GENReports: Market & Tech Analysis

> Enal Razvi, Ph.D. > Tamlyn Oliver

Managing Director Managing Editor
Select Biosciences, Inc. Genetic Engineering & Biotechnology News (GEN)
enal@selectbio.us  

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 Scope of this Report

•  Select   Biosciences   Circula@ng   Biomarkers   2014   Conference   held   in  

Boston,  March  24-­‐25,  2014  aHracted  more  than  180  delegates  from  
around  the  world  
•  Focus  of  the  conference  was  primarily  on  research  and  transla@onal  
trends   in   nucleic   acid-­‐based   circula@ng   biomarkers   as   well   as  
Exosomes  and  Circula@ng  Tumor  Cells  (CTCs)  
•  This   space   is   gaining   trac@on   given   that   circula@ng   biomarkers   can  
be  easily  harvested  from  blood,  urine,  cerebrospinal  fluid  (CSF)  and  
other   biological   fluids   and   present   a   global   picture   of   cellular  
func@onality  and  disease  processes  
•  The   driver   of   this   field   is   currently   cancer   but   we   believe   that  
cardiovascular  diseases  represent  a  close  second    
Circula@ng  Biomarkers  Enable  the  Interroga@on  of  Disease  Processes  in  a  
Minimally-­‐Invasive  Manner  
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 Circulating Biomarkers Give Rise to the Era of
Liquid Biopsies

Value  Drivers  
 
•  Minimally-­‐Invasive  Procedures  to  Interrogate  Pathological  
Processes  in  vivo  
•  Increases  Pa@ent  Compliance  
•  Ability  to  Monitor  Pa@ents’  Disease  Longitudinally  
•  Reduces  Pa@ent  Morbidity  and  Costs  Associated  with  Hospital  
Stays  
•  Enables  Interroga@on  of  the  in  vivo  Situa@on  en  bloc  

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 Analyte  Classes  for  Liquid  Biopsies  
•  The  choice  of  analytes  which  need  to  be  enumerated/
analyzed  in  liquid  biopsies  is  currently  very  controversial  
given  that  different  classes  possess  dis@nct  features  and  
benefits  
•  The  different  analyte  classes  are  as  follows:  
v Circula@ng  Tumor  Cells  (CTCs)  
v Circula@ng  Nucleic  Acids  !  Derived  from  Dead  Cells  
v Circula@ng  Vesicles  (such  as  Exosomes  or  Microvesicles)  
Containing  Biomarker  Cargo  !  Derived  from  Live  Cells  
•  Each  of  the  above  analyte  classes  has  advantages  and  
disadvantages  as  discussed  in  the  next  page  
Which  is  the  Best  Analyte  Class  for  Liquid  Biopsies:  
GENengnews.com   GENReports:  Market  &  Tech  Analysis,  Produced  by  Enal  Razvi,  Ph.D.  ©  2014  
S@ll  Unclear,  Perhaps  a  Combina@on   Assessing  Various  Aspects  of  Disease  
 Comparison  of  Various  Classes  of  Circula@ng  Biomarkers  
vis-­‐à-­‐vis  their  Poten@al  for  Liquid  Biopsies  

Exosomes   MicroRNAs   CTCs   cfDNA   Tissue  

Sample  
Sample  Availability   Yes   Yes   Only  in  Late   Yes   Invasive  
Throughout  the  Disease   Stages   Procedures  
Process   for  Harvest  

Sample  Stability  When   Stable   Stable   Unstable   Stable   Stable  when  

Maintained  Ex  Vivo  [ie.,   processed    
post-­‐explant]  
U@lity  for  Longitudinal   Yes   Yes   Yes  with  caveats   Yes  with   Invasive  
Disease  Monitoring  [ie.,   [ie.,  late  stages   caveats  [ie.,   Procedures  
more  amenable]   late  stages   for  Harvest  
ability  to  harvest  
more  
samples  from  pa@ents  
amenable]  
over  @me]  
Clinical  U@lity  as  a   Not   Not   Only   Not   Yes  
Biomarker   Demonstrated   Demonstrated   Demonstrated  in   Demonstrated  
with  excep@ons   Specific   with  
Scenarios   excep@ons  
Circula@ng   Biomarker  
GENengnews.com   Yes   Yes   Market  &  Tech  AYes  
GENReports:   Yes  
nalysis,  Produced  by  Enal   No  
Razvi,  Ph.D.  ©  2014  
for  Liquid  Biopsy  
 Characteristics of the Various Vesicle Classes
Feature   Exosomes   Microvesicles   Membrane   Apopto@c  
par@cles   vesicles  
Size   50-­‐100nm   100-­‐1,000nm   50-­‐80nm   50-­‐500nm  

