Molecular Targets for Core Symptom Deficits in
ASD and Early Data
Supporting Novel Therapeutics
Evdokia Anagnostou, MD
Cli...
Disclosures

• Consulting:

Neuropharm, Proximagen,
NOVARTIS, Seaside Therapeutics

• Collaborations:

• Funding:

SIEMENS...
Affective
lability
Anxiety/
depression

Socialcommunication
Deficits
Repetitive ASD
behaviors /
restricted
interests

Sens...
Current approaches

Medications to target symptom domains based on
phenotypic overlap of such domains with other disorders...
Suggested new approaches

•

1. Target emerging molecular targets

•

2. Target neuro-circuitry of interest
Genomics of ASD

•

Basic science is
becoming ripe for
translation
– Genetics
– Pinto et al.

Functional
impact of global ...
Treatment

– Use the new knowledge from genetics, imaging, animal
models and novel technologies to develop novel
treatment...
NMDA
inhibitors:
memantine

Arbaclofen
Compounds by
NOVARTIS
ROCHE
Seaside Therapeutics

rapamycin

IGF1
small
molecule
an...
Fragile X syndrome

•

Most common inherited cause of Intellectual disability and
ASD

•

Common other co-morbidites
– Anx...
Fragile X

transcriptional silencing of the
FMR1 gene
loss of the protein FMRP, an
RNA binding protein that inhibits
prote...
Fmr1- mouse

Benjamini et al

Levenga et al
Adesei et al
Agent Reduces Autism-like Behaviors in Mice
Boosts Sociability, Quells Repetitiveness
• NIH Study: Silverman, et al. (Apri...
STX209 for fragile X syndrome:
Analysis in “low sociability”
n=27
subgroup
ABC-Social Withdrawal ≥ 8 at screening and base...
Fig. 3 (A and B) A comparison of the effect of AFQ056 and placebo treatments on the change
from baseline to day 19 or 20 o...
1. Identification of
potential molecular
target: genomics or
other

Drug
approval

2. Model human
mutation in animal
model...
deviation from an optimal range
of synaptic protein synthesis,
irrespectively of direction, may
lead to behavioral and cog...
Co clinical trials ?

Courtesy,
Jason Lerch
Approach 2: target neurocircuitry of
interest
•

Oxytocin
Oxytocin and ASD
•

Decrease blood levels oxytocin in autism

and
•

Absence of normal developmental increase in oxytocin
...
Genetic Associations: OXTR & ASD
5’

Ex 1

Ex 2

Intron 3

Ex 3

Chinese Han (Wu et al. 2005)

Ex 4

3’

rs53576 rs225498 ...
Pilot Study of INOT vs. Placebo in adults
with ASD (Anagnostou et al 2012, Mol Autism)
Social Cognition

B

6 week B

p

M...
Repetitive Behaviours
YBOCS
Oxytocin
Placebo

-.16

.96

.220

12.0 (3.9)
10.3 (2.5)

9.4 (2.9)
8.1 (2.5)

.13

RBS-R High...
Maximum tolerated dose study of INOT in
children and adolescents with ASD
Anagnostou, Brian, Jacob et al

•

Two goals:
– ...
Efficacy
Variable
Abc_SW
Srs_total_raw
Srs_total_tscore
Eyes_hard
Lfi_match_maker_id
asi_general_anxiety_ra
w
asi_general_...
Funded trials in North America
•

Anagnostou et al:
– Oxytocin vs. placebo for children and adolescents with
ASD; funding ...
ASD Research
Study Biology
Genetics
Imaging

Develop Novel Treatments
Change brain structure
and function
New drugs
Early ...
From disability to possibility

Thank you to the families
who participated in the
studies discussed
Emerging findings from clinical trials in ASD
Emerging findings from clinical trials in ASD
Emerging findings from clinical trials in ASD
Emerging findings from clinical trials in ASD
Emerging findings from clinical trials in ASD
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Emerging findings from clinical trials in ASD

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Dr. Evdokia Anagnostou's presentation at the Brain Development Conference 2013

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  • (A and B) A comparison of the effect of AFQ056 and placebo treatments on the change from baseline to day 19 or 20 on the ABC-C score in individual patients with (A) full methylation at the FMR1 promoter and (B) partial methylation at the FMR1 promoter. A decrease in ABC-C score indicates an improvement in behavioral symptoms.
  • Emerging findings from clinical trials in ASD

