WELCOME TO THE NEW YORK TSC CONFERENCE May 5, 2013

TUBEROUS SCLEROSIS COMPLEX SCIENCE & MEDICAL UPDATE Steve Roberds, Ph.D. Chief Scientific Officer 5 March 2013

TSC Clinical Consensus Conference Update recommended diagnosis, surveillance, & management June 14-15, 2012, in Washington, DC Co-organizers Hope Northrup and Darcy Krueger Working groups chaired by international experts – Epilepsy: Elizabeth Thiele – Brain Tumors: Sergiusz Jóźwiak – Behavior, Cognition, and Autism: Petrus de Vries – Dermatology and Dental: Tom Darling – Lung: Frank McCormack – Kidney: Chris Kingswood and John Bissler – Genetics: Julian Sampson – Multiple systems: Steve Sparagana 3

TSC Clinical Consensus Conference Outcomes Diagnostic criteria simplified – Addition of genetics: a known disease-causing mutation in TSC1 or TSC2 is sufficient for diagnosis – “Definite” or “Possible” diagnosis based on major & minor criteria Surveillance and treatment recommendations updated based on most recent clinical studies Scientific manuscripts submitted for peer-review and publication in open-access professional journals Plans to update recommendations on a regular, more frequent basis 4

Surveillance and Management Recommendations for Patients Already Diagnosed with Definite or Possible TSC Organ System or Specialty Area Recommendation Brain MRI of the brain every 1-3 years in asymptomatic TSC patients under age 25 to monitor for new SEGA. Individuals with asymptomatic SEGA in childhood should continue to be imaged periodically as adults to ensure there is no regrowth. Surgical resection should be performed for acutely symptomatic SEGA. Either surgical resection or medical treatment with mTOR inhibitors may be used for growing but otherwise asymptomatic SEGA. Basic screening for neuropsychiatric symptoms at least annually at each clinical visit. Additional formal assessment by specialists where available upon entering primary school, secondary school, and young adulthood. Obtain routine EEG in individuals with known or suspected seizure activity. The frequency of routine EEG should be determined by clinical need. Vigabatrin is the recommended first-line therapy for infantile spasms. ACTH can be used if treatment with vigabatrin is unsuccessful. Anticonvulsant therapy of other seizure types in TSC should generally follow that of other epilepsies.

Surveillance and Management Recommendations for Patients Already Diagnosed with Definite or Possible TSC Organ System or Specialty Area Recommendation Kidney MRI of the abdomen every 1-3 years throughout the lifetime. Assess renal function and blood pressure at least annually. Embolization followed by corticosteroids is first-line therapy for angiomyolipoma (AML) presenting with acute hemorrhage. Nephrectomy is to be avoided. For asymptomatic, growing AML measuring larger than 3 cm in diameter, treatment with an mTOR inhibitor is the recommended first-line therapy. Lung Clinical screening for LAM symptoms at each clinic visit. Counseling regarding smoking risk and estrogen use at each clinic visit. High-resolution CT (HRCT) scan every 5-10 years in asymptomatic individuals at risk of LAM if there is no evidence of lung cysts at baseline. Individuals with lung cysts should have annual pulmonary function testing and more frequent HRCT. mTOR inhibitors may be used to treat LAM patients with moderate to severe lung disease or rapid progression.

Unlocking the Cure Supporting cutting-edge research TSC Natural History Database – 1180 participants and growing – 15 of our 35 TSC Clinics entering data – In 2013, moving to a more effective format and adding Cincinnati and Boston Children’s 19 active research projects with 2012 annual investment of $1,202,810 – Postdoctoral fellowships – Research grants to established laboratories – Rothberg Courage Awards 7

Unlocking the Cure Advancing clinical and translational research Biomarkers: funding work toward methods for earlier detection of disease progression or effects of treatments Drug Screening Program – Screening for combinations of drugs to eliminate tumors – Testing drugs for impact on neurological effects – Testing drugs for effects on tumor-specific metabolism TSC Clinical Research Consortium – Helping to fund data center and study coordinators – Support awareness and recruitment 8

Clinical Research Consortium Two TSC clinical studies funded by NIH Autism Center of Excellence NIH grant – Infrastructure for clinical studies with autism focus – Track development of autism in TSC to identify tools that will identify those at highest risk of autism at an early age – Cognitive evaluation, clinical data, EEG, and imaging NIH grant to identify those at risk of infantile spasms – EEG and imaging as biomarkers – Validation of predictive biomarkers will enable a Phase 2 study of early intervention in TSC infants at highest risk of infantile spasms Current sites – CH Boston, Cincinnati, UA Birmingham, UCLA, UT Houston 9

Advances on the horizon Preventing the onset of infantile spasms Preventing or decreasing the development of autism Personalized medicine – the ideal therapy for each individual – Building on the Human Genome Project – Mapping the Human Brain Elimination of tumors, AMLs, and LAM – beyond shrinkage and stabilization Future studies will likely require global partnership (TSCi) 10