Density  in  sucrose   1.13-­‐1.19g/ml   ND   1.04-­‐1.07g/ml   1.16-­‐1.28g/ml  

Appearance  by  electron     Irregular  shape  and      

microscopy   Cup  shaped   electron  dense   Round   Heterogeneous  
Sedimenta@on   100,000  g   10,000  g   100-­‐200,000  g   1,200g,  10,000g  or  
100,000g  
  cholesterol,     ND   ND  
Lipid  composi@on   sphingomyelin  and   phospha@dylserine  
ceramide,  contain  
lipid  racs,  exposed  
phospha@dylserine  
Main  protein  markers   Tetraspanins   Integrins,  selec@ns   CD133;  no  CD63   Histones  
(CD63,CD9),  Alix  and   and  CD40L  
TSG101  
Intracellular  origin   Internal   Plasma  membrane   Plasma  membrane   -­‐-­‐-­‐  
compartments  
(endosomes)  

GENengnews.com   Source:    Doug  Taylor   GENReports:  Market  &  Tech  Analysis,  Produced  by  Enal  Razvi,  Ph.D.  ©  2014  
 Sources  of  Circula@ng  Biomarkers:  Sources  of  
Analytes  for  Liquid  Biopsies  

Circulating
tumor cells Placental,
(CTCs) Death fetal cells

Necrosis

Apoptosis
Activated
lymphocytes and
other nucleated
cells

GENengnews.com   GENReports:  Market  &  Tech  Analysis,  Produced  by  Enal  Razvi,  Ph.D.  ©  2014  

Source:  Pamela  Pinzani,  Univesità degli Studi di Firenze.  

 In  Summary  
•  This  GEN  Report  provides  a  snapshot  of  the  liquid  biopsy  field  which  
is  being  driven  by  the  various  classes  of  circula@ng  biomarkers  which  
have   been   described   and   are   currently   being   evaluated   for   their  
clinical  u@lity  
•  There   is   currently   a   race   as   to   which   biomarker   class   will   be   the  
leader  for  liquid  biopsies  
–  CTCs  have  an  early  lead  in  this  game  with  US  FDA  approval  of  Veridex/Johnson  &  
Johnson  CellSearch®  system  for  CTC  enumera@on  
–  However,  CTC  enumera@on  may  provide  a  comprehensive  picture  of  a  pa@ent’s  
status  and  therefore  the  search  con@nues  for  other  analyte  classes  
–  This  is  where  circula@ng  DNA  and   exosomes/microvesicles  enter  the  picture  à  
There   is   the   need   for   prospec@ve   clinical   trials   assessing   the   clinical   u@lity   of  
these  biomarker  classes  for  liquid  biopsies  à  S@ll  a  controversial  space  
–  Given   the   huge   interest   in   liquid   biopsies   based   on   academic   research  
developments   [exosome   research,   for   instance],   and   pull   from   the   companies  
interested   in   developing   minimally-­‐invasive   diagnos@cs,   there   is   much   ac@on  
expected  over  the  coming  years  in  this  space  
GENengnews.com   GENReports:  Market  &  Tech  Analysis,  Produced  by  Enal  Razvi,  Ph.D.  ©  2014  
 All  the  Stakeholders  in  Circula@ng  Biomarkers  and  Liquid  
Biopsies  Will  Come  Together  in  San  Diego  in  October  2014  

Select  Biosciences  Conference  Brings  Together  all  the  Stakeholders  in  this  Broad  Space  Composed  of  
Liquid  Biopsies  and  Companion  Diagnos@cs  
•  Circula@ng  Tumor  Cells  (CTCs)  
•  Circula@ng  DNA  
•  Deployment  of  Next-­‐Genera@on  Sequencing  to  Discover  and  Interrogate  Biomarkers  
•  Diagnos@c  Opportuni@es  for  Circula@ng  Biomarkers  [eg.,  Liquid  Biopsies]  
•  Epigene@c  Modifica@ons  of  Circula@ng  DNA  [eg.,  Methylated  Gene@c  Elements]  
•  Exosomes  and  Microvesicles  
•  Extracellular  RNAs  
•  New  Technologies  for  Liquid  Biopsies  
•  Non-­‐invasive  Prenatal  Tes@ng  (NIPT)  using  Circula@ng  Fetal  DNA  
•  Emerging  Disease  Classes  in  Companion  Diagnos@cs  
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Market   nd   Technologies  
 Tech   Deployed  
Analysis,  Produced   by  Enal  tRo  Develop  
azvi,   Ph.D.  ©C
 2DX  
014  
•  Partnering  and  Deal-­‐Making  in  the  Companion  Diagnos@cs  (CDX)  Space