autism RESEARCHCENTRE

ASD clinical trials: what we know and where research is going

Evdokia Anagnostou, MDAssociate Professor, Department of Pediatrics, University of TorontoSenior Clinician Scientist, Bloorview Research InstituteCanada Research Chair, Translational Therapeutics in ASD

Disclosures• Consulting:Roche,Takeda• Funding:

– BrainCanada,OntarioBrainInstitute,CIHR,DoD,HRSA,NCE-NeuroDevNet,AutismSpeaks,PSI,ALVAfoundation

– Unrestrictedgrant:Sanofi-Aventis– Grantsupport:SynapDx

Jason LerchStephen SchererRosanna WeksbergJames EllisKarun SinghSuma JacobRob NicolsonTerry Bennett

AUTISMSPECTRUMDISORDERS

CurrentApproachesPONDnetwork:HB,UofToronto;McMaster;Lawson,WesternU,QueensU

ATN:HB,UofToronto;OSU;Pittsburgh;Vanderbilt;ColumbiaOther:UIC,Minnesota,RushU,MountSinaiNY

• Targetemerginggenomicvariation

• Riluzole• Memantine• Tideglusib

• Targetneuropathologytargets

• Omega3fattyacids

• Pioglitazone

• Targetneurocircuitryofinterest

•Oxytocin

RiluzolevsplaceboinASD(co-Pis:RobNicolson,TerryBennet)

• 60childrenandyouthwithASD– 7-17years– Stablemedsandtherapies

• Randomized1:1• 12weeksexposure• F/u1monthpastlastdose(week16)

Riluzole Placebo p

Age 11.6±3.6* 11.5±2.4 ns

M:F 23:6 24:5 ns

%Caucasian 79% 55% ns

IQ 80.2±28.4 70.1±18.6 ns

Riluzole Placebo p

Baseline Week12 Baseline Week12

ABC-L* 12.1±6.9** 8.6±6.6 12.8±7.8 10.4±8.1 0.3

ABC-I* 11.9±7.7** 7.6±7.8 14.3±9.2 14.0±11.2 0.03

ABC-H 18.9±10.2 13.9±9.7 21.9±11.6 21.2±13.2 0.03

SCAS 18.1±12.1 13.3±11.5 15.0±11.5 14.9±12.1 0.09

Socialabilities:ABCSocialwithdrawal

Externalizingbehaviors

p= 0.02; d= 0.45, coeff estimate for riluzole: -4.56

P=0.02; d=0.4Coeff estimate for riluzole: -5.24

Targeting networks of relevance: the example of oxytocin

RCTofINoxytocininyouthwithASDMethods

• 60youthrandomized,1:1• HollandBloorview,UniversityofToronto• UniversityofMinnesota– DrJacob

– Earlytermination:6:5active,1placebo

• 12weeksexposure• Follow-upat24weeks

• Dose:0.4IU/kg/dose,2dosesaday,8+/- 2hoursapart

RCTofINoxytocininyouthwithASDMethods:Inclusion/Exclusion

• Ages10-17years• VIQandPIQ>70• Stableconcomitantmedications• Stablemedicalhistory• Notonhormonalbirthcontrol

RCTofINoxytocininyouthwithASDBaselineCharacteristics

Oxytocinn=30

Placebon=30

Age 12.5(1.7) 12.4(1.9)

sex 28:2 26:4

FullscaleIQ 106.1(17) 98.9(16.5)

VerbalIQ 101.3(16.6) 98.1(15.9)

Non-verbalIQ 110(20.2) 99.9(16.7)

RaceCaucasianBlackAsianAmIndian/InuitOther

241113

270112

RCTofINoxytocininyouthwithASDLetsFaceIt– facesvshouses– sameordifferent

0 4 8 12 16 20 2480

85

90

95

100Let's Face It: Faces

Week

PlaceboOxytocin

0 4 8 12 16 20 24

70

75

80

85

90

95Let's Face It: Houses

Week

PlaceboOxytocin

RCTofINoxytocininyouthwithASDPedsQL

EmotionalFunctioning

SocialFunctioning

SchoolFunctioning

PsychosocialHealth

PhysicalHealth

TotalScore

-5

0

5

10

15

20

25

Changefrom

baseline

OxytocinPlaceboWeek12Week24

• OxyBloodlevels– Changecomparedtoplacebo

• Otherpredictorsoftreatmentresponse:– PedsQL:Est=0-0.6,F:27.8,p=0.000

– Snps• Deltalog(pOT):p=0.006(drugcond*rs4686302)

• DeltaPQL-soc:p=0.029(drugcond*rs6791619)

