Transcript TSC Clinical Trials Orrin Devinsky MD NYU Langone School of Medicine TS C P ubl i c a t i ons N u.

TSC Clinical Trials
Orrin Devinsky MD
NYU Langone School of Medicine
TS C P ubl i c a t i ons
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N u mb e r
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T SC
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Y ear
Data derived from PubMed at http://www.ncbi.nlm.nih.gov/pubmed/
Study Ar e a
brain
DNA or
tissue
eyes
heart
kidney
lung
Active and
recruiting
skin
Not yet
recruiting
Ongoing, but
recruitment
closed
# sites
Estimated
enrollment or
# enrolled
Age group
(years)
2
2500
8-90
1
no limit
16-80
2
130
18 & older
1
25
3 & older
1
35
18-80
8
450
7-65
1
30
18-65
1
20
18-65
24
118
18 & older
27
117
All ages
1
40
adults
1
unknown
No age limit
Non-invasive eye-screening (Tabacaru; Columbia University)
2
20
2 and older
RAD001 therapy for epilepsy /TSC (Krueger; CCHMC)
1
12
adults
Sabril / adult partial seizures (Pollard; UPENN)
2
50
6-21
~10
230
No age limit
2
60
0-3
1
up to 15
4 and older
1
18-Jan
18-85, women
Safety Study of Sirolimus and Hydroxychloroquine in Women With LAM (SAIL)
5
150
3-6 mos., up to 9
mos. will be allowed
Early biomarkers of ASD in infants with TSC (Sahin; CHB)
5
30
Under 6 mos.
Potential EEG biomarkers -epilepsy-TSC (Sahin; CHB)
45
345
2-76
RAD001 for partial onset seizures -EXIST 3 (Novartis)
1
unknown
not specified
No timeline available
Collection of biospecimens for LAM/TSC research (Kwiatkowski; BWH)
1
unknown
not specified
No timeline available
Allelic expression imbalance in TSC (Narayanan; Barrow Neurological Institute)
1
unknown
not specified
No timeline available
Seeking individuals with TSC in whom genotyping found no mutation (Kwiatkowski; BWH)
Study
Area
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Genetic factors in pathogenesis of lung disease (Moss; NHLBI)
Characterization of pathogenesis of LAM (Moss; NHLBI)
Cutaneous tumorigenesis in patients with TSC (Moss; NHLBI)
RAD001 therapy in SEGA in patients with TSC (Franz; CCHMC)
Effects of fasting on the size of lymphangioleiomyomas in patients with LAM (Taveira-DaSilva; NHLBI)
TSC natural history study: renal (Bissler; CCHMC)
RAD001 therapy of AML - TSC & sporadic LAM (Bissler; CCHMC)
Long term f/u for RAD001 therapy of AML (Bissler; CCHMC)
RAD001 -AML - LAM - EXIST 2 (Novartis)
RAD001 -SEGA - EXIST 1 (Novartis)
Randomized DB, PC trial of doxycycline in LAM (Johnson; U. Nottingham)
RAD001 & neurocognition in TSC (Sahin; BCH)
Phase II topical rapamycin trial (Koenig; UT Houston)
Early screening for autism in TSC (Johnson; BCH)
Topical rapamycin study (Wheless; Le Bonheur Children's)
mTOR Signaling Pathway
TSC1
TSC2
Sirolimus (Rapamycin)
Temsirolimus (CCI-779)
Everolimus (Afinitor®)
Rheb
mTORC1
mTORC2
2009
ProteinLounge.com
Serum
Nutrient
mTOR Pathway
Growth
Factors
C
Hypoxia
Energy
Stress
Insulin
RTK
Insulin
Receptor
PMA
PIP2
IRS1
PIP3
PI3K
Ras
PKC
MAPK
PKCα
PDK-1
Translation On
P
AMP
LKB1
DAG
DGKξ
Akt
Redd1
AMPK
PA
PLD
PC
Scanning
RSK
TSC2
TSC1
FKBP12
Rheb
GβL
RPS6
Raptor
mTORC1
eIF3
eIF4B
eIF4A
p70S6K
mTOR
PP2A
eIF4E
eIF4G
40S
eIF3
mTOR
GβL
Secondary
Structure
Unwinding
Rictor
HIF1α
mTORC2
4EBP
PKC
eIF4B
VEGF
eIF4E
Akt/PKB
Rho
Rac
eIF4B
eIF4E
4EBP
Akt Signaling
Translation off
VEGF
Pathway
eIF4E
eIF4G
Actin
Organization
eIF4A
AUG
AUG
eIF4A
eIF4G
Rapamycin Prevents and Treats Epilepsy in a Mouse
Model of Tuberous Sclerosis Complex
• Early treatment with rapamycin prevented the development
of epilepsy and premature death Tsc1(GFAP)CKO mice.
• Late treatment with rapamycin suppressed seizures and
prolonged survival in Tsc1(GFAP)CKO mice that had already
developed epilepsy.
• Rapamycin inhibited the abnormal activation of the
mammalian target of rapamycin pathway, astrogliosis, and
neuronal disorganization, and increased brain size in
Tsc1(GFAP)CKO mice.
• Rapamycin has strong efficacy for preventing seizures and
prolonging survival in Tsc1(GFAP) KO mice.
• International, multicenter Phase 3 clinical trial being
planned by Novartis Oncology.
