSESS
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COHORT ANALYSIS
• Phenotypic and genotypic homogeneity is beneficial
• Presence/absence of a disease-causing mutation as
inclusion/exclusion criteria in a clinical trial
• Population-level sequencing identifies large, homogeneous
cohorts for specific diseases for clinical trials
• UK Biobank, Finngen, deCode, Genomics Medicine Ireland
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Representative Example Studies
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GAIN OF FUNCTION: V600E
Tiacci et al. NEJM 2011 Jun 16; 364:2305-15.
BRAF mutations in Hairy Cell Leukemia
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GAIN OF FUNCTION: NOTCH2
Kiel et al.J Exp Med2012 Aug 27;209(9):1553-65. 26
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GAIN OF FUNCTION: JAK-STAT
Kiel et al. Blood.2014 Aug 28;124(9):1460-72. 27
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LOSS OF FUNCTION: SEZARY SYNDROME
Kiel et al. Nat Comm 2015 Sep 29;6:8470. 28
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Complex and heterogeneous diseases –examples of strongly activating mutations
Conditions with genetic heterogeneity –pathway homogeneity uncovered by genomics
Across multiple related disease types –convergence of treatment strategies
THE PROMISE OF GENOMICS IN DRUG DISCOVERY
Nat Rev Drug Discovery 2018 March; 17(3):183-196
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A Comprehensive Index of the Genomic Literature, Annotated for Clinical and Functional Variants
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MASTERMIND GENOMIC DATABASE
30MTITLES/ABSTRACTS
SCANNED
6.7MFULL-TEXT GENOMIC ARTICLES INDEXED
10K DISEASES 25K GENES 4.9M VARIANTS
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