• DeltaPQL-psyc:p=0.040(drugcond*rs6791619)

Pioglitazone• PPRgammainhibitor• 5-12years• 16-weeks,singleblind,2-weekplaceborun-in,MTD

• 0.25mg/Kg,0.5mg/Kgand0.75mg/Kg

Pioglitazone

• Maximumtolerateddose0.75mg/kg

Estimate(95%CL) Estimate(95%CL)

t-testp-value

Baseline Week8 Week16 Week16-Baseline

n 27 25 25

ABCSocialWithdrawal10.1

(6.6;13.7)7.5

(4.8;10.3)6.7

(3.8;9.6)3.4

(1.6;5.3) 0.0005

SRSTotal188.4

(73.6;103.2)88.2

(78.9;97.5)85.8

(75.2;96.4)2.6

(-12.0;17.2) 0.7

ABCIrritability13.8

(10.2;17.4)11.2

(8.3;14.0)10.0

(6.9;13.0)3.8

(1.3;6.3)0.004

ABCHyperactivity21.7

(17.6;25.7)18.7

(14.9;22.4)16.5

(13.2;19.7)5.2

(2.6;7.8)0.0003

BASC-2Anxiety28.9

(5.5;12.2)8.1

(5.3;10.8)8.2

(5.2;11.3)0.6

(-1.5;2.8) 0.6

RBSRTotal33.0

(25.7;40.3)27.5

(20.6;34.3)24.5

(17.4;31.5)8.5

(3.7;13.3)0.0009

CY-BOCS112.6

(11.1;14.2)10.7

(9.4;12.1)9.4

(8.0;10.9)3.2

(2.0;4.4) <.0001

• Design– 16weeksRCT

• 16weeksblindeddiscontinuation

• Outcomemeasures:– Primary:BMIzscore– Secondary:BMI,weight– Exploratory:Metabolicparameters;ABCirritability;memory

AdverseEvents

Metformin (n = 28) Placebo (n = 32) Treatment Difference

16-week Change

95% CI p16-week Change

95% CI p16-week change

95% CIEffect Size

p

Total cholesterol (mmol/L) -0.027

(-0.227,0.173) 0.79 -0.085

(-0.268,0.097) 0.35 0.058

(-0.212,0.328) 0.123 0.67

LDL (mmol/L) -0.114(-

0.271,0.043) 0.15 -0.011(-

0.158,0.137) 0.89 -0.104(-

0.318,0.111) 0.278 0.34

HDL (mmol/L) 0.085(-

0.037,0.206) 0.17 -0.025(-

0.136,0.085) 0.65 0.110(-

0.053,0.273) 0.357 0.18

Triglycerides (mmol/L) 0.065(-

0.252,0.382) 0.68 0.070(-

0.222,0.361) 0.63 -0.005(-

0.418,0.408) 0.006 0.98Glucose, fasting (mmol/L) -0.170

(-0.371,0.031) 0.10 -0.134

(-0.320,0.052) 0.16 -0.036

(-0.287,0.215) 0.064 0.78

Insulin, fasting (pmol/L) 13.7 (-72.5,99.9) 0.75 20.5 (-58.6,99.7) 0.61 -6.8

(-123.7,110.1) 0.030 0.91

HOMA-IR 0.53 (-2.39,3.44) 0.72 0.59 (-2.07,3.26) 0.66 -0.07 (-3.99,3.86) 0.009 0.97Hgb A1C (mmol/mol) -0.59 (-1.56,0.39) 0.23 0.37 (-0.51,1.25) 0.41 -0.95 (-2.26,0.35) 0.403 0.15

ABC Lethargy -2.08 (-4.80,0.63) 0.13 -1.06 (-3.64,1.52) 0.41 -1.02 (-4.54,2.50) 0.146 0.56ABC Stereotypy -0.34 (-1.54,0.85) 0.57 -1.16 (-2.30,-0.03) 0.044 0.82 (-0.72,2.36) 0.239 0.29ABC Hyperactivity -1.14 (-3.79,1.50) 0.39 -1.60 (-4.10,0.89) 0.20 0.46 (-3.09,4.00) 0.069 0.80ABC Inappropriate Speech -0.67 (-1.37,0.03) 0.060 -0.11 (-0.77,0.55) 0.74 -0.56 (-1.50,0.38) 0.305 0.24

Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight

Associated with Atypical Antipsychotic Use

Authorship List

Michael G. Aman, Ph.D., Jill A. Hollway, Ph.D., J. Veenstra-VanderWeele, M.D., Benjamin L. Handen, Ph.D., Kevin B. Sanders, M.D., James Chan, M.S., Eric Macklin, Ph.D., L. Eugene Arnold, M.D., M.Ed.,

Taylor Wong, B.S., Cassandra Newsom, M.D., Rianne Hastie Adams, M.S.W., Sarah Marler, M.A., Naomi Peleg, M.Sc., and Evdokia A. Anagnostou, M.D.

