a peek at dpharm 2012
DESCRIPTION
Disruptive Innovation presentation from 2nd Annual Disruptive Innovations to Advance Clinical Trials, Sept 2012, Boston, MA on 'A new model to reduce waste in clinical development', from Chas BountraTRANSCRIPT
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SGC Oxford SGC Toronto
A new model to reduce waste in clinical development:
open access collaboration
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Outline(
• SGC$$%$what$is$it$$%$our$objec3ves$$%$achievements$$%$impact$(2$examples)$
• Now$extending$this$model$into$clinic:$create$a$new$PPP$to$do$Phase$II$studies$with$novel$targets,$pre%compe33vely$
• Lessons$$
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What(is(SGC?(• PPP$ $%$GSK,$Pfizer,$Novar3s,$Lilly,$AbboJ,$Takeda$
$ $%$GC,$Ontario,$CIHR,$Wellcome$Trust$$• Two$other$pharmas$joining$by$end$month$$
• Private$funding $ $%$2003:$$5M$
$ $ $ $%$2007:$$15M$
$ $ $ $%$2012:$$64M$
$• 200$scien3sts$in$Universi3es$of$Toronto$and$Oxford$
• Academic$network:$>250$labs$
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Output(
• Generate$freely$available$reagents:$$$%$novel$human$therapeu3cally$relevant$$ $proteins,$$$%$novel$assays,$$$%$novel$structures,$$$%$novel$inhibitors,$$$%$novel$an3bodies$
• Give$to$collaborators$to$discover$new$targets$for$drug$discovery$
$
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This(model(is(working(
SGC: $$
$
• structures$ $(2003%$$$$$)$
• inhibitors$ $(2009%$$$$$)$
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Achievements(• Have$purified$>$2000$human$proteins$
• More$than$1300$human$protein$structures$(nearly$25%$of$PDB)$
• 12$inhibitors$(probes)$of$epigene3c$proteins$
• >1$publica3on$per$week$(Science,$Cell$or$Nature$–$every$month)$
• Several$hundred$reagents$distributed$freely$every$year$(academia,$biotech,$pharma)$
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Nature, Dec 23, 2010
Novel inhibitor for BET sub-family (JQ1)
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JQ1(has(ac@ve(and(inac@ve(enan@omers((
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JQ1(reduces(prolifera@on(in((two(pa@ent(derived(cell(lines(
797 403
0
20
40
60
80
100
Vehicle JQ1 Vehicle JQ1
Ki67
Pos
itive
( %
)
KI67 positive = proliferating
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JQ1(induces(apoptosis(
Annexin V, marker of early apoptosis PI = propidium iodide, marker of late apoptosis STA = Staurosporine
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JQ1(reduces(tumour(size$$
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Scien@fic,(drug(discovery(&(economic(impact((
! Published Dec 23 2010 - already cited >90 times
! Distributed to >250 labs/companies - profile in several therapeutic areas
! Pharmas - started proprietary efforts
! Harvard spin off - $15 M seed funding
! Opened new area:
Zuber$et$al$:$$ $BRD4$as$target$in$acute$leukaemia $ $Nature,$2011$Aug$3$Delmore$et$al:$ $JQ1$suppresses$myc$in$mul3ple$myeloma$ $Cell,$2011$Volume$146,$$904%917,$16$Dawson$et$al:$ $BRD4$in$MLL$(isoxazole$inhibitor) $ $Nature$2011,$Oct$2.$Blobel$et$al:$$ $Novel$Targets$in$AML $ $ $Cancer(Cell,$2011,$Sep$13$Mertz$et$al$:$ $Myc$dependent$cancer $ $ $PNAS,$2011,$Oct$4$Zhao$et$al:$ $ $Post$mito3c$transcrip3onal$re%ac3va3on $Nature(Cell(Biology,$2011$Oct$9$
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Lysine(Demethylases(
SGC structure
Non SGC structure
Catalytic domain purified
Alphascreen in place
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OXFORD CENTRE FOR OA PATHOGENESIS!!Novel(JMJD3(inhibitor(produces(dose(related(inhibi@on((
of(TNF(release(from(human(macrophages(
Inhibitor$$% increases$K27me3,$$% decreases$RNApolII$% no$change$in$H3$
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JMJD3(inhibitor(reduces((bone(resorp@ve(ac@vity(in(osteoclasts(
RANKL$=$receptor$ac3vator$of$nuclear$factor$KB$ligand$RANK$=$osteoclast$cell$surface$receptor$$
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Vehicle
D3 inhib
Red$dots:$propidium$iodide$stained$apopto3c$cells$D3$inhibi3on,$increases$K27me3,$decreases$BCL2,$increases$apoptosis$
JMJD3 inhibitor increases apoptosis in human breast cancer cells
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UHRF1$
SMYD3$
MLL$
PRMT3$
SETDB1$
FALZ$
BRD9$
PCAF$
JMJD2$2nd$$
JMJD3$2nd$$
PB1@2$
PHIP$
PRMT5$
SMYD2$
BRPF3$
ATAD2$
PB1@5$
JMJD1$
CECR2$
BAZ2A$
SETD7$
FBXL11$2nd$
JMJD2B$
MMSET$
SUV420H1/2$
JMJD3$3rd$
Screen
ing$/$Ch
emistry$
In vitro assay Cell assay
JARID1A$
Potent & Selective
Potent
Weak
None
Probe/ Tool Compound
TIF1α$
JMJD2A$
JMJD2C$
SPIN1$
SUV39H2$
EP300$
L3MBTL1$
53BP1$
SETD8$
JMJD3$
BET$2nd$$
G9a/GLP$BET$
PHD2$
L3MBTL3$
CREBBP$4th$
WDR5$
DOT1L$BAZ2B/A$
JMJD2$
CREBBP$1%3$
G9a/GLP$2nd$$
SMARCA4$
Cell activity
Pan$2%OG$
