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Novel Biomarkers for Diagnostics and Drug
R&D – What is industry looking for?

Tom Metcalfe, F. Hoffmann-La Roche AG
Ontario Genomics Institute, Markers to Markets Workshop,
Toronto, June 22nd, 2010
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A call for more effective and safer drugs

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Biomarkers are essential tools in modern drug development
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                             Pharmacodiagnostic
                             Biomarkers
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   Biomarkers                  perspective

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                Biomarkers                         Biomarkers
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                • Mechanism of action                  Recurrence
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MDM2 Biomarker Program


• MDM2 is the master regulator of
  p53
• Antagonists of p53-MDM2
  binding can activate the p53
  pathway and restore cell cycle
                                             MDM2 inh binds to MDM2   min the p53 binding
  arrest and apoptosis                                                pocket

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                                        Roche Diagnostics developing a test
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Novel biomarkers for diagnostics and drug R&D: What is industry looking for?

  • 1. Novel Biomarkers for Diagnostics and Drug R&D – What is industry looking for? Tom Metcalfe, F. Hoffmann-La Roche AG Ontario Genomics Institute, Markers to Markets Workshop, Toronto, June 22nd, 2010
  • 4. A"B)C(1D"(+)50)8&#/<")1/)%&")*&#(7#)E/?,+%(B !"#$%&'#(")*("++,("+- 6'5/571')*("++,("+- 9":);"'&/5$5<1"+- ."/"01%231+4)3#%15 85+%2."/"01%)3#%15 6=>#/?"?)8#>#@1$1%1"+ ;
  • 5. A"B)C(1D"(+)50)8&#/<")1/)F,()E/?,+%(B A call for more effective and safer drugs 6001'#'B J#0"%B I/#$<"+1'+ C(,<)3"+>5/+")3#%"G)H L>M IB >'/.1# '7)/0#$ JB K.7'*0#$ ;B 8#/'"( :'4)* !B K.7'*0#$ B =->2)'*$-)0-'&?@-+*)/3$-A.&-A)3@-!BB=C-!-D'E'*.9 )0-'&?@-FGAG@-=HHI <