Table2.EffectsofMetforminvs.Placebo(Panel2)andeffectofTimeandMetformin(Panel3)onMemoryPerformance

PBOPhase1vs.MetPhase1 BaselinetoWeek32

Variable n PBO-Ph1 MetPh1 Estim. p E.S. PBO-Met Met-Met Estim. pNEPSYMemoryforDesigns

MDContentScore(0-60)a 45 2.126 2.718 0.593 0.732 0.084 3.447 6.100 2.653 0.206

MDSpatialScore(0-30)b 45 1.210 -0.769 -1.979 0.042 0.464 0.589 2.017 1.428 0.228

MDTotalScore(0-150)c 45 12.727 5.370 -7.357 0.208 0.357 15.269 20.280 5.011 0.491

MDDContentScore(0-20)d 37 1.108 1.378 0.270 0.718 0.129 1.159 0.361 -0.799 0.494

MDDSpatialScores(0-10)e 37 0.988 0.405 -0.583 0.107 0.451 0.380 0.395 0.015 0.976

MDDTotalScore(0-50)f 37 6.089 2.593 -3.497 0.182 0.514 3.622 1.761 -1.861 0.592

Mod.CaliforniaVerbalLearningTest-C

ShortDelayRecallScore(0-50) 48 1.344 0.084 -1.261 0.530 0.184 4.672 3.270 -1.403 0.421

LongDelayRecallScore(0-10) 48 -0.067 0.303 0.370 0.555 0.183 0.492 1.360 0.868 0.098

Recognitions&RejectionsScore(0-20) 440.161 4.430 4.268 0.127 0.340 4.020 4.791 0.771 0.795

Knowledge TranslationBiostatistics

co-clinical trials in neurodevelopmental disorders

Jason Lerch and Evdokia Anagnostou

Co-Clinical Trials for Lung Cancer

MEK inhibitor (selumetinib)

100%

Kras Kras + p53 Kras + Lkb1

100% 0% 10%Chen, Zhao, Katherine Cheng, Zandra Walton, Yuchuan Wang, Hiromichi Ebi, Takeshi Shimamura, Yan Liu, and others. "A Murine Lung Cancer Co-clinical Trial Identifies

Genetic Modifiers of Therapeutic Response." Nature 483, no. 7391 (2012): doi:10.1038/nature10937.

Co-Clinical Trials for Lung Cancer

MEK inhibitor (selumetinib)

100%

Kras Kras + p53 Kras + Lkb1

100% 0% 10%Chen, Zhao, Katherine Cheng, Zandra Walton, Yuchuan Wang, Hiromichi Ebi, Takeshi Shimamura, Yan Liu, and others. "A Murine Lung Cancer Co-clinical Trial Identifies

Genetic Modifiers of Therapeutic Response." Nature 483, no. 7391 (2012): doi:10.1038/nature10937.

GSK3 PATHWAYS

TIdeglusib

Figure 2: The effect of tideglusib on cognitive deficits and hyperactivity in the open field in the FMR1 knockout transgenic mouse model of Fragile X Syndrome. The figure shows Vehicle (V) and tideglusib (T) in wild type (WT) and FMR1 knockout mice (FXS). Panel A shows the performance on a test of context-dependent fear conditioning. Panel B shows activity in the open field. Note that p <0.05 compared with untreated wild type mice (Franklin et al 2013)

TIDE: RCT of tideglusib vs placebo in ASD

• 90 youths 12-17

• What we do different:• 1. Embeded in POND• 2. Additional biomarkers • 3. added social adaptive function to battery

Next study:Arbacofen vs placebo

• What we do different:• co clinical trial• Embeded in POND• Electrophysiology as an exploratory marker• Collaboration with EU-AIMS to double the sample size

• Change of primary to social adaptive function• Extend exposure to 16 weeks• Limit to verbal children

From disability to possibility

Thank you to families and individuals who have participated in our studies

TIDEGLUSIB (GSK3 inhibitor)● Regulates circadian clock

● Regulates inflammatory response (reduces pro-inflammatory cytokines, increases anti-inflammatory cytokines)

● Regulates neurogenesis/cell differentiation

● Phosphorylates histone deacetylase 3

● Key role in synaptic plasticity (via NMDA mediated LTD).