1. Neurological Outcomes (Epilepsy) in Clinical Trials for TSC and Related Disorders Working Group D International TSC Research Conference Summit on Drug Discovery in TSC and Related Disorders July 8, 2011

2. Outline A. Significance/Problems of Epilepsy in TSC B. Goals of Treatment C. Issues in Designing/Conducting a Late/Symptomatic Treatment Trial D. Issues in Designing/Conducting a Early/Preventative/Disease-modifying Trial E. Future Issues/Recommendations

3. Significance/Problems of Epilepsy in TSC A. High prevalence (~80%) B. Relationship with cognitive dysfunction/autism/psychiatric/sleep C. Other disability (decreased QOL) – driving, employment D. Safety – accidents E. Status epilepticus/Sudden Unexplained Death in Epilepsy (SUDEP) F. Social stigma/embarassment G. Medication side effects H. Intractability (~70%) I. Lack of preventative/disease-modifying therapies General perception that epilepsy is a high impact problem in TSC, especially when linked to other neurocognitive issues.

4. Goals of Epilepsy Treatment A. Seizure freedom B. No side effects C. Improved neurocognitive outcome D. Improved QOL E. Decreased accidents, social stigma. F. If not seizure-free, clinically-meaningful decrease in seizures: - difficult to quantify; reduction in seizure severity may be more important than reduction in seizure frequency - side effects of medication may outweigh uncontrolled seizures G. Develop antiepileptogenic/disease-modifying therapies

5. Issues in Designing/Conducting Late/Symptomatic Clinical Trials Briefly reviewed the design and results from previous and ongoing trials, which show promise but have limitations: - positive trials have been open label, small numbers - uncontrolled variables in larger trials without epilepsy as primary endpoint can affect interpretability of results - A multicenter, phase III placebo-controlled epilepsy trial is in development (hoped initiation in late 2011 or early 2012): Would resolve the shortcomings of prior studies to provide definitive evidence of benefit or not Could lead to FDA approval for this indication, which would expand access of drug to pediatric and adult patients with TSC and make early/preventative trial more feasible. Goal/Rationale: To determine whether mTOR inhibitors decrease seizures in TSC patients with intractable epilepsy.

6. Issues in Designing/Conducting Late/Symptomatic Clinical Trials General issues in epilepsy trial design: - reliability of seizure diaries - use of EEG: routine vs. 24 hour monitoring, interictal vs. ictal; expense - measure of seizure severity, e.g. Early Childhood Epilepsy Severity Scale (E-CHESS; Humphrey et al. 2008)

7. Issues in Designing/Conducting Early/Preventative Clinical Trials Goal: To determine whether mTOR inhibitors prevent or decrease the onset of epilepsy in presymptomatic TSC patients. Rationale: - Mouse model data and different mechanism of action suggesting antiepileptogenic properties. - A subset of TSC patients represent feasible candidates for a preventative/antiepileptogenic therapeutic approach due to early identification of presymptomatic or early symptomatic of patients at high risk. - Long-term risk/benefit analysis of preventative treatment (e.g. “Number Needed to Treat”) may be favorable.

8. Issues in Designing/Conducting Early/Preventative Clinical Trials Rationale: - Data of “high risk/burden” of epilepsy in TSC (continued)(Chu-Shore et al. 2010; retrospective review, n=291) n=246, 85% epilepsy n=155, 53% intractable epilepsy (63% of pts with epilepsy) n=110, 38% infantile spasms n=106, 96% of patients with IS developed other seizures n=83, 75% of patients with IS developed intractable epilepsy (duration between IS and subsequent seizures not reported, but based on anecdotal experience, could be years) Age of seizure onset <3 years in 82% 60% cognitive impairment with seizures vs. 12% without seizure 74% cognitive impairment with IS vs. 39% without IS Correlation between age of sz onset and cognitive outcome This data suggest TSC is an appropriate population to target with an antiepileptogenic approach. - TSC has been proposed to be a “model disease” for epilepsy in general. May serve as “proof-of-concept” for other epilepsies

9. Issues in Designing/Conducting Early/Preventative Clinical Trials Issues: A.Patient Selection/Age: prenatal, asymptomatic infant, abnormal EEG or MRI, first seizure, onset of infantile spasms? B.Potential utility of EEG as a biomarker of epilepsy/spasms (e.g Jozwiak) C. Outcome Measures: seizure diaries, EEG, neurocognitive function (secondary measure), QOL? D. Timing of follow-up necessary to detect a preventative/ antiepileptogenic effect – years? E.With IS, concurrent use of vigabatrin confounding the results or prolonging the follow-up time needed. F.Long-term safety and adverse effects of treating the developing brain/body with mTOR inhibitors not known. G.Practical issues of conducting preventative trials – feasibility, IRB approval, cost (longer duration studies). H.Risk/benefit analysis is harder to assess with preventative trials (e.g. Number Needed to Treat).