  • 6. A"B)C(1D"(+)50)8&#/<")1/)F,()E/?,+%(B Economic pressures intensify focus on improved benefit-cost ratio R?>?-Q)'&0,%'*)->2)/3#/S@-R>T-:#&&#./$- R?>?-Q)'&0,%'*)->2)/3-'$-U-.1-L"8 OMMM NMH NLMM KP KOH H KLMM !BBB !BBI !B=< !BBB !BBI !B=< >.9*%)N-O)/0)*$-1.*-A)3#%'*)-'/3-A)3#%'#3@-P11#%)-.1-0,)-G%09'*4@-K'0#./'&-Q)'&0,->0'0#$0#%$-L*.92 J
  • 7. A"B)C(1D"(+)50)8&#/<")1/)F,()E/?,+%(B) Step-change needed in Pharma R&D LX 9":)R5$"',$#()6/%1%1"+)S9R6T U)OV)./) NO NK U)KV)./) KW) KWWP) NMMV MY MW 3QC)J>"/? >.9*%)$N-W"GXO"Y5 "'0'@-8,5AG 3'0'@-8*#%)-Z'0)*,.9$)-O..2)*$-'/'&4$#$@-8,'*('-!B!B V
  • 8. 6D5$,%15/)50)R"?1'1/")[)[)[)#/?)*!8 Progress in therapy driven by new technologies 6D5$,%15/)50)R"?1'1/" Z,%,(" ! ;5?#B JB+%"7+).15$5<B R5$"',$#( E77,/5$5<B R"?1'1/" F/'5$5<B KWVM ;(#/+>$#/%#%15/ R5?"(/ 8(1%1'#$)8#(" R"?1'1/" R1'(5@15$5<B ^#''1/#%15/ 6#($B KYLM J,(<"(B R"?1'1/" .$""?1/< KNMM I/%1_," R"?1'1/" ! 6D5$,%15/)50) ;5,'&G)J7"$$) C1++"'%15/ R1'(52 2(#B R"%#@5$1%" 2571'+ .152 ;"'&/5$5<1"+ Q);#+%" +'5>" I/#$B]"(+ S1["[)*83T 1/05(7#%1'+ I
  • 9. A"B)C(1D"(+)50)8&#/<");5:#(?+)*"(+5/#$1+"? !"#$%&'#(")S*!8T PHC is key to enabling highly differentiated medicines !"#$%&'#(")*("++,("+- 6'5/571')*("++,("+- 9":);"'&/5$5<1"+- ."/"01%231+4)3#%15 ."/"01%285+%)3#%15 6=>#/?"?)8#>#@1$1%1"+ 9""?)05()&1<&$B)?100"("/%1#%"?)7"?1'1/"+ %&#%)>5+1%1D"$B)17>#'%)>,@$1')&"#$%& J5'1"%B)#/?)>#B5(+ :1$$)(":#(?)+1</101'#/%)1//5D#%15/ H
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  • 17. C(,<)?"D"$5>7"/%)#/?)'57>#/15/)?1#</5+%1') ?"D"$5>7"/%)#(")50%"/)/5%)#$1</"? *&#(7#)3QC)>(5'"++) 8$1/1'#$) Q)?"'1+15/)>51/%+ 8#/?1?#%") 6/%(B)E/%5) J"$"'%15/ !,7#/ Z1$1/< C1+'5D"(B 6=>$5(#%5(B))))))))))))))))))))) 85/01(7#%5(B))))))))))))))))))))))) *&#+" *&#+" *58 *&#+" .157#(4"()C1+'5D"(B) .157#(4"()8#/?1?#%"+)))))))))))))))) .157#(4"()8#/?1?#%"+)C1+'5D"(BN- C1+'5D"(B K.7)&-,42.0,)$#$h L)/)*'0#/S-$0*'0)S4 Q)C"D"$5>7"/% ;"'&/1'#$b)8$1/1'#$)^#$1?#%15/-) ;"'&/1'#$b)))))))))))))))))) Q42.0,)$#$-#$-^)#/S-7'&#3'0)3-X-)/0)*#/S- 8$1/1'#$)))))))))))))))))))))) %&#/#%'&-7'&#3'0#./ ^#$1?#%15/ E^C)C"D"$5>7"/%N-:#.('*c)*-'$$'4-#/- %&#/#%'&-7'&#3'0#./ E^C)C"D"$5>7"/% =V
