A Peek at Dpharm 2012

SGC OxfordSGC 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
Ki67Positive(%)
KI67 positive = proliferating

JQ1(induces(apoptosis(
Annexin V, marker of early apoptosis
PI = propidium iodide, marker of late apoptosis
STA = Staurosporine

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$3rd$
Screening$/$Chemistry$
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$

A Peek at Dpharm 2012

More Related Content

Similar to A Peek at Dpharm 2012 (20)

More from ConferenceForum (20)

Recently uploaded (20)

A Peek at Dpharm 2012