Zeng, Xu, Gutmann, Wong (2008) Ann Neurol63:444–453
Anti-epileptogenesis in TSC
• Referral of all infants with cardiac rhabdomyomas or
TSC at birth
• Monthly EEG and monitoring
• Treat with vigabatrin when first identify abnormal EEG
(prior to first clinical seizure)
• Significantly reduced incidence of infantile spasms
• Seizures that do occur are not refractory
• Significantly improved cognitive outcomes
• Do we need to shift our mindset to preventing seizures
rather than trying to treat them once they manifest? In
other words, should all individuals with TSC receive an
EEG at diagnosis and at follow-up? Should we treat the
EEG and not wait for clinical seizures to appear?
• NINDS to issue RFP for anti-epileptogenesis “Center
Without Walls” in 2012
Unpublished observations, Sergiusz Jozwiak, MD, PhD, Warsaw, Poland
Early Biomarkers of Autism in Infants with TSC
BCH (Shahin), Cincinnati CH (Krueger), UCLA
(Wu), UT-Houston (Northrup), UAB (Bebin)
3-9 mo old infants
Behavioral tests, MRI, EEG
Early Screening for Autism in TSC
BCH (Shahin), UCLA (Wu)
0-36 mo old infants
Behavioral tests, event-related potentials
(ERPs),EEG
Testing the Effects of RAD001 on Cognition and Autism
in Children (Age 6 to 21)
BCH (Shahin), Cincinnati CH (Franz)
6-21 yo old children
IQ >=60
Randomized to 6 mos of RAD001 v. Placebo
9 visits, followup calls
Neuropsychological testing
Potential EEG Biomarkers and Antiepileptogenic
Strategies for Epilepsy in TSC
BCH (Shahin), Cincinnati CH (Krueger), UCLA
(Wu), UT-Houston (Northrup), UAB (Bebin)
<6 mo old children
Is EEG during infancy is a reliable biomarker to identify
TSC patients that will develop infantile
spasms/epilepsy in the near future and thus are
appropriate candidates for an antiepileptogenic drug
trial.9 visits, followup calls
One blood sample from child and parent
Everolimus to Treate Epilepsy in TSC:
Epilepsy Study Consortium
NYU
Children’s Colorado
Swedish Neuroscience – Seattle UAB
Cincinnati
Children’s Oakland
CHOP
Wash U St Louis
Minnesota Epilepsy Group
UCLA
LeBonheur Children’s – Memphis
DMC Detroit Childrens
Baylor
Kennedy Krieger
Nationwide OH
Conn Children’s Hospital
Children’s Fairfax
VA
Everolimus to Treat Partial Epilepsy in TSC:
Epilepsy Study Consortium
• Male or female between the ages of 2 and 65.
• At least 16 reported quantifiable (no cluster or innumerable
seizures) partial-onset seizures over 8 weeks
– Failure to control partial seizures despite >= 2 AEDs .
– Prior or concurrent use of vagal nerve stimulator (VNS) is
allowed.
– Prior epilepsy surgery allowed >12 months before study entry.
• Receiving one, two, or three AEDs at a stable dose
• Patient or caregiver must be able to reliably record seizures and
keep a diary and recall adverse events.
Everolimus to Treat Partial Epilepsy in TSC:
Exclusion Criteria
• Seizures due to metabolic, toxic, infectious or psychogenic disorder
or drug abuse
• Presence of only non-motor simple partial seizures.
• SEGA in need of immediate surgical intervention.
• Patients with active infantile spasms.
• Episode of status epilepticus within 1 year
• Patients with an active, bleeding diathesis.
• Patient with uncontrolled hyperlipidemia
• major surgery or significant traumatic injury within 4 weeks of study
entry
• Patients on > 3 AEDs or felbamate < 1 year
RAD001 mTOR inhibition before Epilepsy Surgery in
TSC and Focal Cortical Dysplasia
• NYU (Devinsky & Weiner)
• 1-40 y old with TSC or FCD
Everolimus 7-28 days before epilepsy surgery
• Feasibility and safety of recruiting patients into a
prospective study
• Assess everolimus therapy in TSC and FCD
patients with TRE will reduce mTOR signaling
(S6 phosphorylation) v. controls
Sirolimus and Autophagy Inhibition in LAM (SAIL)
Research Trial in Women
• Brigham & Women’s Hospital, Boston, MA
• Clinical trial to test safety of sirolimus
(Rapamycin) with hydroxychloroquine.
• All subjects will receive study drug provided by
the trial.
• 7 visits over 1 year; physical exams, blood and
urine samples, X-rays, CT scans, MRIs, breathing
&, exercise tests, questionnaires, at-home diary.
STARS: TS Clinical Research Study
•
•
•
•
U Penn (Pollard)
> 18 yo
> 1 seizure/month
8 month study
– 4 visits to Penn Epilepsy Center
– 8 phone calls with study staff
• Study safety and efficacy of Sabril in adults with
TSC
Non-Invasive Eye Screening
• Columbia (Tabacaru or Li)
• No touch retinal imaging to assess vigabatrin
induced visual field loss
• Can this imaging be a surrogate for efficacy of
mTOR inhibition and monitor vigabatrin toxicity
• 8 month study
– 4 visits to Penn Epilepsy Center
– 8 phone calls with study staff
• Study safety and efficacy of Sabril in adults with
TSC
Seeking Individuals with TSC in Whom Genotyping
Found No Mutation
• Brigham and Women’s (Kwiatkowski)
• individuals with TSC: 1) definite diagnosis of
TSC by an expert; 2) no TSC1/TSC2 mutations
by expert lab; 3) willing to have entire genome
sequence analyzed; 4) TSC individual and both
parents give a blood sample for these analyses.
• See to identify genetic cause in these
individuals