Me$Lys$Binders$BRD$ (H)MT$ KDM$HAT$ TUD$2OG$Oxygenase$ WD$Domain$
SMARCA4$2nd$$
JARID1C$
BAZ2B/A$2nd$$
EZH2$
Epigene@cs(inhibitor(pipeline(
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Nearly(all(novel(targets(fail(at((clinical(POC(
Target((ID/((
Discovery(
Hit/((Probe/((Lead((ID(
Clinical((candidate((
ID(
Tox./((Pharmacy(
Phase((I(
Phase((IIa/(b(
HTS LO
10% 30% 30% 90+% 50%
this is killing our industry
…we can generate “safe” molecules, but they are not developable in chosen patient group
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This(failure(is(repeated,(many(@mes(
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
HTS
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
30% 30% 90+%
Target$$ID/$$
Discovery$
Hit/$$Probe/$$Lead$$ID$
Clinical$$candidate$$
ID$
Toxicology/$$Pharmacy$
Phase$$I$
Phase$$IIa/$b$
10% 30% 30% 90+% 50%
LO
…and(outcomes(are(not(shared((
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Most companies have patents for TRPV1
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…in probably all therapeutic areas
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Building(a(new(PPP(to((validate(novel(targets(in(pa@ents(
• Academics,$regulators,$ci3zens,$health$industry,$through$to$Proof$Of$Clinical$Mechanism$$
• POCM:$Phase$IIa,$Exp$Med,$highlight$clinical$poten3al$
• Regulators$$and$pa3ent$groups$$want$to$be$ac3ve$par3cipants$
• Knowledge$crea3on$endeavour$
• All$reagents$will$be$freely$shared$
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Pa@ent(groups(will(enable(faster(and(cheaper(studies(
• Will$facilitate$recruitment$
• Will$minimise$payments$
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Unprecedented(input(from(regulators(
$• help$design$new$clinical$studies$
• help$validate$new$biomarkers$
• pave$path$for$new$targets$
• host$Arch2POCM$data$$
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Reagents(and(publica@ons(will(facilitate(collabora@on,((leveraged(funds,(and(POCMs$
!Lead(
iden@fica@on($
$$$$$$$$$$$$$$$((
$$$$$$$$ $$$$$$$$Phase(I($$$$$$
$$$$$$$$$Phase(II($
Preclinical
Lead optimisation
Efficacy in cellular assays
Efficacy in in vivo “disease” models
ADME, toxicology
Human safety & tolerability
Efficacy in patients
Lead Clinical
candidate Phase I asset
Phase II asset POCM
in vitro probe
in vivo probe
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What(happens(aYer(POCM?(
Develop((molecule*(
Non((developable(molecule(
Developable(molecule(
Develop(proprietary((molecules(
Develop(proprietary(molecules(
Invalid(mechanism(
Publish(quickly(
Proceeds(to(independent(
fund(
Valid((mechanism(
POCM Auc@on((IND((
90%
10% 30%
70%
*Based on existing market exclusivity laws
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Status(
• Established$SAB$(Bell,$Feldman,$Hyman,$Ford$Hutchison)$
• Project$started$in$cancer$• Project$under$discussion$in$neuroscience$
$%$schizo,$au3sm,$depression,$AD$$%$CIHR$earmarked$$30M,$likely$get$other$$public$funds$$%$6$pharmas$interested$$$%$high$level$mee3ng$being$arranged$in$OJawa$$
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Advantages(of(no(IP(before(POCM$$
$• $ pool$private$funds$and$capabili3es$• $ access$significant$public$funds$• $$$$$$access$philanthropic$funds$• $ access$many$academic$labs$quickly$and$
$freely$• $ access$input$of$pa3ent$groups$• $ access$regulatory$input$in$an$
$unprecedented$way$
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Output/(impact(of(this(model(
• Generate$clinically$validated/$de%risked$targets$for$industry$$
• More$novel$medicines$for$pa3ents$
• Reduce$duplica3on$and$wastage$
• Stop$pa3ents$being$needlessly$dosed$
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Lessons(• Academia$needs$quality$probes/$candidates$to$help$discover/$
validate$new$targets$
• Pre%compe33ve$efforts$catalyse$compe33ve$endeavours$
• Based$on$cellular$data$it$is$almost$impossible$to$predict$which$pa3ents$will$benefit$
• Target$valida3on$occurs$in$pa3ents$with$quality$molecules$
• Industry$needs$$$%$novel$validated$targets,$$
$%$novel$biomarkers$
$%$novel$methodologies$to$stra3fy$pa3ents$
$%$to$share$risk$
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Drug(Discovery(is(high(risk(
• We$must$$% pool$resources$and$capabili3es$% rapidly$disseminate$$findings$% delay$IP$un3l$aqer$target$is$validated$in$pa3ents$
• If$we$do$not$WE$will$$% have$few$new$drugs$% will$con3nue$to$waste$money$% will$con3nue$to$harm$pa3ents$% further$erode$the$this$industry$$
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Acknowledgements(• SGC:$Aled$Edwards,$Stefan$Knapp,$Udo$Oppermann$$• SAGE$Bionetworks:$Stephen$Friend,$Thea$Norman$$• Harvard:$Jay$Bradner$$• CIHR,$Genome$Canada,$Ontario,$Wellcome$Trust$
• GSK$(Rab$Prinjha,$David$Wilson),$Novar3s,$Pfizer$(Kevin$Lee),$Lilly,$AbboJ,$Takeda$