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GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
> Enal Razvi, Ph.D. Biotechnology Analyst, Managing Director Select Biosciences, Inc. enal@selectbio.us!
GENReports: Market & Tech Analysis
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
• The,focus,of,this,GEN,Market,&,Tech,Analysis,Report,is,to,frame,a,very,Amely,and,expanding,development, in, the, life, sciences,field:,,The,PotenAal,of,Liquid,Biopsies,
• A,major, current, challenge, in, the, cancer, biomarkers, field, is, that,samples, of, tumor, Assue, need, to, be, harvested, in, order, to,understand,somaAc,mutaAons,as,a,means,to,target,therapies.,,This,is,the,premise,of,cancer,precision,medicine.,
– The! challenge! is! that! these! ?ssue! biopsies! tend! to! be! invasive! and! costly! [in!terms!of!procedure!costs,!hospital!stays,!and!loss!of!produc?vity]!
– Furthermore,! pa?ent! compliance!with! these! procedures! is! variable! given! their!invasive!nature!as!well!as!discomfort!
– Finally,! these! invasive! ?ssue! biopsies! cannot! be! performed! longitudinally! over!?me!and!therefore!the!informa?on!about!the!progression!of!a!disease!process!is!lost!
– These! are! the! drivers! for! the! development! of! liquid! biopsies!! MinimallyIInvasive!means!for!Harves?ng!Biomarkers!from!Pa?ents!for!Disease!Monitoring!
Why,Liquid,Biopsies?!
MinimallyMInvasive,Means,for,HarvesAng,Biomarkers,from,PaAents,for,Disease,Monitoring,Over,Time,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
• The!choice!of!analytes!which!need!to!be!enumerated/analyzed!in!biofluid!biopsies!is!currently!controversial!given!that!different!classes!possess!dis?nct!features!and!benefits!
• The,different,classes,are,as,follows:,1. CirculaAng,Tumor,Cells,(CTCs),2. CirculaAng,Nucleic,Acids,3. CirculaAng,Vesicles,(such,as,Exosomes,or,Microvesicles),
Containing,Biomarker,Cargo,4. CirculaAng,Proteins,
• Each!of!the!above!analyte!classes!has!advantages!and!disadvantages!as!discussed!in!the!next!page,
CirculaAng,Biomarkers,Enable,Liquid,Biopsies!
Which,is,the,Best,Analyte,Class,for,Liquid,Biopsies?,SAll,Unclear,,MostMLikely,a,CombinaAon,Assessing,Various,Aspects,of,
Disease,and,Different,for,DisAnct,Disease,Classes,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
• One!of!the!challenges!in!the!development!of!biofluid!biopsies!is!the!“sample!prepara?on”!on!the!frontIend!from!clinicallyIrelevant!pa?ent!samples!
• Currently,,the,most,commonly,studied,biofluid,samples,are,– Whole!Blood!–!for!CTC!Capture!– Plasma!–!for!Extracellular!Vesicles!(EVs)!and!Extracellular!Nucleic!
Acids!!– Serum!–!for!Extracellular!Vesicles!(EVs)!and!Extracellular!Nucleic!
Acids!– Urine!–!for!Extracellular!Vesicles!(EVs)!and!Extracellular!Nucleic!
Acids!• Less,common,biofluid,classes,currently,
– Cerebrospinal!fluid!(CSF)!
Which,Biofluid,Class,to,UAlize,for,a,Liquid,Biopsy?!
Which,is,the,Best,Analyte,Class,for,Liquid,Biopsy,Development:,SAll,Unclear,,MostMLikely,a,CombinaAon,Assessing,Various,Aspects,of,Disease,and,Different,for,DisAnct,Disease,Classes,based,on,Anatomy,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Comparison,of,Various,Classes,of,CirculaAng,Biomarkers,visMàMvis,their,Suitability,for,Liquid,Biopsy,Development,
Exosomes,,Microvesicles,
CirculaAng,RNA,
CTCs, CirculaAng,CellMFree,DNA,
Tissue,Sample,[as,a,Benchmark],
Sample!Availability!Throughout!the!Disease!Process!