  • 18. 35'&"g+)3"+"#('&)#/?)6#($B)C"D"$5>7"/%)R5?"$ Bringing the right disciplines together at the centre of drug discovery & early development ;(#/+$#%15/#$)R"?1'1/" JB+%"7).15$5<B !1<&"()_,#$1%B) !"#$%&'()*+)#',- 7-+)/#$3-+*1%&86)9'$: '$1/1'#$) '#/?1?#%"+ C1+'5D"(B)#/?);(#/+$#%15/#$)I("#+ E7>(5D"?) 89J C1+"#+" ^1(5$5<B F/'5$5<B R"%#@5$1') C1+"#+" E/0$#77#%15/ ,/?"(+%#/?1/<) 50)?1+"#+" ."%%"() R5?"$1/<)Q)J17,$#%15/ .157#(4"(+ '#/?1?#%") ./'0)*+)1'#'%-2&34'-, 5)6)03-$*$%%6# @157#(4"(+ =I
  • 19. .157#(4"(+ Essential to enabling translational medicine and drug development [ f/?"(+%#/?1/<)>#%&:#B+)#/?)7"'&#/1+7+ )?S?-0'*S)0$@-(.&)%9&'*-()%,'/#$($-'/3-2'0,.2,4$#.&.S4]- [ E7>(5D"?)?"'1+15/)7#41/<)1/)3QC )?S?-0..&$-1.*-2*.1#&#/S-0'*S)0$@-%.(2.9/3$@-8"-'/3-$'1)04- A'*c)*$] [ C(1D"(+)05()>&#(7#'5?1#</5+%1')?"D"$5>7"/% )/,'/%#/S-*)$2./$)-*'0)$@-#(2*.7#/S-^)/)1#0X*#$c-*'0#.@- %.(2'/#./-3#'S/.$0#%$] =H
  • 20. .157#(4"(+)#/?)*&#(7#'5?1#</5+%1'+ Biomarkers are essential tools in modern drug development and key to Personalised Healthcare Pharmacodiagnostic Biomarkers • Treatment eligibility • Response prediction • Safety and Efficacy Biomarkers perspective Pharmacological Disease Biomarkers Biomarkers • Pharmacodynamic • Patient risk markers • Early detection • Pharmacokinetic • Prognosis markers • Monitoring/ • Mechanism of action Recurrence markers !B
  • 21. h,#$101'#%15/)50)/5D"$)@157#(4"(+ 8$1/1'#$)^#$1?1%B I/#$B%1'#$)^#$1?1%B [ R/3)*$0'/3-7'*#'^#&#04-#/-0,)-()'$9*#/S- [ R/3)*$0'/3-'/3-'%%.9/0-1.*-^#.&.S#%'&- $4$0)( 7'*#'^#&#04 [ D#(#0X%./0*.&-$.9*%)$-.1-7'*#'^#&#04 [ `/0)*2*)0-7'*#'^#&#04-#/-0,)-%./0)e0-.1- #/0)/3)3-9$) [ O&#/#%'&-90#&#04-)$0'^&#$,)3-^4-9$#/S-'- 7'&#3-^#.('*c)*-#/-0,)-%&#/#% +,)-GOOY 1*'()b.*c-G/'&40#%'&-7'&#3#04@-O&#/#%'&-7'&#3#04@ O&#/#%'&-90#&#04@-Y0,#%'&@-D)S'&-'/3->.%#'&-%./$#3)*'0#./$]@-#$-'22&#%'^&) 0.-1.*($-.1-(.&)%9&'*-3#'S/.$0#%$-'/3-^#.('*c)* ;&")1/%"/?"?),+")50)%&")@157#(4"()+&#>"+)7,'&)50)%&")?"D"$5>7"/%):5(4)#/?) /""?+)%5)@")?"'1?"?)#%)#/)"#($B)+%#<" !=
  • 22. `&#%)#@5,%)7,$%1>$")7#(4"()>#/"$+a G33#0#./'&-%.(2&)e#04N [ Y'%,-()(^)*-.1-0,)-2'/)&-'33$-'/-'33#0#./'&-$.9*%)-.1- 2.0)/0#'&-)**.*-h0*'3)h.11$-#/-'33)3-$)/$#0#7#04-'0-2.0)/0#'&-%.$0- 0.-$2)%#1#%#04-(9$0-^)-('3) [ O./0*.&-1.*-#/0)*1)*)/%)-^)0b))/-)'%,-#/3#7#39'&-()(^)*-.1-0,)- 2'/)& [ `/%*)'$)3-%./$0*'#/0$-./ f >'(2&)-%.&&)%0#./@-2*)2'*'0#./-'/3-$0.*'S) f A)'$9*)()/0-$4$0)( f O./0*.&@-%'&#^*'0#./@-$0'/3'*3#E'0#./-%./%)20$ [ O.&&)%0#/S-3'0'-./-0,)-^#.('*c)*-2'/)&_$-2)*1.*('/%)-#/-0,)- #/0)/3)3-$)00#/S@-'22&#)3-0.-0,)-#/0)/3)3-%&#/#%'&-2.29&'0#./- !! )$$)/0#'&