10. Prenatal Treatment Trial Positives/Advantages: - Earliest treatment has biggest potential for efficacy (e.g. prevent tuber formation and other molecular/cellular/pathological abnormalities?) Negative/Disadvantages: - Earliest treatment has biggest potential for adverse effects in developing brain/body (although sirolimus has been used in pregnancy; FDA pregnancy category C) - Longer follow-up time required to see an effect. - Very difficult to get IRB approval 0 votes Design: - Treat pregnant mom with TSC and prenatal ultrasound evidence of TSC (placebo vs. mTOR inhibitor, primary outcome time to first seizure or incidence of epilepsy over some time period)

11. Asymptomatic Infant Treatment Trial Positives/Advantages: - Treatment in infancy still has good potential for antiepileptogenic efficacy, but perhaps less risk than prenatal treatment. - If EEG can be validated as biomarker of epilepsy/spasms, risk/benefit ratio may favor treatment. - Likely relatively short duration of study with primary outcome being time to first seizure/spasms, especially with abnormal EEG. Negative/Disadvantages: - Still with significant or unknown long-term risks - Still may be difficult to get IRB approval - Use of abnormal EEG or MRI not validated biomarkers of future epilepsy. Standard clinical approach – treat seizures not the EEG. ~5 votes/25 Design - Asymptomatic infant (placebo vs. mTOR inhibitor, with time to first seizure as primary outcome) - Asymptomatic infant with abnormal EEG (placebo vs. mTOR inhibitor, with time to first seizure as primary outcome or epilepsy incidence/time) - Asymptomatic infant with abnormal brain MRI (placebo vs. mTOR inhibitor, with time to first seizure as primary outcome or epilepsy incidence/time)

12. Early Symptomatic Treatment Trial Positives/Advantages: - Treatment in infancy still has good potential for antiepileptogenic efficacy, but perhaps less risk than prenatal treatment. Risk/benefit ratio may favor treatment. - Spasms clearly has poorer prognosis. Risk/benefit ratio may favor treatment. - Easier to justify to IRB? Negative/Disadvantages: - Still with significant or unknown long-term risks - Still may be difficult to get IRB approval - Use of vigabatrin may confound or decrease the chance of seeing an effect of mTOR inhibitors by prolonging duration of study. ~20 votes/25 Design - Presentation of 1 st seizure (of any type) - Presentation of infantile spasms (VGB versus VGB+mTOR inhibitor, with long-term seizure frequency >1 year?, as primary outcome) - Presentation of infantile spasms (VGB failure, then second line agent versus second line agent + mTOR inhibitor, with long-term seizure frequency >1 year?, as primary outcome)

13. Future Issues/Questions to Address - Consider adding seizure severity scale to outcome measures - More long-term natural history data on epilepsy/spasms to guide trial design. - Validation of EEG or other biomarkers as predictors of epilepsy/spasms - Decide on target patient/age for antiepileptogenic drug trials** - Duration of treatment – for clinical trial, dependent on natural history data - Long-term safety data on use of mTOR inhibitors during early development. - Cost/funding of preventative trials. - Stepwise-approach – first complete late/symptomatic trials, then consider early/preventative trials. But what if the late/symptomatic trials have negative results? (i.e. if a drug does not have symptomatic effects, does that mean it will not have antiepileptogenic effects? No! Mechanisms of action are different for ictogenesis and epileptogenesis. Standard anticonvulsant drugs did not have preventative effects in clinical trials of posttraumatic epilepsy) - Retrospective review of TSC patients without epilepsy started on mTOR inhibitors for other reasons to determine frequency of developing epilepsy (control group?). - More questions than answers, but this reflects progress!