GENReports: Market & Tech Analysis
Next-Generation Sequencing (NGS): Research to Clinic > Enal Razvi, Ph.D. Biotechnology Analyst, Managing Director SELECTBIO US
[email protected] GENengnews.com
GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
Topic Introduction and Summary •
In this GEN Market & Tech Analysis Report we examine the trajectory of next generation sequencing (NGS) as it migrates from the research environment towards the clinic – The First Clinical NGS System wins FDA Approval – The Migration of NGS towards Clinical Utilization will be a Driver for the Broader Personalized Medicine Space – The Opportunities for NGS in the Clinic are Immense Æ Diagnosing Disease by Characterizing the Mutations (Somatic or Germline) and Targeting Disease by Therapeutically‐Modulating the Mutated Gene Products – The Challenge is Moving Towards Demonstrating Clinical Utility of NGS in the Clinic as a bona fide Diagnostic and therefore Winning the Economic Argument vis‐à‐vis its Utilization in Clinical Practice
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GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
Illumina, Inc. Receives US FDA Approval for 4 NGS Products on November 19, 2013 1.
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The US FDA granted Illumina marketing approval to promote its MiSeqDx system as the first high‐throughput NGS system for clinical use Illumina Universal Kit reagents for developing NGS assays In addition to the MiSeqDx, Illumina received FDA approval to market its MiSeqDx Cystic Fibrosis 139‐Variant Assay, which checks specific points in the patient’s CFTR gene sequence to detect known variants in the gene The Illumina MiSeqDx Cystic Fibrosis Clinical Sequencing Assay, which sequences a large portion of the CFTR gene to detect any difference in the CFTR gene compared to a reference CFTR gene
The FDA reviewed the Illumina MiSeqDx instrument platform and the Illumina Universal Kit reagents through its de novo classification process, a regulatory pathway for some novel low‐to‐moderate risk medical devices that are not substantially equivalent to an GENengnews.com GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013 already legally‐marketed device.
Growth of Next-Generation Sequencing Focused Publications
Number of Publications per Year
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This Exponential Growth of NGS‐Focused Publications in PubMed Attests to the Expansion of NGS and its Penetration into Life Science Research Now with FDA Approval, we predict more publications utilizing clinical samples with clinical annotation as clinician‐scientists will be attracted to this space
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GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
Evolution of NGS: A Perspective from an Industry Participant •
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In light of the first NGS system receiving FDA approval, we discussed how this will impact the evolution of the broader personalized medicine space with a respected industry participant. Dr. Maureen Cronin is Executive Director, Strategic Information Management, Celgene Corporation and shared her perspectives on the progression of this field. The opinions and discussions presented herein are based on Dr. Cronin’s discussions with SELECTBIO and do not represent the opinions of Celgene or any other companies in this space. Indeed, Cancer is the driver of NGS moving into the clinic and constitutes the “bulk” of the literature and research activity. However, we must not forget the increasing impact on genetic disease as well as infectious disease, cautions Dr. Cronin. The ability to rapidly sequence infectious organisms will be key in ID diagnostics in the future. In spite of the fact that the instrumentation and reagents for NGS are becoming established, a big challenge remains in the computational analysis of the NGS data and its mining to gain its full impact vis‐à‐vis predictive power.
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GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
What are the Big Potential Opportunities in the NGS: Research to Clinic Translation? •
According to Dr. Cronin, in less than 5 years we should start seeing germ‐line sequence in patient electronic medical records (EMRs), and this opens up options for disease pre‐disposition management –
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This is a debatable point as to “depositing patient sequence into EMRs” but it is yet to be clarified
The paradigm for “single mutation” coupled with “targeted therapeutic” is probably not sustainable given the small‐sized patient population and development costs Rather, a more plausible scenario would be to perform NGS to characterize the somatic mutations in a tumor, for instance, and then ask which of these mutations “actionable”—ie., therapeutically‐addressable, in this manner this broad sweep for mutations/genomic alterations brings value for targeted patient care Drug developers on the other hand, would be developing therapeutic agents targeting defined mutations in specific genes (BRAF, EGFR, KRAS, etc.), and in this manner will offer up a portfolio of target agents the choice of which is made by the oncologist/clinician after an NGS‐based sweep for actionable alterations
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GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
Segmentation of the Current NGS Marketplace by Area of Focus Studying Cancer using NGS 18%
Studying Non‐coding RNAs using NGS 1%
Basic Academic Research 49%
Utilization of NGS for Discovering Disease‐ associated Variations/Mutations 32%
Bottom‐Up Worldwide Analysis of Researchers in the NGS Space GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013 Source: SELECTBIO
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Selected NGS-based Tests with Clinical Application Company
Test Name
Foundation Medicine Foundation One™
Technology
NGS Platform
