FACILITATING DRUG DEVELOPMENT FOR TUBEROUS SCLEROSIS COMPLEX Steven L. Roberds, Ph.D. Chief Scientific Officer, TS Alliance

ABOUT TUBEROUS SCLEROSIS COMPLEX Tuberous sclerosis complex (or TSC) is a genetic disorder that causes tumors to form in vital organs, primarily the brain, eyes, heart, kidney, liver, lungs and skin. TSC affects ~1 in 6,000 live births. An estimated 50,000 Americans have TSC, and more than 1 million worldwide. No two people are affected the same way, not even identical twins. Neurological manifestations are often the most devastating – affecting almost all with TSC in some manner, from mild to severe. TSC is a leading genetic cause of autism and epilepsy.

Tuberous Sclerosis Alliance (TS Alliance) The TS Alliance, founded in 1974, is committed to finding a cure for tuberous sclerosis complex while improving the lives of those affected: by developing programs, support services and resource information; by stimulating and sponsoring research; and by creating and implementing public and professional education programs designed to heighten awareness of the disease.

Annual investments in TSC research NIH, TSCRP, and TS Alliance

IMPACTING DRUG DEVELOPMENT WITH LIMITED, FOCUSED FUNDING Lead optimization Phase 1 Hypothesis generation Drug screening Preclinical Development Phase 2 Phase 3 Approved TS Alliance research investments are focused in areas where we can have relatively high impact for relatively low cost. The Natural History Database collects clinical data to help us better understand disease progression for the purpose of facilitating large clinical research investments by others, such as pharmaceutical companies. Establishment of a clinical research network and funding of research to identify biomarkers can also make TSC more attractive for investment by companies who can fund clinical trials. Targeted drug screening, particularly of existing drugs that can be repurposed for TSC, can generate early data needed prior to investments by NIH (e.g., NCATS and TRND) or industry into more costly drug development stages. Research grants attract researchers to the TSC field by funding early research to enable them to generate preliminary data necessary for larger grants from NIH, DOD, etc.

Improved quality of life, personalized treatment, cure TS ALLIANCE Research Initiatives and Collaborations to accelerate discovery of new treatments and a cure Improved quality of life, personalized treatment, cure

TSC NATURAL HISTORY DATABASE Since 2006, enrolled 2,000 participants Data entered at 18 TSC Clinics throughout the US 2016-2018 strategy is to increase depth of data in areas related to TSC constituents’ research priorities: The final question of the survey was, “if you could choose one question for researchers to answer over the next five years, what would it be?” and was answered by 295 participants. Only one choice was permitted per participant. A common theme was elimination of manifestations—seizures, lymphangioleiomyomatosis (LAM) & angiomyolipomas, and TSC-associated neuropsychiatric disorders (TAND); 51% chose one of those responses. The third most common choice overall was how not to pass TSC on to children.

Voluntary TSC NHD Participants TSC Biosample Repository Linked to clinical data in Natural History Database Voluntary TSC NHD Participants Examples of Research Needs Understanding phenotypic heterogeneity Development of clinical biomarkers Patient-derived cells for drug testing DNA Plasma Tissue

TSC CLINICAL RESEARCH CONSORTIUM Biomarker studies initiated in 2013 funded by NIH Identify early markers of risk for autism in TSC (NINDS, NICHD) Identify early markers of risk for epilepsy in TSC (NINDS) Regular EEG and imaging evaluation of 40 infants Interim results published in October for 28 infants Sensitivity-73.7% Specificity- 100% Positive Predictive Value (PPV)-100% Negative Predictive Value(NPV)--64% Clinical seizures No clinical seizures Abnormal EEG 14 Normal EEG 5 9 Wu et al (2016) Pediatr Neurol 54:29-34

PREVENTING EPILEPSY USING VIGABATRIN IN INFANTS WITH TSC (PREVeNT) TRIAL NINDS-funded Phase II study Projected start date: Fall 2016 Multicenter: 7 sites across the US Study objective: impact of early versus delayed treatment with vigabatrin on development, assessed at 24 and 36 months of age

TSC Preclinical Consortium Key piece of strategy to accelerate drug development Standardize models, tests and assays for preclinical drug development Re-purpose compounds of interest Test analogs with improved safety profiles Investigate novel compounds and mechanisms of action Engage industry and increase opportunities for clinical trials Focus on Transparency, Robustness, Replication, Rigor and Translatability

EPILEPSY IN TSC: EPIDEMIOLOGY & NATURAL HISTORY Epilepsy occurs in ~85% of individuals with TSC (Sparagana et al., 2003; Devlin et al., 2006; Chu-Shore et al. 2010). Age of seizure onset is <1 year in 63% and <3 years in 82% (Chu-Shore et al. 2010). Multiple seizure types occur in about one-half of TSC patients, including focal and generalized seizures and infantile spasms. ~2/3 of TSC patients with epilepsy are drug-resistant, as opposed to ~1/3 intractability rate in general epilepsy population. - one exception: vigabatrin for spasms in TSC However, a subset of TSC patients may achieve prolonged seizure remission, including off seizure medication. (with thanks to M. Wong)

EPILEPSY MODEL TOP PRIORITY: GFAP-TSC1 CKO (with thanks to M. Wong)

CONSORTIUM STRUCTURE

TSC PRECLINICAL CONSORTIUM Industry screening buckets Initial Commitment Screening Type Bucket Public Bucket A. Reference compounds with results released to consortium. No IP implication. Company Consortium Member Access to all validation, phenotypic and reference compound results including raw data Bucket B. Company's compound with results released to consortium. Escrow period to protect IP. Private Bucket C. Company's compound with results not released to consortium. No strings attached.

Improved quality of life, personalized treatment, cure TS ALLIANCE Research Initiatives and Collaborations to accelerate discovery of new treatments and a cure Improved quality of life, personalized treatment, cure

Improved quality of life, personalized treatment, cure ACKNOWLEDGMENTS Researchers TSC Clinics Individuals with TSC and their families Industry Partners Donors and Funders Improved quality of life, personalized treatment, cure