  • 23. .157#(4"()C1+'5D"(B)Q)C"D"$5>7"/% Analytical validation/quality needs differ according to intended use ;"'&/1'#$)b) .157#(4"()8#/?1?#%"+)C1+'5D"(B E^C)C"D"$5>7"/% 8$1/1'#$)D#$1?#%15/ 95[)50).157#(4"(+)#/?)I++#B+ h,#$1%B)("_,1("7"/%+)S'$1/1'#$)#/? #/#$B%1'#$)D#$1?1%B)50)#++#B+T !6
  • 24. Z5',+)5/),/?"(+%#/?1/<)?1+"#+")#%)%&")75$"',$#()$"D"$ Increased effort to understand disease biology and translational medicine to achieve PHC "[<[))F/'5$5<B-) [ `")&#D")17>(5D"?)>(5'"++"+)05()>#%1"/%)+#7>$")'5$$"'%15/ f '()/3)3-`/1.*()3-O./$)/0@-('/3'0.*4-$'(2&)-%.&&)%0#./- $0*'0)S#)$ [ `")&#D")1/'("#+"?)5,()"005(%)1/)>("'$1/1'#$)>(501$1/< f #/%*)'$)3-3)20,-.1-2*)%&#/#%'&-2*.1#&#/S-./-%&9$0)*$-.1- (.&)%9&)$ )?S?-'/0#h'/S#.S)/)$#$]-#/%&93#/S-('*c)0)3-.*- &'0)-$0'S)-(.&)%9&)$ [ `")&#D")"=>#/?"?)5,()>#(%/"(+&1>+):1%&)#'#?"71') '577,/1%1"+ f +*'/$&'0#./'&-A)3#%#/)-Q9^-#/->#/S'2.*)-.2)*'0#./'&#E)3 #/- )'*&4-!B=B !;
  • 25. 8$1/1'#$),%1$1%B)50)("+>5/+")>("?1'%15/ 5&'#$6#.$1,%+&-/ [ 5#$c$-'/3-^)/)1#0$-*)&'0)3-0.-jY(2#*#%-G22*.'%,_ f 2*)$9(20#7)-0*)'0()/0-7)*$9$-0)$0-'/3-0*)'0 f /'09*)-.1-#&&/)$$-'%90)@-&#1)h0,*)'0)/#/S]-'/3-0*)'0()/0-'&0)*/'0#7)$ [ +,)*'2)90#%-*)$2./$)-*'0) f 5)&'0#7)&4-,#S,-kJBU]-.*-&.b-l-6BU]? [ 5)&'0#7)-%.$0$ f 0.0'&-%.$0-.1-'%a9#*#/S-0)$0-#/1.*('0#./-0#()-'/3-(./)4]-7)*$9$ $'7#/S$-1*.(- 0)$0#/S f 2)*%)#7)3-'33#0#./'&-7'&9)-39)-0.-*)39%0#./-.1-2'0#)/0-9/%)*0'#/04 [ 5)&'0#7)-2*)3#%0#7)-7'&9) f ,.b-b)&&-3.)$-0,)-0)$0-#/1.*(-%&#/#%'&-3)%#$#./-('c#/Sd [ `$$9)$-*)&'0)3-0.-('*c)0-'%%)20'/%)X2*'%0#%'&#04 f 0)$0-2&'01.*(-'7'#&'^#&#04@-2,4$#%#'/-)39%'0#./-'/3-'%%)20'/%)-)0%? !<
  • 26. J57"%17"+)+%#(%1/<)>51/%)05()("+>5/+")7#(4"(+)5@D15,+[[ MDM2 Biomarker Program • MDM2 is the master regulator of p53 • Antagonists of p53-MDM2 binding can activate the p53 pathway and restore cell cycle MDM2 inh binds to MDM2 min the p53 binding arrest and apoptosis pocket [ A"A! '/0'S./#$0$-b#&&-&#c)&4-/.0-^)-^)/)1#%#'&-1.*-2'0#)/0$-b#0,-09(.*$-(90'0)3-1.*-2<6 '22*.e-<B-U-.1-,9('/-09(.*$] [ 8'0#)/0-$0*'0#1#%'0#./-^4-2<6-S)/)-$0'09$-*)a9#*)3-0.-#3)/0#14-2.0)/0#'&-*)$2./3)*$ Roche Diagnostics developing a test platform for p53 resequencing p53 AmpliChip !J Roche RMD