Sequenom MaterniT21 PLUS test NGS Platform Heredi‐T™ CF Test NGS Platform
Application/Diease Area
Pan‐Solid Tumor Test
Fetal chromosomal aneuploidies Cystic Fibrosis
SensiGene™ Fetal RHD Genotyping test NGS Platform RetnaGene AMD GENengnews.com
NGS Platform
Age related Macular Degeneration
Genes Interrogated CLIA‐certified NGS‐based LDT which sequences 236 known cancer genes (interrogating 3,704 exons and 47 introns) from DNA derived from cancer patient FFPE samples. The NGS is composed of 250x median exon coverage and more than 99.5 percent of exons are covered by more than 100x sequencing depth DNA is analyzed for autosomal and Y chromosomal material and converted into a genomic DNA library for the determination of chromosome 21, 18, 13, X and Y representation Looks at 136 mutations plus 5 variants Clarify fetal RHD status without testing the father, Clarify fetal RHD status when maternal anti‐D titers are unclear, Identify the RHD (‐) fetus in mothers who are opposed to immunization(s) and vaccines, RhD (‐) sensitized patients Genetic profile of 12 disease‐associated single nucleotide polymorphisms (SNPs)
GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
Selected NGS-based Tests with Clinical Application Company Ambry Genetics
Test Name
Technology
First‐Tier Exome
NGS Platform
Clinical Diagnostic Exome
NGS Platform
BreastNext
NGS Platform
CancerNext
NGS Platform
ColoNext
NGS Platform
OvaNext
NGS Platform
Arrhythmia Panel
NGS Platform
Brugada Syndrome Panel
NGS Platform
LongQT Syndrome Panel
NGS Platform
Marfan, Aneurysm and Related Disorders
NGS Platform
Cardiomyopathy
NGS Platform
GENengnews.com Pan Cardio Panel
NGS Platform
XLID Next‐Gen Panel
NGS Platform
Application/Diease Area
Genes Interrogated
Only analyzes the genes that have been implicated in human disease, Analysis of ~4,000 characterized genes (HGMD defined around 20% of the human exome genes) Analyzes the entire coding region of the human genome Testing of trios; analysis of ~20,000 RefSeq genes ATM, BARD1, BRIP1, CDH1, CHEK2, MRE11A, MUTYH, NBN, PALB2, PTEN, RAD50, RAD51C, STK11 and TP53 Analyzes 22 genes that APC, ATM, BARD1, BRIP1, BMPR1A, CDH1, CHEK2, EPCAM, contribute to increased risk for breast, colon, ovarian, uterine and MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, SMAD4, STK11, and TP53 other cancers APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 Colon Cancer ATM, BARD1, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, Breast, Ovarian and Uterine Cancer RAD51C, STK11, and TP53 AKAP9, ANK2, CACNA1C, CACNA2D1, CACNB2, CASQ2, CAV3, DES, DSC2, DSG2, DSP, GPD1L, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNJ8, KCNQ1, LMNA, PKP2, RYR2, SCN1B, Arrhythmia SCN3B, SCN4B, SCN5A, SNTA1, TMEM43 CACNA1C, CACNA2D1, CACNB2, GPD1L, KCNE3, KCNJ8, Brugada Syndrome SCN1B, SCN3B, SCN5A AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, LongQT Syndrome KCNJ2, KCNQ1, SCN4B, SCN5A, SNTA1 Marfan Syndrome, Familial Aortic Aneurysm (FAA) and Thoracic Aortic ACTA2, CBS, FBN1, FBN2, MYH11, COL3A1, SLC2A10, SMAD3, Aneurysm and Dissection (TAAD) TGFBR1 and TGFBR2 Offer a DCM and HCM based test as well as a test for ARVD/C Test for multiple cardiovascular disorders including cardiomyopathies, cardiac channelopathies/arrhythmias and GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013 structural heart defects Analyzes 79 genes Analyzes 81 genes implicated in X‐Linked intellectual X‐Linked Intellectual disability disability
Summary and Key Takeaways
• SELECTBIO presents a snapshot of the NGS space as it is translating from research towards the clinic • The NGS space now has the first FDA‐approved system for clinical application based on MiSeqDx • In addition, numerous NGS‐based tests are being performed in the CLIA setting both in academic laboratories and in companies • Finally, we’ve presented a snapshot of tests based on NGS with clinical application Æ The driver of this is better patient care, elucidation of a patient’s molecular lesion[s] and ultimately targeted care [personalized medicine] GENengnews.com
GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
What are the Challenges in the NGS: Research to Clinic Translation? • Cost of the NGS Testing in the Clinic is High – List Price of FoundationOne™ is US$5,800 although the ASP to patients in reality is lower
• Currently, most of these are being Reimbursed by Patients or on a Case‐by‐Case Basis by Payors Æ For Broad Sustained Adoption of NGS into the Clinic, Reimbursement Must be by the Professional Payors (insurance companies, etc.) and for this event to take place, a Clear Economic Argument for NGS‐ based Testing in the Clinic must be Articulated • Also, COGs for NGS‐based Tests is High Æ This needs to scale down as vendors offer more solutions for front‐end sample processing and the front‐end becomes “commoditized” • Unlike the Genomic Health OncoType Dx® qPCR‐based test which has received wide appeal in the clinic and is reimbursed by the Payors, NGS‐based testing cost structure is significantly higher GENengnews.com
GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013
This conference focuses on front‐end sample preparation for NGS, research tools/technologies being developed for NGS, NGS on rare cellular populations, the utilization of NGS in oncology as well as in NIPT, and the informatics resources that are being developed to handle and analyze the data being generated via the various NGS efforts in different application areas. Front‐end Sample Preparation for NGS Informatics and Data Handling/Analysis NGS Big Data Handling New Technology Development in NGS Instrumentation Platforms Reagent Offerings NGS for Clinical Testing NGS in Non‐Invasive Prenatal Testing (NIPT) Oncology Space and the Penetrance of NGS in Cancer Mutation Discovery Regulatory Landscape and Commercial Trends GENengnews.com GENReports: Market & Tech Analysis, Produced by Enal Razvi, Ph.D. © 2013 NGS on Rare Cells (such as Circulating Tumor Cells) NGS on Exosomes, Extracellular Vesicles, and Biological Fluids