    1. 1. Molecular Targets for Core Symptom Deficits in ASD and Early Data Supporting Novel Therapeutics Evdokia Anagnostou, MD Clinician Scientist, Bloorview Research Institute Assistant Professor, Department of Pediatrics, University of Toronto
    2. 2. Disclosures • Consulting: Neuropharm, Proximagen, NOVARTIS, Seaside Therapeutics • Collaborations: • Funding: SIEMENS DOD, CIHR, Autism Speaks, PSI, ALVA foundation, HRSA, NeuroDevNet, Ontario Brain Institute
    3. 3. Affective lability Anxiety/ depression Socialcommunication Deficits Repetitive ASD behaviors / restricted interests Sensory-motor dysfunction GI dysfunction, sleep dysfunction, ADHD – “like” epilepsy Impulsive aggression Learning Attention Memory
    4. 4. Current approaches Medications to target symptom domains based on phenotypic overlap of such domains with other disorders, i.e. – SSRI for repetitive behaviors (from OCD) – Atypical antipsychotics for maladaptive behaviors (irritability and aggression across several other disorders) – Stimulants, non-stimulants for inattention (overlap with ADHD)
    5. 5. Suggested new approaches • 1. Target emerging molecular targets • 2. Target neuro-circuitry of interest
    6. 6. Genomics of ASD • Basic science is becoming ripe for translation – Genetics – Pinto et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010 Jul 15;466(7304):36872.
    7. 7. Treatment – Use the new knowledge from genetics, imaging, animal models and novel technologies to develop novel treatments – Where is the lesion? – Distributed-Pervasive – What is the lesion? – functional and structural disconnectivity – dynamic
    8. 8. NMDA inhibitors: memantine Arbaclofen Compounds by NOVARTIS ROCHE Seaside Therapeutics rapamycin IGF1 small molecule analog
    9. 9. Fragile X syndrome • Most common inherited cause of Intellectual disability and ASD • Common other co-morbidites – Anxiety disorders – ADHD like – Irritability aggression – Epilepsy – Sensory dysregulation – GI dysfunction – Macro-orchidism – Dysmorphic faces
    10. 10. Fragile X transcriptional silencing of the FMR1 gene loss of the protein FMRP, an RNA binding protein that inhibits protein synthesis
    11. 11. Fmr1- mouse Benjamini et al Levenga et al Adesei et al
    12. 12. Agent Reduces Autism-like Behaviors in Mice Boosts Sociability, Quells Repetitiveness • NIH Study: Silverman, et al. (April 25, 2012). Science Translational Medicine. • • • GRN-529 is a member of a class of agents that inhibit activity of a subtype of receptor protein on brain cells for glutamate (m-Glu R 5 inhibitors) BTBR mice (potential ASD model) injected with GRN529 showed reduced levels of repetitive self-grooming and spent more time around – and sniffing nose-tonose with – a strange mouse. GRN-529 almost completely stopped repetitive jumping in another strain of mice.
    13. 13. STX209 for fragile X syndrome: Analysis in “low sociability” n=27 subgroup ABC-Social Withdrawal ≥ 8 at screening and baseline STX209 (mean ± SD) Placebo (mean ± SD) p-value -4.3 ± 6.3 -0.4 ± 7.1 < 0.05 14.2 ± 19.0 4.6 ± 10.8 < 0.05 CGI-I 2.7 ± 1.1 3.5 ± 1.2 < 0.01 CGI-S -1.0 ± 1.1 -0.3 ± 0.9 = 0.01 Treatment preference (clinician) 63% 19% < 0.01 Treatment preference (parent) 67% 19% = 0.001 Responders (CGI-I =1 or 2, and ABC-SW improvement ≥ 25%) 42% 7% < 0.01 ABC-Social Withdrawal Vineland – Socialization (raw) 16
    14. 14. Fig. 3 (A and B) A comparison of the effect of AFQ056 and placebo treatments on the change from baseline to day 19 or 20 on the ABC-C score in individual patients with (A) full methylation at the FMR1 promoter and (B) partial methylation at the FMR1 promoter. S. Jacquemont et al., Sci Transl Med 2011;3:64ra1 Published by AAAS
    15. 15. 1. Identification of potential molecular target: genomics or other Drug approval 2. Model human mutation in animal model 5. Clinical trial in syndrome sharing biology with 4. 3. Preclinical trial 4. Clinical trial in syndrome related to molecular target identified Drug approval Anagnostou , Nature 2013
    16. 16. deviation from an optimal range of synaptic protein synthesis, irrespectively of direction, may lead to behavioral and cognitive difficulties Behavior can not distinguish adequately Urgent need to identify relevant biomarkers fro stratification
