Emerging Treatment Strategies for Tuberous Sclerosis Complex

1
Emerging Treatment Strategies for Tuberous
Sclerosis Complex
David Neal Franz, MD Director, Tuberous Sclerosis
ClinicCincinnati Childrens Hospital Medical
CenterCincinnati, Ohio
2
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

3
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. 20041478-85.
4
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.
200419643-649.
5
TSC Onset of Symptoms
6
Hypopigmented Macule and Shagreen Patch
7
Facial Angiofibroma
8
Periungual Fibroma
9
Dental Pits and Gingival Fibromas
10
Retinal Hamartomas and Achromic Patches
11
Cardiac Rhabdomyoma
12
Lymphangioleiomyomatosis (LAM)
13
Renal Angiomyolipoma and Renal Cysts
14
Angiomyolipoma
15
Cerebral Manifestations of TSC
16
Cortical Tuber
17
Subependymal Nodules
18
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)

19
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 Clinical Variables Associated With Mental Retardation in Patients With TSC and Infantile Spasmsb Clinical Variables Associated With Mental Retardation in Patients With TSC and Infantile Spasmsb Clinical Variables Associated With Mental Retardation in Patients With TSC and Infantile Spasmsb
Variable 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
a OCallaghan FJ, et al. Arch Dis Child.
200489530-533. b Goh S, et al. Neurology.
200565235-238.
20
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.
19991471-74.
21
Epilepsy in TSC

• About 90 of patients with TSC experience
  seizures
• Virtually all seizure types have been reported
  (simple partial, complex partial, generalized
  tonic-clonic, absence)
• Aggressive treatment is necessary to reduce risk
  for negative neurologic outcome (development,
  cognition, behavior)

22
Surgical Outcome of Epilepsy Surgery in TSC

• Outcome (Engels classification)
• Class I (seizure free) 37/69
• Class II (some seizures) 8/69
• Class III (gt 90 reduction) 13/69
• Class IV (lt 90 reduction) 12/69

Connolly M, et al. Child Nerv Syst.
200622896-908. Madhavan D, et al. Epilepsia.
2007481625-1628.
23
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 Sleep Index SD
TSC children 4.9 3.1
Unaffected siblings 0.6 1.0
Age/gender-matched controls 0.4 0.7
Children with mixed learning disabilities 2.8 2.5
Hunt A . J Intellectual Disability Res.
19933741-51. Hunt A , Stores G. Dev Med Child
Neurol. 199436108-115.
24
Subependymal Giant Cell Astrocytoma (SEGA)
25
Acute Hydrocephalus With SEGA
26
Serial Monitoring for SEGA
27
Traditional Surgical Resection of SEGA
28
Stereotactic Angioplasty Balloon Technique
Levine NB, et al. Minim Invasive Neurosurg.
200649317-320.
29
Genetics of TSC
Autosomal dominant Near 100 penetrance Variable
expression
No Mutation Identified (10-15)
9
16
30
TSC1/TSC2 and mTORC1
31
Rapamycin and Everolimus (RAD001)
Rapamycin (sirolimus)
RAD001 (everolimus)
32
Everolimus and Sirolimus Comparison of Properties
Characteristic Everolimus Sirolimus
Molecular weight (Kd) 958a 914b
Solubility in water (µg/mL) 8-fold higherb 2.6b
Hydrophobicity Lessc Extremeb
Bioavailability () 11a 1.6e
Bloodplasma () 26 freea
Brain accumulation 3.11f 5.71f
Tmax (hrs) 1-2 0.8d
T1/2 (hrs) 30a 86d
Vss (L/kg) 44 -52a 23d
Clearance (mL/hrkg) 1200a(rat) 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. 200723292. c
Formica RN, et al. Transplant Proc. 200436(Suppl
25S)495S-499S. d Brattstrom C, et al. Ther Drug
Monit. 200022537-544.5. e Kahan BD, et al.
Transplantation. 199152185-191. f Serkova N,
et al. Br J Pharmacol. 2001133875-885.
33
Rapamycin for Treatment of Angiomyolipoma
A
B
Bissler JJ, et al. N Engl J Med. 2008358140-151.
34
Rapamycin Effect on LAM
Bissler JJ, McCormack FX, Young LR, et al. N Engl
J Med. 2008358140-151.
35
Rapamycin for the Treatment of SEGA
Franz DN, et al. Ann Neurol. 200659490-498.
36
Everolimus Effect on SEGA in TSC
Baseline
6 months RAD001
37
Cerebellar Tuber Growth
38
Cerebellar Tuber Before and After Treatment With
Rapamycin
39
RAD001 Effect on SEGA Volume
40
Angiomyolipoma Before and After Treatment
Before Treatment
Everolimus x 3 months
41
Chylothorax in LAM
42
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)

43
Current Clinical Trials Related to TSC (cont)

• Efficacy and Safety of Aromatase Inhibition for
  Tuberous Sclerosis Complex Lymphangioleiomyomatosi
  s (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

44
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

45
Thank you for participatingin this
activity. To proceed to the online CME test,
click on the Earn CME Credit link on this
page.