Emerging Treatment Strategies for
Tuberous Sclerosis Complex
David Neal Franz, MD
Director, Tuberous Sclerosis Clinic
Cincinnati Children’s Hospital Medical Center
Cincinnati, Ohio
Goals
• Describe the manifestations of tuberous sclerosis complex
(TSC) in various organ systems and the most frequent causes
of neurologic, renal, and pulmonary morbidity and mortality
• Review the molecular pathophysiology of TSC and how this
forms the basis for novel therapeutic approaches
• Compare the rationale and initial clinical trial evidence for
emerging treatment approaches for TSC
• Summarize ongoing clinical trials evaluating treatment
approaches for TSC, including the goals of the trials, patient
eligibility criteria, and other key factors
Clinical Manifestations of TSC
• Brain: cortical tubers, subependymal nodules, subependymal
giant cell astrocytomas
• Eye: retinal hamartomas
• Heart: cardiac rhabdomyomas
• Kidney: benign angiomyolipomas, cysts, malignant
angiomyolipomas, renal cell carcinoma
• Lung: lymphangioleiomyomatosis, multifocal micronodular
pneumocyte hyperplasia
• Skin: hypomelanotic macules, shagreen patches, periungual or
subungual fibromas, facial angiofibromas
• Behavior: mental retardation, autism, bipolar disorder
Pan D, et al. Trends Cell Biol. 2004;14:78-85.
Clinical Diagnostic Criteria
Major Features
Minor Features
Cortical tubers
Multiple, randomly distributed
pits in dental enamel
Subependymal nodules
Hamartomatous rectal polyps
Subependymal giant cell astrocytoma
Bone cysts
Hypomelanotic macules (3 or more)
Cerebral white matter radial
migration lines
Shagreen patch (connective tissue nevus)
Gingival fibromas
Facial angiofibromas or forehead plaque
Nonrenal hamartoma
Multiple retinal nodular hamartomas
Retinal achromic patch
Nontraumatic ungual or periungual fibromas
“Confetti” skin lesions
Cardiac rhabdomyoma, single or multiple
Multiple renal cysts
Pulmonary lymphangioleiomyomatosis and/or
renal angiomyolipomas
Roach ES, Sparagana SP. J Child Neurol. 2004;19:643-649.
TSC: Onset of Symptoms
Cardiac
Renal
Cerebral
Skin
Lung
0
20
40
Age in Years
60
80
Hypopigmented Macule and
Shagreen Patch
Facial Angiofibroma
Periungual Fibroma
Dental Pits and Gingival Fibromas
Retinal Hamartomas and Achromic
Patches
Cardiac Rhabdomyoma
Lymphangioleiomyomatosis (LAM)
Renal Angiomyolipoma and Renal Cysts
Angiomyolipoma
Cerebral Manifestations of TSC
Cortical Tuber
Subependymal Nodules
Neurologic/Behavioral Manifestations
• Seizures (90%)
• Mental retardation and learning difficulties
(60%-70%)
• Sleep disorders (60%)
• Autism and behavioral difficulties (30%-50%)
• Subependymal giant cell astrocytoma (15%20%)
Seizures, Infantile Spasms, and
Cognitive Outcome
• Infantile spasms correlated with increased risk
for poor neurologic outcomea
Clinical Variables Associated With Mental Retardation in Patients With TSC and
Infantile Spasmsb
Variable
a
Odds Ratio
95% CI
P Value
Time from treatment initiation until clinical
cessation
1.07
1.01-1.14
.018
Total duration of infantile spasms from clinical
onset to cessation
1.09
1.03-1.15
.004
Poor control of other seizures after cessation of
infantile spasms
17.76
3.47-129.1
.00004
O’Callaghan FJ, et al. Arch Dis Child. 2004;89:530-533.
b Goh S, et al. Neurology. 2005;65:235-238.
Infantile Spasms in TSC
• Vigabatrin is the treatment of choice in TSC
– Risk for adverse effect on peripheral vision
– As high as 95% response rate in TSCa
• Steroids are second-line treatment
(adrenocorticotropic hormone or oral prednisone)
• Valproate, topiramate, clonazepam minimally
effective as single agents but may have beneficial
adjunctive use
aHancock
EC, Osborne JP. J Child Neurol. 1999;14:71-74.
Epilepsy in TSC
• About 90% of patients with TSC experience
seizures
• Virtually all seizure types have been reported
(simple partial, complex partial, generalized tonicclonic, absence)
• Aggressive treatment is necessary to reduce risk
for negative neurologic outcome (development,
cognition, behavior)
Surgical Outcome of Epilepsy Surgery in TSC
• Outcome (Engel’s classification):
–
–
–
–
Class I (seizure free): 37/69
Class II (some seizures): 8/69
Class III (> 90% reduction): 13/69
Class IV (< 90% reduction): 12/69
Connolly M, et al. Child Nerv Syst. 2006;22:896-908.
Madhavan D, et al. Epilepsia. 2007;48:1625-1628.
Sleep Problems in TSC
• Survey of 300 TSC patients (age 0.5-74 years):
– 58% with sleep problems in general
• Survey of 40 pediatric TSC patients (age 2-15 yrs):
Study Group
TSC children
Unaffected siblings
Age/gender-matched controls
Children with mixed learning
disabilities
Hunt A . J Intellectual Disability Res. 1993;37:41-51.
