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THANK YOU CVG SPONSORS
B Round
A Round
Venture Capital Sponsors Professional Service Firms
Marketing at the Speed of LightWelcome
Konstantine DrakonakisDirector, New HavenLaunchCapital
CTNEXT: New Haven Hub
Derek KochUsha Pillai
Three Minute Pitches
Marcia Fournier
Judson Brewer
Lew Bender
John Bala SterileWave Medical Corp.
Keynote
Edison T. Liu, M.DPresident & CEOThe Jackson Laboratory
Marketing at the Speed of LightNavigating the FDA: Getting to Market
Introduction
Paul HughesPartnerWiggin and Dana LLP
The Jackson Laboratory To discover precise genomic solutions for better medicine
We discover precise genomic solutions for disease and empower the global biomedical community in
our shared quest to improve human health.
Oct 1997
Then: Single biomarker, spurred by a somelaboratory findings, years of development before reaching clinic
One marker many samples
Now: Interrogation of a cancer genome,in silico validation,identification of new therapeutic targets
Many markers few samples
Biomarker Discovery in Cancer
HER2 and clinical trialsAnn Thor Don BerrySoon Paik Mei HeLynn DresslerCraig HendersonHyman Muss
J Natl Cancer Inst. 90(18):1346-60 (1998)
Patients with acute myeloid leukemia and RAS mutations benefit most from postremission treatment with high-dose cytarabine: a Cancer and Leukemia Group B study.Neubauer A, et al. J Clin Oncol. 26(28):4603-9, 2008.
9 years per marker, over 1,500 patients: There has got to be a better way
In vitro observation: ARAC – RAS interactionKoo, et al. Can Res 59:6057, 1999
Start of study CALGB 8869: 1989Publication of final paper: 1998
Oct 1997
Then: Single biomarker, spurred by a somelaboratory findings, years of development before reaching clinic
One marker many samples
Now: Interrogation of a cancer genome,in silico validation,identification of new therapeutic targets
Many markers few samples
Biomarker Discovery in Cancer
Sequenced Breast Cancers: focusing on structural mutations
PET library construction& sequencing
SOLiD
PET sequences mappingto reference genome
Concordant PETs
Discordant PETs
Concordant PET tag density
PET mapping span
1Kb 10Kb
Automated cancer genome assembly:7 month analysis to4 days
Analysis of CancerSpecific Mutations
Deletion
Abnormal length
Unpaired inversion (Inverted orientation)
Different strand
Tandem Duplication
Incorrect order
Translocation
Different chromosome
Structure variations
Fusion points predict fusion genes
Structural Genomic Changes in Breast Cancer
Genome Research 21(5):665-75 (2011)
Cancer rearrangements are most often private and unique:Irrelevant mutations or part of the “long tail”
Inaki K, et al. Transcriptional consequences of genomic structural aberrations in breast cancer. Genome Res. 2011 May;21(5):676-87.
Gene ontology (GO) analysis of genes with break points in cancer genomes: There is a higher organization to the collection of single structural mutations
Breast cancer Gastric cancerGenes with break points1)
Biological Process3) RefGene
Expected
Observed +/‐ P value RefGen
eExpecte
dObserved +/‐ P value
Cell adhesion‐mediated signaling
386 20.88 51 + 2.22E‐06 Cell adhesion 592 31.61 73 + 2.62E‐09
Cell adhesion 592 32.02 65 + 3.47E‐06Cell adhesion‐mediated signaling
386 20.61 49 + 9.66E‐06
Neuronal activities 561 30.34 54 + 1.52E‐03 Signal transduction 3256 173.84 222 + 1.53E‐03
Biological process unclassified 5972 322.97 269 ‐ 3.04E‐03 Synaptic transmission 275 14.68 33 + 3.24E‐03
Electron transport 230 12.44 2 ‐ 1.05E‐02 Cell communication 1207 64.44 98 + 4.47E‐03
Other intracellular signaling cascade 212 11.47 27 + 1.12E‐02 Neuronal activities 561 29.95 51 + 6.94E‐03
Cell communication 1207 65.28 97 + 1.16E‐02 Biological process unclassified 5972 318.84 273 ‐ 2.36E‐02
Chemosensory perception 204 11.03 1 ‐ 2.67E‐02 Chemosensory perception 204 10.89 1 ‐ 3.04E‐02
Developmental processes 2065 111.68 144 + 2.97E‐02
Genes in recurrent high copy regions2)
Signal transduction 3256 151.33 100 ‐ 2.35E‐05
Chromatin packaging and remodeling 194 2.21 11 + 0.00249
Cell surface receptor mediated signal transduction 1576 73.25 41 ‐ 2.05E‐
03
Developmental processes 2066 96.02 65 ‐ 7.74E‐03
G‐protein mediated signaling 793 36.86 16 ‐ 1.39E‐02
TMEM RPS6K(~100kb)
5’
RPS6KB1‐TMEM49 fusion gene induced by tandem replication is found in 30% of breast cancers.
