Transcript Roberds Rett symposium 2016x

FACILITATING DRUG DEVELOPMENT FOR
TUBEROUS SCLEROSIS COMPLEX
Steven L. Roberds, Ph.D.
Chief Scientific Officer, TS Alliance
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ABOUT TUBEROUS SCLEROSIS COMPLEX
• Tuberous sclerosis complex (or TSC) is a
genetic disorder that causes tumors to
form in vital organs, primarily the brain,
eyes, heart, kidney, liver, lungs and skin.
• TSC affects ~1 in 6,000 live births.
• An estimated 50,000 Americans have
TSC, and more than 1 million worldwide.
• No two people are affected the same way, not even identical twins.
• Neurological manifestations are often the most devastating – affecting
almost all with TSC in some manner, from mild to severe.
• TSC is a leading genetic cause of autism and epilepsy.
TUBEROUS SCLEROSIS ALLIANCE (TS ALLIANCE)
The TS Alliance, founded in 1974,
is committed to finding a cure for
tuberous sclerosis complex while
improving the lives of those
affected:
• by developing programs,
support services and resource
information;
• by stimulating and sponsoring
research; and
• by creating and implementing public and professional education
programs designed to heighten awareness of the disease.
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ANNUAL INVESTMENTS IN TSC RESEARCH
NIH, TSCRP, and TS Alliance
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IMPACTING DRUG DEVELOPMENT WITH
LIMITED, FOCUSED FUNDING
Lead optimization
Drug
Hypothesis
generation screening
Phase 1
Preclinical
Development
Phase 2
Phase 3
Approved
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TS ALLIANCE RESEARCH INITIATIVES AND COLLABORATIONS
to accelerate discovery of new treatments and a cure
Improved quality of life,
personalized treatment, cure
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TSC NATURAL HISTORY DATABASE
• Since 2006, enrolled 2,000 participants
• Data entered at 18 TSC Clinics throughout the US
• 2016-2018 strategy is to increase depth of data in areas
related to TSC constituents’ research priorities:
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TSC BIOSAMPLE REPOSITORY
Linked to clinical data in Natural History Database
Voluntary TSC NHD Participants
Examples of Research Needs
• Understanding phenotypic
heterogeneity
• Development of clinical
biomarkers
• Patient-derived cells for
drug testing
DNA
Plasma
Tissue
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TSC CLINICAL RESEARCH CONSORTIUM
Biomarker studies initiated in 2013 funded by NIH
• Identify early markers of risk for autism in TSC (NINDS, NICHD)
• Identify early markers of risk for epilepsy in TSC (NINDS)
– Regular EEG and imaging evaluation of 40 infants
– Interim results published in October for 28 infants
Clinical seizures
No clinical
seizures
Abnormal EEG
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0
Normal EEG
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•
•
•
•
Sensitivity-73.7%
Specificity- 100%
Positive Predictive Value (PPV)-100%
Negative Predictive Value(NPV)--64%
Wu et al (2016) Pediatr Neurol 54:29-34
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PREVENTING EPILEPSY USING VIGABATRIN IN
INFANTS WITH TSC (PREVeNT) TRIAL
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•
•
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NINDS-funded Phase II study
Projected start date: Fall 2016
Multicenter: 7 sites across the US
Study objective: impact of early versus delayed treatment
with vigabatrin on development, assessed at 24 and 36
months of age
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TSC PRECLINICAL CONSORTIUM
Key piece of strategy to accelerate drug development
• Standardize models, tests and assays for preclinical drug
development
– Re-purpose compounds of interest
– Test analogs with improved safety profiles
– Investigate novel compounds and mechanisms of action
• Engage industry and increase opportunities for clinical trials
• Focus on Transparency, Robustness, Replication, Rigor and
Translatability
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EPILEPSY IN TSC: EPIDEMIOLOGY & NATURAL HISTORY
• Epilepsy occurs in ~85% of individuals with TSC (Sparagana et al., 2003; Devlin et
al., 2006; Chu-Shore et al. 2010).
• Age of seizure onset is <1 year in 63% and
<3 years in 82% (Chu-Shore et al. 2010).
• Multiple seizure types occur in about one-half
of TSC patients, including focal and generalized
seizures and infantile spasms.
• ~2/3 of TSC patients with epilepsy are
drug-resistant, as opposed to ~1/3
intractability rate in general epilepsy population.
- one exception: vigabatrin for spasms in TSC
• However, a subset of TSC patients may
achieve prolonged seizure remission,
including off seizure medication.
(with thanks to M. Wong)
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EPILEPSY MODEL TOP PRIORITY: GFAP-TSC1 CKO
(with thanks to M. Wong)
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CONSORTIUM STRUCTURE
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TSC PRECLINICAL CONSORTIUM
Industry screening buckets
Initial Commitment
Company Consortium
Member
Access to all validation,
phenotypic and
reference compound
results including raw
data
Screening Type
Bucket
Public
Bucket A. Reference
compounds with results
released to consortium. No IP
implication.
Bucket B. Company's
compound with results
released to consortium.
Escrow period to protect IP.
Private
Bucket C. Company's
compound with results not
released to consortium. No
strings attached.
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TS ALLIANCE RESEARCH INITIATIVES AND COLLABORATIONS
to accelerate discovery of new treatments and a cure
Improved quality of life,
personalized treatment, cure
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ACKNOWLEDGMENTS
Researchers
TSC Clinics
Individuals
with TSC and
their families
Industry
Partners
Donors and
Funders
Improved quality of life,
personalized treatment, cure
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