  • 27. ;#(<"%1/<).3IZ R,%#%15/+)1/)8#/'"( One promising early phase example [ ;5<= <"/")7,%#%15/+)?"%"'%"?)1/)iVH)50)#$$) '#/'"(+ f R2-0.-VBU-.1-('&#S/'/0-()&'/.('$ f R2-0.-<6U-.1-2'2#&&'*4-0,4*.#3-%'*%#/.('$ f R2-0.-=<U-.1-%.&.*)%0'&-09(.*$ [ R5+%)'5775/)7,%#%15/)@B)0#(-)^PMM6)1/)"=5/)KL f n-VBU-()&'/.('$@-0,4*.#3-'/3-%.&.*)%0'&-%'/%)*$-- b#0,-(90'0)3-=>?@ 5GW-'%0#7'0)$-0,)-AG8M-$#S/'&#/S-2'0,b'4 :5GW-%'/-^)-'%0#7'0)3-^4-'-$#/S&)-(90'0#./-gJBBY] *eOMXN N-K.7)&-$('&&h(.&)%9&)- #/,#^#0.*-1*.(-8&)ee#c./ 85C=)/""?N-+'a('/o 8O5h^'$)3- 8)94%#):#!"4)!6NJVV=-!BB<]-A-:))*'( (&),4;<)9,#!(.)9(44)JN6=6-!BB;]-AF-L'*/)00-'/3-5-A'*'#$- gJBBY (90'0#./-3)0)%0#./ !V
  • 28. C"01/1/<)("+>5/+")1/)>#%1"/%+):1%&)3&",7#%51?)I(%&(1%1+ 3"+>5/+")7"#+,("?)@B)'57>5+1%")+'5("+ f I83)S17>(5D"7"/%)/5%)#'%1D1%BT [ GO5!B-f '-!BU-#(2*.7)()/0-#/-+FO-'/3->FO-'/3-#/-6-.1-0,)-1.&&.b#/S- f 8'0#)/0-S&.^'&-'$$)$$()/0 f 8,4$#%#'/$-S&.^'&-'$$)$$()/0 f 8'0#)/0$-'$$)$$()/0-.1-2'#/ f ")S*))-.1-3#$'^#&#04- f D)7)&-.1-'%90)-2,'$)-*)'%0'/0$ f CIJ)S17>(5D"7"/%)#/?)#'%1D1%BT [ `/%&93)$-'*0#%9&'*-#/3)e@->FO@-Y>5@-8'0#)/0-S&.^'&-'$$)$$()/0 f L..3-*)$2./$)-"G>-l!?;C-"k=?! f K./h*)$2./3)*-"G>-k6?VC-"lB?J f C100"("/%)%&"(#>1"+)7#B)>(5?,'")?100"("/%)"00"'%+)5/)%&")'57>5/"/%+)50)#) '57>5+1%")+'5(")j #/?)%&"("05(")5/)%&")7"#+,("7"/%)50)("+>5/+" !I
  • 29. C1+'5D"(1/<)#/?)1/%"<(#%1/<)/5D"$)("+>5/+") 7#(4"(+)1/%5)?(,<)?"D"$5>7"/% O,'&&)/S)$m [ O.**)&'0#./-.1-/.7)&-('*c)*$-b#0,-*)$2./$)-*)a9#*)$-0,'0-0,)*)-^)-$911#%#)/0- *)$2./3)*$-#/-)'*&4-3)7)&.2()/0 [ ".-b)-,'7)-0,)-*#S,0-*)$2./$)-2,)/.042)d-)?S?-09(.*-*)$2./$)-7)*$9$- $9*7#7'& [ ".)$-0,)-('*c)*-3)1#/)-*)$2./$)-2*)3#%0#7)]-.*-'-3#11)*)/0-%.9*$)-.1-3#$)'$)- 2*.S/.$0#%]-.*-^.0,d [ Q'7)-b)-S.0-'%%)$$-0.-0,)-*#S,0-042)-.1-%&#/#%'&-$'(2&)$d-'/3-,'7)-0,)4- ^))/-$0.*)3-%.**)%0&4m?] [ Q42.0,)$#$-1*))-'22*.'%,)$-)?S?-ZLG>@-0*'/$%*#20.(#%$]-()'/-0,'0-b)-3./_0- ,'7)-0.-$0'*0-b#0,-'-,42.0,)$#$@-^90-b#&&-&)'3-0.-('/4-1'&$)-p7)_$ [ A'4-.10)/-*)$9&0-#/-$0*'0#1#%'0#./-,42.0,)$)$-^)#/S-3)7)&.2)3-2.$0-#/#0#'&- &#%)/$#/S-.1-(.&)%9&)m? !H
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