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. 3

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. 4

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 outcomea 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 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 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): 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. 1993;37:41-51. Hunt A , Stores G. Dev Med Child Neurol. 1994;36:108-115.

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.

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

TSC1/TSC2 and mTORC1

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

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* Blood:plasma (%) 26% freea Brain accumulation** 3.1:1f 5.7:1f Tmax (hrs) 1-2 0.8d T1/2 (hrs) 30a 86d Vss (L/kg) 44 -52a 23d Clearance (mL/hr•kg) 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. 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 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

Angiomyolipoma Before and After Treatment Before Treatment Everolimus x 3 months 40 40

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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