MB Callaghan, DE Donnelly, PJ Morrison A Complete Population Survey of Epilepsy in Tuberous Sclerosis Complex Patients in Northern Ireland MB Callaghan, DE Donnelly, PJ Morrison Northern Ireland Regional Clinical Genetic Centre Belfast City Hospital BCH Postgraduate Lecture Theatre Friday 30th June 2017

Tuberous Sclerosis Complex (TSC) Genetic condition that affects many body systems Autosomal dominant inheritance with variable expressivity Completely penetrant Around 50% of cases are the result of sporadic mutations

TSC Genetics TSC1 tumour suppressor gene located on Chr. 9q34 codes for protein hamartin TSC2 tumour suppressor gene located on Chr. 16p13.3 codes for protein tuberin Hamartin & tuberin together suppress activation of mTOR signalling & act as a “brake” on processes that drive cell growth & cell division Mutations in TSC1 & TSC2 result is uncontrolled cell growth & division

TSC: A Multi-organ Disease

Diagnostic criteria for TS B. Clinical criteria: Diagnostic criteria for TS Genetic criteria: “The identification of either a TSC1 or TSC2 pathogenic mutation in DNA from normal tissue is sufficient to make a definitive diagnosis of tuberous sclerosis complex.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080684/pdf/nihms587050.pdf Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference . Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference

Neurological consequences of TSC Seizures Learning difficulties Developmental delay autism Behavioural problems OCD ADHD Common CNS radiological findings in TSC: Giant cell astrocytomas Cortical & subcortical tubers Subependymal nodules White matter cystic lesions

TSC Prevalence Population prevalence of TSC is ~ 1:20,000 Population of Northern Ireland is ~ 1.811 million Expected size of the TSC population in N.I. - 91 Actual size of TSC population in N.I. - 111 Age range 1 - 81 years Maybe doctors have a lower threshold for referring patients with seizures & skin signs to Clinical Genetics? Maybe being a small island population that has remained relatively stable from the genetic point of view has played a part?

Study Methods Retrospective study of TSC patients using TSC database & ECR Descriptive statistics used to record: Genotype Proportion with epilepsy Brain imaging Neurosurgery Number of anti-epileptic drugs used – poorly controlled if ≥3 Learning difficulties

Genotype

At least 55 mutations found & no common mutation, 74% had mutation found, Number of pedigrees in NI TS population = 72

Epilepsy, brain imaging & neurosurgery

TSC & Epilepsy Around 80% TSC patients have epilepsy N.I. TS database 89/111 have epilepsy = 80% 80% with epilepsy (71/89) on anti-epileptic drugs Many of our TS patients with epilepsy have had brain imaging performed MRI done No. of pts % of pts Yes 48/89 54% No 39/89 44% Unknown 2/89 2% Of the patients who had MRI brain performed, 100% had abnormalities associated with TSC 7/48 required neurosurgery

Anti-epileptic Drugs

26% of patients are taking 3+ AEDs (= 24 people)

Learning difficulty in TS patients with epilepsy

Learning difficulty is common in patients with TSC Severity is very variable % of patients with learning difficulty: 63/89 = 70% 10/63 mild; 2/63 mild-moderate; 10/63 moderate; 3/63 moderate-severe; 37/63 severe Of those with severe LD, 18/37 are prescribed 3 or more AEDs. One of those has had neurosurgery. One has had neurosurgery and is currently prescribed Everolimus. Of those with moderate-severe LD, 1 in prescribed 3 AEDs, 1 is currently on Everolimus, one is neither. None have undergone neurosurgery. Of those with moderate LD, 1 was prescribed 5 AEDs, 2 had undergone neurosurgery, one had been prescribed Everolimus for a non-seizure related indication but had been switched to Sutent, and one was currently on Everolimus. Of those with mild-moderate LD, both were prescribed 1 AED and both were prescribed Everolimus for a non-epilepsy related indication. It is noteworthy that they belong to the same pedigree. Of those with mild LD, none were prescribed 3 or more AEDs, one had undergone neurosurgery. If Everolimus offered to those who have required neurosurgery for seizure control: 7-2 already on the drug: 5 patients x £36,135 per patient per year. = £180,675 If Everolimus offered to those with severe LD on 3 or more AEDs (excluding the one patient that is already prescribed the drug): 17 patients x £36,135 per patient per year. = £614,295 to fund Everolimus for this patient group for a year. If Everolimus offered to those prescribed 3 or more AEDs = 24-1 patient already prescribed the drug: 23 patients x £36,135 per patient per year. = £831,105 to fund Everolimus for this patient group for a year. Votubia brand 10 mg od = £36,135 per patient per year.

mTOR inhibitors: clinical trials as treatment for various aspects of TS

mTOR inhibitors & TSC mTOR inhibitors, e.g. Everolimus, provide tumour suppressor activity 3 clinical trials of Everolimus have been carried out: EXIST-1 Trial to determine whether Everolimus might be able to reduce the size of (2008-2012) subependymal giant cell astrocytomas (SEGAs) in TS patients EXIST-2 Trial to determine whether Everolimus might be able to reduce the size of (2008-2013) angiomyolipomas (AMLs) in TS patients EXIST-3 Trial to determine whether Everolimus might be able to reduce seizure (2012-2016) frequency in TS patients

EXIST-3 trial: association between Everolimus & reduction in seizure frequency1 Type of study: Phase 3 double-blind placebo-controlled RCT Population: TSC & treatment-resistant seizures, 2-65 years (mean age was 10), 25 countries, 366 patients Intervention: Everolimus given as an adjunct to current AEDs Comparison: placebo 3 arms of study: High-exposure Everolimus (defined by plasma trough concentration of 9-15 ng/ml) Low-exposure Everolimus (defined by plasma trough concentration of 3-7 ng/ml) Placebo

Outcomes Reduction in seizure frequency was: 40% in high-exposure arm (95% CI 31·5–49·0; 52 patients; p<0·0001) 28% in low-exposure arm (95% CI 20·3–37·3; 33 patients; p=0·0077) 5% in placebo arm. (95% CI 9·2–22·8; 18 patients)

What % of N.I. T.S.C. patients might benefit from Everolimus for seizures? Proposed group: those with poorly-controlled epilepsy. Q – How to best define poorly-controlled epilepsy? A – One possible definition is those on 3 or more AEDs plus those who have required neurosurgery. 24 (26%) patients in N.I. on 3 or more AEDs 7 patients with neurosurgery (6 frontal lobe, 1 corpus callosum): 1 on Everolimus for renal AMLs + 3 AEDs 1 on Everolimus for renal AMLs & < 3 AEDs 1 on 3 AEDs (therefore already included in group above) 4 eligible patients from the neurosurgery group

Cost of Everolimus versus potential cost of not prescribing it If not prescribed, potentially… Greater number of seizures  added cost of hospital admissions, additional outpatient clinic appointments, prescription of additional AEDs Cost of time missed from school/work by patients. Cost of time missed from work by parents of affected children.

Conclusion Intended clinical outcome is: Everolimus may be of benefit for some of Northern Ireland’s TSC patients who experience seizures Intended clinical outcome is: Reduced seizure frequency Likely secondary clinical outcomes: Reduce the size of AMLs Reduce the size of subependymal giant cell astrocytomas Intended benefits for the patients: Improvement in quality of life Delayed progression of disease

References 1. French JA, Lawson JA et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 2015; 388: 2153-63. 2. Northrup H, Krueger DA. Tuberous Sclerosis Complex Diagnostic Criteria Update: Recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Published in: Pediatr Neurol. 2013 October ; 49(4): 243–254.