TMEM RPS6K(~100kb)
5’ TMEM RPS6K(~100kb)
TMEM RPS6K(~100kb)
5’
EMRPTMEM5’ RPS6K
RPS6KB1-TMEM49 fusion gene
Expression of RPS6KB1‐VMP1 fusionis correlated with:‐Poor prognosis‐Expression of neighboring oncogenes around the tandem duplication‐Expression of oncogenes in ~3Mb adjacent region‐ Associated with gene amplification of locus
The fusion gene is always associated with amplification of this region
Historical data
Our data
S6K‐TMEM Fusion Transcript is an indicatorof genomic instability in an “oncogenic region” of the genome harboring at least 2 oncogenic
components
TMEM 49
miRNA21
S6Kinase
Indicator structural mutation: S6K‐TMEM Fusion Transcript is an indicator
of the amplification of an “oncogenic region” of the genome
TMEM 49
miRNA21
S6Kinase
TMEM 49
miRNA21
TMEM 49
miRNA21
S6KinaseS6Kinase
Oncogenicbloc
Tandemduplication
Gene Amplification
Genomic Organization and Cancer:
Higher order organization of mutations incancer genomes
Chromosome as an oncogenic organizerChromosomal “origami” to generate
cancer gene cassettes
Effect of the germline on cancer therapeutic outcome
Focus on Structural Mutations in Cancer
Systems Oncogenomics
Chronic Myelogenous Leukemia (CML)Optimizing treatment for CML based on genetic
makeup of the patientKP Ng, Axel Hillmer,… Yijun Ruan. Ong Sin TiongNat Med. 2012 Mar 18;18(4):521‐8.
Imatianib (Gleevec) – primary and effective treatmentClinical Challenge: Drug resistance• Acquired resistance – resistance after long term
treatment ‐ due to second ABL mutation• Primary resistance – resistance at the beginning of
treatment. • In Asia, complete cytogenetic response rates are lower ‐
50% vs. 74%. Mechanism unknown
Question: is there a reason why 25% of CML cases do notrespond to imatinib?
Approach: Compared the genomes of three CML cases with primary resistance to Imatinib with two CML cases sensitive to Imatinib therapyResults:
3/3 resistance cases had the same 2.9kb deletion in the BIM gene not seen in sensitive cases (0/2)
Ng KP, Nat Med. 18(4):521-8(2012)
BIM:
• BIM is a gene that activates cell death (pro‐apoptotic). • Activated BCR‐ABL1, suppresses BIM function thus
allowing leukemia cells to survive. When CML cells are treated with Imatinib, BIM expression goes up cell death
Bcr-ABL: CML Intact BIM Death of Leukemia cells
Imatinib
How does it work?: The 2.9kb BIM deletion polymorphism results an abnormal transcript (E3) that a produces a truncated and inactive BIM protein
Bcr-ABL: CML Intact BIM Death of Leukemia cells
Imatinib
Bcr-ABL: CML BIM E3
Primary Drug Resistance
Imatinib
NormalTranscripts
E3
Deletion Polymorphism
BIM deletion polymorphism:
• This deletion polymorphism is 3‐5X more common in CML cases resistant to imatinib that sensitive cases
• This 2.9 kb 2 deletion of BIM is not a mutation, but is a polymorphism present in normal genomes (a germlinepolymorphism):
12% in Asian individuals0% in Africans
0% in Caucasians
We used this genomic intelligence to overcome this resistance:
Bcr-ABL: CML BIM 3 Primary Drug
Resistance
Imatinib
Imatinib
Bcr-ABL: CML BIM
BH3 mimetics
Death of Leukemia
cellsNg KP, Nat Med. 18(4):521-8 (2012)
This genomic experiment with 5 patients explains the lower response rate In North Asians to a life saving treatment in CML. Personalizing medicine in Asia
Now: New
CML Patientin Asia Check for bcr-ABL
rearrangementCheck for 2.9kb
deletion polymorphism in BIM
YES
~50% cytogenetic response
YESNO
Imatinib
Imatinib&
BH3-mimetic
75% cytogenetic response
>75% cytogenetic response
??
