Ped audio lecture-franz-tsc-4-1

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 Roach ES, Sparagana SP. J Child Neurol. 2004;19:643-649. 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

TSC: Onset of Symptoms

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 outcome a
a O’Callaghan FJ, et al. Arch Dis Child. 2004;89:530-533. b Goh S, et al. Neurology . 2005;65:235-238. Clinical Variables Associated With Mental Retardation in Patients With TSC and Infantile Spasms b 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

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 TSC a
Steroids are second-line treatment (adrenocorticotropic hormone or oral prednisone)
Valproate, topiramate, clonazepam minimally effective as single agents but may have beneficial adjunctive use
a Hancock 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 tonic-clonic, 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):
Hunt A . J Intellectual Disability Res. 1993;37:41-51. Hunt A , Stores G. Dev Med Child Neurol. 1994;36:108-115. 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

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 9 16 Autosomal dominant Near 100% penetrance Variable expression No Mutation Identified (10%-15%) TSC1 (15%-20%) TSC2 (60%-70%) PKD1

TSC1/TSC2 and mTORC1

Rapamycin and Everolimus (RAD001) Rapamycin (sirolimus) RAD001 (everolimus) O O O H O O O N O O O O O H O H O O O O H O O O N O O O O O O H O O H

Everolimus and Sirolimus Comparison of Properties a RAD001 Investigators Brochure (6 th 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 . *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 Characteristic Everolimus Sirolimus Molecular weight (Kd) 958 a 914 b Solubility in water ( μ g/mL) 8-fold higher b 2.6 b Hydrophobicity Less c Extreme b Bioavailability (%) ≥ 11 a* 1.6 e* Blood:plasma (%) 26% free a Brain accumulation** 3.1:1 f 5.7:1 f Tmax (hrs) 1-2 0.8 d T1/2 (hrs) 30 a 86 d Vss (L/kg) 44 -52 a 23 d Clearance (mL/hr•kg) 1200 a (rat) 256 d (man)

Rapamycin for Treatment of Angiomyolipoma A B Bissler JJ, et al. N Engl J Med. 2008;358:140-151.

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

Before Treatment Everolimus x 3 months Angiomyolipoma Before and After Treatment

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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Ped audio lecture-franz-tsc-4-1

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