    17. 17. Co clinical trials ? Courtesy, Jason Lerch
    18. 18. Approach 2: target neurocircuitry of interest • Oxytocin
    19. 19. Oxytocin and ASD • Decrease blood levels oxytocin in autism and • Absence of normal developmental increase in oxytocin blood levels with age in autism – Altemus et al 1994, Modahl et al 1998, Green et al 2001, Kosfeld et al, 2005, Kirsch et al, 2005 • Gene expression studies: – Increased methylation of CpG islands known to regulate OXTR expression in peripheral blood and temporal cortex. (Gregory et al BMC medicine 2009) – Weksberg laboratory has replicated increased OXTR DNA methylation in an independent cohort of 40 ASD patients and 20 controls.
    20. 20. Genetic Associations: OXTR & ASD 5’ Ex 1 Ex 2 Intron 3 Ex 3 Chinese Han (Wu et al. 2005) Ex 4 3’ rs53576 rs225498 (A) Japanese (Liu et al. 2010) Caucasian-Chicago (Jacob et al. 2007) Caucasian-Israel (Lerer et al. 2007) Caucasian-Yale (Yrigollen et al. 2008) rs225498 (G) rs2268494 rs1042778 rs2268493 German HF-ASD (Wermter et al. 2009)--haplotype 5’to Intron 3 Irish, Portugese & UK x 2 and Slovak --mixed results 5’, 3’ and exon 3 (Chakrabarti et al 2009, Kelemenova et al 2010, Tansey et al. 2010--SNPs in Intron 3 related to gene expression)
    21. 21. Pilot Study of INOT vs. Placebo in adults with ASD (Anagnostou et al 2012, Mol Autism) Social Cognition B 6 week B p Mean (SD) Week 0 Mean (SD) Week 6 d RMET Oxytocin Placebo ----- 22% 0.004 0.002* 48% (20%) 74% (14%) 61% (24%) 63% (12%) 1.2 DANVA-Face 2.33 .381 32.6 (8.8) 39.1 (8.4) 33.5 (6.4) 37.4 (7.4) 13.98 Oxytocin Placebo DANVA- Paralanguage Oxytocin Placebo 0.33 1.96 11.76 .351 27.8 (5.7) 34.1 (3.0) 30.5 (2.7) 35.2 (4.7) 0.38 Social Function CGI-Social .582 30% Improved 11% Improved Oxytocin Placebo SRS Oxytocin OR=3. 4 .58 3.48 .664 92.3 (29.9) 84.5 (23.3) 111.4 (13.5) 96.5 (13.0) 0.34
    22. 22. Repetitive Behaviours YBOCS Oxytocin Placebo -.16 .96 .220 12.0 (3.9) 10.3 (2.5) 9.4 (2.9) 8.1 (2.5) .13 RBS-R Higher Order ----- 4.57 .301 17.0 (10.6) 20.0 (10.8) 17.7 (16.2) 17.8 (13.3) -.22 ----- -2.25 .045 .065* 5.8 (4.6) 4.9 (3.7) 2.4 (2.3) 3.7 (2.6) .64 ----- 9.5% .034 .031* 47.8% (16.3%) 65.2% (12.3%) 59.5% (16.0%) 63.2% (12.3%) .84 Oxytocin Placebo RBS-R Lower Order Oxytocin Placebo Quality of Life WOQOL-emotional
    23. 23. Maximum tolerated dose study of INOT in children and adolescents with ASD Anagnostou, Brian, Jacob et al • Two goals: – MTD: – Dose range: 0.2, 0.26. 0.33. 0.4 IU/kg/dose – 3 patient increments – Measures sensitive to change – Pilot large battery
    24. 24. Efficacy Variable Abc_SW Srs_total_raw Srs_total_tscore Eyes_hard Lfi_match_maker_id asi_general_anxiety_ra w asi_general_anxiety_tsc ore asi_sep_anx_raw asi_sep_anx_tscore Ir_em_irony_1ord Srst_social_tot Basc_Bsi_raw Basc_Bsi_tscore Basc_socskills_raw Basc_socskills_tscore Basc_func_comm_raw Basc_func_comm_tscore Estimate (0-12 weeks) 3.0 20.8 9.8 -0.14 -10.93 3.32 11.00 1.07 7.50 -1.64 -1.36 20.64 4.29 -1.47 -2.84 -2.44 -4.10 CL 0.04;5.96 8.1;33.5 3.8; 15.8 -0.82; -1.99 -19.28;-2.59 1.29; 5.36 3.97; 18.03 0.25; 1.89 0.22; 14.78 -3.02; -0.27 -2.72; 0.008 3.40; 37.87 0.46; 8.12 -2.65;-0.29 -5.31; -0.38 -3.67; -1.22 -6.23; -1.97 0-12 pvalue 0.05 0.002 0.002 0.7 0.01 0.003 0.004 0.01 0.04 0.02 0.05 0.02 0.03 0.02 0.03 0.0004 0.0006 0-24 pvalue 0.2 0.06 0.06 0.009 0.1 0.2 0.1 0.5 0.2 0.01 0.7 0.02 0.03 0.1 0.2 0.01 0.01
    25. 25. Funded trials in North America • Anagnostou et al: – Oxytocin vs. placebo for children and adolescents with ASD; funding source: DOD; phase II – Open label, dose finding – Randomized controlled trial (subcontract UIC) – Includes genomics, epigenetics, blood levels – Oxytocin vs. placebo adults with ASD; funding Source: CIHR; phase IIb – Includes genomics, epigenetics, blood levels • Sikich et al: – Oxytcoin vs placebo in children with ASD; funding source: NICHD, phase IIb
    26. 26. ASD Research Study Biology Genetics Imaging Develop Novel Treatments Change brain structure and function New drugs Early intervention Technology-based intervention Nervous system
    27. 27. From disability to possibility Thank you to the families who participated in the studies discussed

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