Date post: | 17-Dec-2014 |
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SGC Oxford SGC Toronto
A new model to reduce waste in clinical development:
open access collaboration
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$$
What(is(SGC?(• PPP$ $%$GSK,$Pfizer,$Novar3s,$Lilly,$AbboJ,$Takeda$
$ $%$GC,$Ontario,$CIHR,$Wellcome$Trust$$• 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$labs$
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$discovery$
$
This(model(is(working(
SGC: $$
$
• structures$ $(2003%$$$$$)$
• inhibitors$ $(2009%$$$$$)$
Achievements(• Have$purified$>$2000$human$proteins$
• More$than$1300$human$protein$structures$(nearly$25%$of$PDB)$
• 12$inhibitors$(probes)$of$epigene3c$proteins$
• >1$publica3on$per$week$(Science,$Cell$or$Nature$–$every$month)$
• Several$hundred$reagents$distributed$freely$every$year$(academia,$biotech,$pharma)$
Nature, Dec 23, 2010
Novel inhibitor for BET sub-family (JQ1)
JQ1(has(ac@ve(and(inac@ve(enan@omers((
JQ1(reduces(prolifera@on(in((two(pa@ent(derived(cell(lines(
797 403
0
20
40
60
80
100
Vehicle JQ1 Vehicle JQ1
Ki67
Pos
itive
( %
)
KI67 positive = proliferating
JQ1(induces(apoptosis(
Annexin V, marker of early apoptosis PI = propidium iodide, marker of late apoptosis STA = Staurosporine
JQ1(reduces(tumour(size$$
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:$$ $Novel$Targets$in$AML $ $ $Cancer(Cell,$2011,$Sep$13$Mertz$et$al$:$ $Myc$dependent$cancer $ $ $PNAS,$2011,$Oct$4$Zhao$et$al:$ $ $Post$mito3c$transcrip3onal$re%ac3va3on $Nature(Cell(Biology,$2011$Oct$9$
Lysine(Demethylases(
SGC structure
Non SGC structure
Catalytic domain purified
Alphascreen in place
OXFORD CENTRE FOR OA PATHOGENESIS!!Novel(JMJD3(inhibitor(produces(dose(related(inhibi@on((
of(TNF(release(from(human(macrophages(
Inhibitor$$% increases$K27me3,$$% decreases$RNApolII$% no$change$in$H3$
JMJD3(inhibitor(reduces((bone(resorp@ve(ac@vity(in(osteoclasts(
RANKL$=$receptor$ac3vator$of$nuclear$factor$KB$ligand$RANK$=$osteoclast$cell$surface$receptor$$
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
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(
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
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((
Most companies have patents for TRPV1
…in probably all therapeutic areas
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$$want$to$be$ac3ve$par3cipants$
• Knowledge$crea3on$endeavour$
• All$reagents$will$be$freely$shared$
Pa@ent(groups(will(enable(faster(and(cheaper(studies(
• Will$facilitate$recruitment$
• Will$minimise$payments$
Unprecedented(input(from(regulators(
$• help$design$new$clinical$studies$
• help$validate$new$biomarkers$
• pave$path$for$new$targets$
• host$Arch2POCM$data$$
Reagents(and(publica@ons(will(facilitate(collabora@on,((leveraged(funds,(and(POCMs$
!Lead(
iden@fica@on($
$$$$$$$$$$$$$$$((
$$$$$$$$ $$$$$$$$Phase(I($$$$$$
$$$$$$$$$Phase(II($
Preclinical
Lead optimisation
Efficacy in cellular assays
Efficacy in in vivo “disease” models
ADME, toxicology
Human safety & tolerability
Efficacy in patients
Lead Clinical
candidate Phase I asset
Phase II asset POCM
in vitro probe
in vivo probe
What(happens(aYer(POCM?(
Develop((molecule*(
Non((developable(molecule(
Developable(molecule(
Develop(proprietary((molecules(
Develop(proprietary(molecules(
Invalid(mechanism(
Publish(quickly(
Proceeds(to(independent(
fund(
Valid((mechanism(
POCM Auc@on((IND((
90%
10% 30%
70%
*Based on existing market exclusivity laws
Status(
• Established$SAB$(Bell,$Feldman,$Hyman,$Ford$Hutchison)$
• Project$started$in$cancer$• Project$under$discussion$in$neuroscience$
$%$schizo,$au3sm,$depression,$AD$$%$CIHR$earmarked$$30M,$likely$get$other$$public$funds$$%$6$pharmas$interested$$$%$high$level$mee3ng$being$arranged$in$OJawa$$
Advantages(of(no(IP(before(POCM$$
$• $ pool$private$funds$and$capabili3es$• $ access$significant$public$funds$• $$$$$$access$philanthropic$funds$• $ access$many$academic$labs$quickly$and$
$freely$• $ access$input$of$pa3ent$groups$• $ access$regulatory$input$in$an$
$unprecedented$way$
Output/(impact(of(this(model(
• Generate$clinically$validated/$de%risked$targets$for$industry$$
• More$novel$medicines$for$pa3ents$
• Reduce$duplica3on$and$wastage$
• Stop$pa3ents$being$needlessly$dosed$
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$
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$$% have$few$new$drugs$% will$con3nue$to$waste$money$% will$con3nue$to$harm$pa3ents$% further$erode$the$this$industry$$
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,$Takeda$