?
Translation Initiative
We will construct avatars of your cancer:So that we can discover the best drugs for
your cancerSo that we can devise personalized and
private diagnostic for your cancerSo that we understand the nature of your
cancer and explore the reasons for drug resistance
So that we may project how your cancer might evolve
PDX of patient = Patient “Avatar” of Drug Response
Drug 1
Single tumor from a patient
Drug 2
Drug 3
Drug 4
Questions Addressed:
What drugs will be effective for my tumor?
How to combine these drugs?
Activity of afatinib, cetuximab and erlotinib in LG703
Predictive for Therapeutics
Cancer Avatar: General workflow
Patient Tumorfrom Hartford Hospital
Deep Sequencing PDX Model:Test Drugs predicted by genomics
Genome Analysis: Extract the Source Code
Personalized Diagnostic
Future Treatments
Immediate Treatment Plan
JAX WestJAX CT/BH
RadiologistRadiologist of the Genome
Interprets complex datarendered through
computational algorithmsIs the consultants
to doctors
What is the field looking for?
• Tools and processes to enhance efficiency in the medical system
• Life style enhancement: prolonging productive lifeand healthspan
preventive therapeuticshealth monitoringperformance enhancement mobility and independence
• Personalization of information and medical care
Navigating the FDAMarch 15,2013
Edison Liu, M.D.
Marketing at the Speed of LightNavigating the FDA: Getting to Market
Panelists
Pamela BunesCEO, President & DirectorEpiEP, Inc.
Harry PennerCo-founder, Executive ChairmanNew Haven Pharmaceuticals
Dr. Frank SciavolinoCo-founder, Board Member, Chief Scientific Officer & PresidentThetis Pharmaceuticals LLC
March 2013 Crossroads Venture Group
Navigating the FDA:
Getting to Market
Overview
Pre-Clinical Requirements
Shift in Approval Requirements
Clinical Trial Sizing
Diagnostics
505(b)2
36
Premier Chemistry – Yale - Multiple Partners
Pfizer – Schering Plough – Merck – Am. Home
Anxiety / Alzheimers / Sleep / Obesity / Schiz.
FDA Pre-Clinical Requirements Increased
37
Multiple Programs - Antibiotics
Nobel Laureate Science – Tom Steitz (Yale)
Premier Investors
FDA Changed Approval Criteria After Phase II
38
In-Licensed Programs – Purdue + Yale
Premier Investor Base – Domain / Canaan / FMP
Epilepsy – Core Focus
Equivocal Trial Results – Too Small “n”
39
n
Diagnostic - CSF Detection
CI / Launch Capital / Management Financed
Ambitious Multi-antibody Strip Test
510k vs. PMA
40
In-licensed Programs – Flamel + Yale
CI + Ironwood + Enhanced + Kuzari + EJ Funds
Lead Product – Anti-Platelet
505(b)2 – Multiple FDA Interactions
CMC + Approval Issues
41
Closing Points
Stay Abreast of All FDA Related Trends
– Pre-clinical to Approval
Maintain Strong Contact to FDA
– Except When It Might Be Judicious Not To
March to NDA - Process is Critical
– The Longest Path to Approval Is a Short Cut
42
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