Yes, Yes, Only,in,Late,Stages, Yes, Invasive,Procedures,for,Harvest,
Sample!Stability!When!Maintained!Ex#Vivo#[ie.,!postIexplant]#
Stable, Stable, Unstable, Stable, Stable,when,processed,,
U?lity!for!Longitudinal!Disease!Monitoring![ie.,!ability!to!harvest!samples!from!pa?ents!over!?me]!
Yes, Yes, Yes,with,caveats,[ie.,,late,stages,more,amenable],
Yes,with,caveats,[ie.,,late,stages,more,amenable],
Invasive,Procedures,for,Harvest,
Clinical!U?lity!as!a!Biomarker!
Not,Demonstrated,
Not,Demonstrated,with,excepAons,
Only,Demonstrated,in,Specific,Disease,
Classes,
Not,Demonstrated,with,excepAons,
Yes,
Suitable,for,Liquid,Biopsy,
Development,
Yes, Yes, Yes, Yes, No,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Various,Sources,of,CirculaAng,Biomarkers:,Analytes,for,Liquid,Biopsies!
Placental, fetal cells
(utilized in NIPT)
Circulating tumor cells
(CTCs)
Activated lymphocytes and other nucleated
cells
Lysis
Necrosis
Apoptosis
Source:!Pamela!Pinzani,!Univesità degli Studi di Firenze.!
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Classes,of,Extracellular,Vesicles,(EVs):,PotenAal,for,Liquid,Biopsy,Development,
" Extracellular,vesicles,(EVs),represent,a,source,of,circulaAng,biomarker,cargo,encapsulated,in,a,lipid,coat,
" There,is,extensive,diversity,of,size,and,biomarker,cargo,within,the,EVs,suggesAng,that,different,classes,may,have,potenAal,for,liquid,biopsy,development,in,different,disease,classes,–,oncosomes,,for,instance,,associated,with,various,cancers,
" Harvest,and,interrogaAon,of,EV,biomarker,cargo,for,liquid,biopsies,
EV,Size,DistribuAon,May,Reflect,FuncAonal,Significance,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
CirculaAng,DNA,(cfDNA,,ctDNA),as,a,CirculaAng,Biomarker,for,Liquid,Biopsies,
" Cancer,is,the,Driver," 5M7,ng,per,mL,of,plasma," More,concordance,with,
clinical,progression,than,CTCs,
" The,cancerMfocused,pharmas,are,evaluaAng,by,performing,NGS,on,cfDNA,to,look,for,cancer,mutaAons,
" Development,of,Liquid,Biopsies,
" PotenAal,CompeAtor,to,Extracellular,Vesicles,and,CTCs,as,CirculaAng,Biomarkers,
" Figure,Source:,Jonathan,Bailey,,NHGRI,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Source:,Luis,Diaz,et#al.,,www.ScienceTranslaAonalMedicine.org,19,February,2014,Vol,6,Issue,224,224ra24,
Clinical,UAlity,of,ctDNA,
In,Many,Cancer,Classes:,
Note,that,many,cancers,demonstrate,detectable,ctDNA,,ie.,,the,use,of,ctDNA,
for,disease,monitoring,is,
potenAally,across,many,cancer,classes,,
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Challenges,and,OpportuniAes,in,the,Liquid,Biopsy,Space!
