Vanderbilt Center for Neuroscience Drug Discovery

Vanderbilt Center for Neuroscience Drug
Discovery: Translating Basic Science into
Patient Care
P. Jeffrey Conn
Department of Pharmacology
Vanderbilt Center for Neuroscience Drug Discovery
Vanderbilt Center for Neuroscience Drug Discovery
Molecular Pharm
Colleen Niswender
Med. Chem.
In Vivo/ Behavioral
DMPK
Carrie Jones
Scott Daniels
Craig Lindsley
Mission: to promote translation of advances in basic science to novel
therapeutics by de risking efforts focused on novel approaches for
treatment of serious brain disorders.
- Led by world leaders in drug discovery and staffed by veteran drug
discovery scientists recruited from major pharmaceutical companies.
(Members of VCNDD leadership team have advanced > 40 drug candidates into
clinical development while in industry positions)
- Includes all major infrastructure for drug discovery traditionally found
only in industry settings.
- Approximately 100 full time FTEs in the VCNDD
VCNDD resources are leveraged with large
research infrastructure at Vanderbilt
VCNDD
Molecular Pharm
In Vivo/ Behavior
Department of Pharmacology
Metabolic Core
Vanderbilt Mass Spec
Research Center
Vanderbilt Inst. for
Chemical Biology
Rodent Bio-behavioral
Facility
Clinical Pharmacology
Division
Center for Molecular
Neuroscience
DMPK
Vanderbilt Imaging
Research Center
Center for
Translational
Science
Advances
Center for Structural
Biology
Vanderbilt Brain
Institute
Med Chem
Vanderbilt Ingram
Cancer Center
Dept. of Psychiatry
Molecular Libraries Probe
Center Network
Small Molecule NMR
Facility
Imaging Studies in VCNDD Efforts
PET
PET (experimental)
CT-MRI (template)
Cerebellum
Hippocampus
Striatum
Cortex
Vehicle
1 mg/kg
3 mg/kg
10 mg/kg
30 mg/kg
VU0409106 50% Occupancy gives full efficacy in primary PD model
fMRI
Pretreatment
Baseline
20 min
Start
functional
scan
Post-Challenge
30 min
30 min
Drug or
Vehicle
PCP or
Vehicle
Has predicted activity important in brain circuits important for Schizophrenia
End of scan
Vanderbilt Institute for Clinical and Translational Research
Mission
• Systematically remove
impediments to translation
• Create novel, researchenabling infrastructure
• Train the next generation of
investigators
• Evaluate program
effectiveness.
VCNDD
Imaging
CTSA
(VUIIS)
Psychiatry
Integrated effort to
advance mGluR5 NAMs
into POC studies for major
depression using animal
models, animal and
human PET and fMRI, and
clinical POC studies
Parkinson’s Disease
Characterized by:
Tremor
Bradykinesia
Rigidity
Disturbance of posture
Current treatments effective early but have
severe adverse effects and lose efficacy as
the disease progresses
Dyskinesias - grimacing, head bobbing, oscillatory
rocking movements of arms, legs, or trunk.
Behavioral disturbances - hallucinations, paranoia,
mania, insomnia, anxiety, nightmares,
Fluctuations in response – Lack of reliable efficacy
combined with severe motor side effects
CORTEX
STRIATUM
D2
x
D1
SNc
GPe
Thal
STN
GPi/SNr
Antiparkinsonian activity of mGluR4 agonists
CORTEX
STRIATUM
D2
x
D1
SNc
GPe
Asymmetry Score
Gene profiling
reveals mGluR4
mRNA in striatum
Activation of mGLuR4 has
robust efficacy in multiple
animal models
80
L-AP4
L-DOPA
60
40
20
*
0
*
-20
-40
Pre-Drug
Post-Drug
Thal
mGluR4 protein in presynaptic
terminials at overactive striatoGpe synapse
STN
GPi/SNr
Activation of mGluR4 reduces
transmission at overactive
striato-Gpe synapse.
Funding by Michael J. Fox Foundation allowed discovery
of new drug candidates
In partnership with MJFF we have optimized drug candidates that are
positive allosteric modulators and are ready to advance to clinical testing
in PD patients!
Current mGluR4 PAM clinical candidates have
excellent profile for advancing to clinical development
ED50=1.4 mg/kg (0.6-3.9)
• EC50 values 20 – 100 nM ; in vivo potencies 0.5 – 2 mg/kg
• Highly selective for mGlu4relative to other mGluR subtypes
• Clean ancillary pharmacology; no activity at cardiac channels, Excellent CYP profile
• Clean in AMES (gene tox) tests
• High oral bioavailability; Highly brain penetrant
• Robust efficacy in relevant animal models of Parkinson’s disease
Staging of Pipeline
Target ID/Validation
mGluR3
In Vivo POC
Lead
Optimization
M5 PAMs
mGluR7
mGluR8
GLP-1 agonists
MCH antagonists
AKT1
T-type Ca channels
Phospholipase D
KCNQ
Clinical
Development
Candidate
mGluR2 PAMs
(schizophrenia)
M1 allosteric
3Q 2010
agonists/PAMs
(Sz/Alzheimers)
M1 antagonists
(FXS/Dystonia)
2Q 2011
M4 PAMs
(Sz/Alzheimers)
Choline Transporter
Traditional Academic
funding NIH,
Foundations, etc.
mGluR5 NAMs
(FXS; depression)
2011
mGluR5 PAMs
(Schizophrenia)
2011
mGluR4 PAMS
(Parkinson’s)
2011
4Q 2010
GlyT1 Inhibitors
(Schizophrenia)
VPDD Budget and Growth
Unique Training Grant for Neuroscience Drug Discovery
VCNDD productivity and recognition
119
•
119 patents filed, 2007-present. Represents over 11% of all
Vanderbilt University Disclosures!
•
>160 manuscripts published 2007-present.
•
Growth from zero to >$85 million external funding since 2004
(> $18M in 2011).
•
4 partnerships for fully engaged drug discovery efforts: 1)
Parkinson’s (MJFF), 2) Schizophrenia (J&J/Janssen), 3) Fragile
X/Autism (Seaside Therapeutics), 4)Schizophrenia (NIH)
•
>40 Companies have contacted VPDD over past 3 yr asking for
opportunities to partner or license IP.
Patents
160
Papers
$85M
Total
Funding
4
Partnerships
40
Contacts
VCNDD productivity and recognition
HEALTH INDUSTRYJANUARY 9, 2009.
J&J, Vanderbilt Team Up on Schizophrenia Drugs
Ryan Reynolds helps Fox foundation
Daring to Think Differently About Schizophrenia