Hunt A , Stores G. Dev Med Child Neurol. 1994;36:108-115.
Sleep Index ± SD
4.9 ± 3.1
0.6 ± 1.0
0.4 ± 0.7
2.8 ± 2.5
Subependymal Giant Cell Astrocytoma (SEGA)
Acute Hydrocephalus With SEGA
Serial Monitoring for SEGA
Traditional Surgical Resection of SEGA
Stereotactic Angioplasty Balloon Technique
Levine NB, et al. Minim Invasive Neurosurg. 2006;49:317-320.
Genetics of TSC
Autosomal dominant
Near 100% penetrance
Variable expression
PKD1
TSC2
(60%-70%)
9
TSC1
(15%-20%)
No Mutation
Identified
(10%-15%)
16
TSC1/TSC2 and mTORC1
Rapamycin and Everolimus (RAD001)
HO
HO
O
O
O
O
N
O O
OH
O O
O
O
OH
O
Rapamycin
(sirolimus)
O
O
N
O O
OH
O O
O
O
OH
O
RAD001
(everolimus)
O
Everolimus and Sirolimus
Comparison of Properties
Characteristic
Everolimus
Sirolimus
Molecular weight (Kd)
Solubility in water (μg/mL)
Hydrophobicity
Bioavailability (%)
Blood:plasma (%)
Brain accumulation**
Tmax (hrs)
T1/2 (hrs)
Vss (L/kg)
Clearance (mL/hr•kg)
958a
8-fold higherb
Lessc
≥ 11a*
26% freea
3.1:1f
1-2
30a
44 -52a
1200a(rat)
914b
2.6b
Extremeb
1.6e*
5.7:1f
0.8d
86d
23d
256d (man)
*Varies with formulation, dose, and co-medications. Everolimus has greater bioavailability than sirolimus.
**Ratio of drug in blood (ng/mL) and brain (ng/g) following 6 days oral dosing at 3 mg/kg in rats.f
a
RAD001 Investigators Brochure (6th ed). b Buech G, et al. J Ocul Pharmacol Ther. 2007;23:292.
c Formica RN, et al. Transplant Proc. 2004;36(Suppl 25S):495S-499S.
d Brattstrom C, et al. Ther Drug Monit. 2000;22:537-544.5. e Kahan BD, et al.
Transplantation. 1991;52:185-191. f Serkova N, et al. Br J Pharmacol. 2001;133:875-885.
Rapamycin for Treatment of Angiomyolipoma
A
Bissler JJ, et al. N Engl J Med. 2008;358:140-151.
B
Rapamycin Effect on LAM
Bissler JJ, McCormack FX, Young LR, et al. N Engl J Med. 2008;358:140-151.
Rapamycin for the Treatment of SEGA
Franz DN, et al. Ann Neurol. 2006;59:490-498.
Everolimus Effect on SEGA in TSC
Baseline
6 months RAD001
Cerebellar Tuber Growth
Cerebellar Tuber Before and After
Treatment With Rapamycin
RAD001 Effect on SEGA Volume
Angiomyolipoma Before and After Treatment
Before Treatment
Everolimus x 3 months
Chylothorax in LAM
Current Clinical Trials Related to TSC
• EXIST-1: Efficacy and Safety of RAD001 in Patients of All Ages With
Subependymal Giant Cell Astrocytoma Associated With Tuberous
Sclerosis Complex (TSC)
• EXIST-2: Efficacy and Safety of RAD001 in Patients 18 Years and Over
With Angiomyolipoma Associated With Either Tuberous Sclerosis
Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)
• MILES: Efficacy and Safety of Rapamycin in Patients with Tuberous
Sclerosis Complex Lymphangioleiomyomatosis (TSC-LAM) or
Sporadic Lymphangioleiomyomatosis (S-LAM)
• Long-term Follow-Up for RAD001 Therapy of Angiomyolipomata in
Patients With Tuberous Sclerosis Complex (TSC) and Sporadic
Lymphangioleiomyomatosis (LAM)
• Long-term Follow-Up for RAD001 Therapy of Subependymal Giant
Cell Astrocytoma in Patients With Tuberous Sclerosis Complex (TSC)
Current Clinical Trials Related to TSC (cont)
• Efficacy and Safety of Aromatase Inhibition for Tuberous
Sclerosis Complex Lymphangioleiomyomatosis (TSC-LAM)
or Sporadic Lymphangioleiomyomatosis (S-LAM)
• Study of Skin Tumors in Tuberous Sclerosis
• Tuberous Sclerosis Complex Natural History Study:
Renal Manifestations
• Study of the Disease Process of Lymphangioleiomyomatosis
• Effect of Fasting on the Size of Abdominal Lymphatic Tumors
in Women
• Role of Genetic Factors in the Development of Lung Disease
Summary
• Tuberous sclerosis is a multiorgan disorder with
variable penetrance and severity
• Highest disease morbidity is associated with
cerebral, renal, and pulmonary manifestations
• Molecular-based therapies using mTOR inhibitors
are showing promise in treating patients with TSC
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