Classes of Circulating Biomarkers
Downside Upside
" CirculaAng,Free,DNA,(cfDNA),
" CirculaAng,microRNAs,[freely,circulaAng,or,enveloped,within,exosomes],
" CirculaAng,mRNAs,[enveloped,within,exosomes],
" CirculaAng,Oncoproteins,
" CirculaAng,Exosomes,,Microvesicles,
" CirculaAng,Tumor,Cells,(CTCs),
" Identification of potential biomarkers associated with disease are required – This is Difficult
" Minimally-invasive diagnostics development
" Samples are reflective of the in vivo situation in the patient as opposed to a “segment” of the tumor
" Appropriate samples that are indicative of disease
" Robust assays/approaches to characterize the circulating biomarkers in the liquid biopsy samples
" Longitudinal analyses of patient response to therapies [such as cancer therapeutics] without the need for costly, painful invasive procedures
" Identifying those that are the most relevant with prognostic and/or predictive value
" Acceleration of adoption of precision medicine
" Demonstration of clinical relevance for prognosis in the absence of large, multi-year prospective clinical trials of patient survival
" Tissue Specificity of Origin of Disease can be Studied
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Liquid,Biopsies,will,Move,to,the,PointMofMCare,(POC),Sekng,Eventually!
• There! is! moun?ng! evidence! that! liquid! biopsies! will!migrate!towards!the!“pointIofIcare”!(POC)!sebng!for!the!following!reasons!– Beyond! cancer,! biofluids! may! be! harvested! for! other! disease! classes!
including! trauma?c! brain! injury! (TBI)! where! biopsies! of! the! brain! are!not!feasible!and!biofluids!offer!an!important!alterna?ve!–!diagnoses!of!TBI!must!necessitate!movement!towards!the!POC!sebng!
– If!biofluids!are!to!be!deployed!for!rou?ne!cancer!screening!in!otherwise!“clinicallyIhealthy”! subjects,! this! of! course! must! be! performed! in!doctor’s!offices,!outpa?ent!clinics!–!the!“POC”!sebng!
– Technology! development! for! POC! diagnos?cs! such! as! smartphoneIbased! diagnos?cs! is! proceeding! at! a! rapid! pace! and! we! believe! that!these! technologies!will! impact! biofluidIbased! diagnos?cs! especially! in!resourceIlimited!sebngs!and!for!public!health!
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
The,Liquid,Biopsies,Space,is,AlracAve,and,Evolving!
• 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!the!US!FDA!approval!of!Veridex/Johnson!&!Johnson!CellSearch®!system!for!CTC!enumera?on!
– However,!CTC!enumera?on!may!not!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!!!There!is!the!need!for!prospec?ve!clinical!trials!assessing!the!clinical!u?lity!of!these!biomarker!classes!for!biofluid!biopsies!!!S?ll!a!controversial!field!
– Given!the!huge!interest! in!liquid!biopsies!based!on!academic!research!developments![exosome!and!cfDNA/cfRNA,!for!instance],!and!pull!from!the!companies!interested!in!developing! minimallyIinvasive! diagnos?cs,! there! is! much! ac?on! expected! over! the!coming!years!in!this!space!
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Biofluid Biopsies and High-Value Diagnostics 2015 Boston – November 16-17, 2015
" Dedicated!Conference!on!Liquid!Biopsies!" All!Key!Opinion!Leaders!(KOLs)!from!Around!the!World!
Akending!and!Presen?ng!" Network!and!Engage!with!KOLs!–!All!Classes!of!Liquid!
Biopsies!Represented!" Please!Scan!QR!Code!with!iPhone/iPad/Android!to!Navigate!
to!Conference!Website!with!All!Conference!Details!
GENReports:,Market,&,Tech,Analysis,!Produced!by!Enal!Razvi,!Ph.D.!©!2015,GENengnews.com,
Exosomes and Liquid Biopsies Asia 2016: April 7-8, 2016, Taipei, Taiwan
" Dedicated!Conference!on!Liquid!Biopsies!Asia!" Key!Opinion!Leaders!(KOLs)!Akending!and!Presen?ng!" Delegates!from!Across!Asia/Pacific!Region!" Network!and!Engage!with!KOLs!–!All!Classes!of!Liquid!
Biopsies!Represented!" Please!Scan!QR!Code!with!iPhone/iPad/Android!to!Navigate!
to!Conference!Website!with!All!Conference!Details!
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