1. Progress in TSC Dr Chris Kingswood 2014

2. Research Update Care &Treatment

3. International Guidelines Diagnosis – Northrup, H., et al. Pediatr Neurol 49(4): 243-254 2013. Monitoring and treatment – Krueger D and Northrup H. Pediatr Neurol. 2013; 49(4):255-265

4. Europe Austria*, Belgium*, Czech Republic*, Denmark*, Estonia, France*, Germany*, Greece*, Italy*, Latvia, Lithuania, Netherlands*, Norway*, Poland*, Portugal, Romania, Slovakia, Slovenia*, Spain*, Sweden*, United Kingdom* EGM Australia, China, Israel, Korea, Taiwan, Thailand, Turkey, Russia, South Africa Japan *EU countries involved in TOSCA PASS TOSCA Countries involved and patients enrolled TOSCA: 2201 patients enrolled as of Aug 10, 2014 (LPFV) TOSCA PASS: 185 patients enrolled as of Nov 10, 2014

5. Epilepsy Krueger DA, Wilfong AA, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 2013 75% improvement Exist-3 mTOR and resistant epilepsy

6. Infantile Spasms Early seizures cause more seizures cause intellectual impairment & probably ASD Infantile Spasms are the worst

7. Early Vigabatrin Bombardieri, Curatolo EJPN 2010 Jozwiak, et al EJPN 2011

8. Vigabatrin to stop IS Standard TreatmentPreventative Number3114 Epilepsy71%43% Resistant Epilepsy42%7% Seizure free at 24 Months10%80% Mean IQ6992 Normal IQ52%86% Mod to severe ID320 Jozwiak EJPN 201i

9. What Next? www.epistop.eu What about mTOR Inhibitors?

10. Never Give Up Hope “It is a genetic disease, there is no point in research” Care for today – Hope for tomorrow

11. TSC1 TSC2 Food Building Blocks mTORI Orders Cell size & number Cell movement Blood supply Cell metabolism Pathobiology Ch 16 Ch 9

12. Rapamycin or Sirolimus

13. Exist-1 78 on Everolimus - 39 on Placebo SEGA shrinkage in 95% on E – 0% on P SEGA enlargement in 0 on E – 15% on P Skin rash improved in 43% 0n E – 11% on P

14. Neuropsychiatric Disorders in TSC Across the Lifespan Developmental/ Psychological Manifestations Lifetime PrevalenceYears 01246810 12141618 … 30 … Intellectual disability40%-50% ASD40%-50% Severe aggressive behavior/outbursts 28%-58% Severe sleep problems~40% ADHD and related disorders30%-55% Anxiety disorders28%-59% Depressive disorders26%-35% Indicates approximate period of development Indicates continued symptoms with decrease in severity Indicates continued symptoms Adapted from: Hallett L et al. Curr Med Res Opin. 2011;27:1571-1583 and de Vries PJ. In: Kwiatkowski DJ, Holets-Whittemore V, Thiele EA, eds. Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics. 2010: chapter 12.

15. TAND

17. Kidneys 80% AMLs – Bleeding – CKD

18. Exist-2 Everolimus – 93% AMLs stable, 81% shrank Placebo – 78% enlarged SEGAs, Skin, ? Epilepsy, ?Lung disease Side Effects 5 years on – good results maintained (n=113)

19. EXIST-2: Best Percentage Change From Baseline in Renal Angiomyolipoma Volume—2.45-Year Update ‒ 100 ‒ 75 ‒ 50 ‒ 25 0 25 50 75 100 Everolimus, n (%) Decrease in best percentage change from baseline96 (97) Increase in best percentage change from baseline3 (3) Patients for whom the best % change in sum of volumes of target renal angiomyolipoma lesions was not available and patients with “overall angiomyolipoma response = not evaluable” were excluded from the graph. Best % Change From Baseline (Sum of Volumes of Target Renal Angiomyolipoma Lesions) Everolimus (n=99) Extension-Phase Cutoff: May 1, 2013

20. Exist-1 78 on Everolimus - 39 on Placebo SEGA shrinkage in 95% on E – 0% on P SEGA enlargement in 0 on E – 15% on P Skin rash improved in 43% 0n E – 11% on P By 48 weeks AML shrinkage in 100% on E (By 30% 0r more) AML on P all enlarged except in 1 child

21. Exist-1 & 2 Outcome 5 years on – No bleeding – Kidney function stable (In most)

22. What about LAM? MILES trial – Sirolimus stops LAM progressing Everolimus Study in progress

23. Side effects of mTOR inhibitors Mouth ulcers Acne Raised cholesterol ? Infections Allergy (3%) Other Decrease markedly over time

24. EXIST-2 Adverse Events by Preferred Term and Year of Emergence Occurring in >10% of Patients: 2.45-Year Update Everolimus Adverse event, n (%) ≤ 12 months (n = 112) 13-24 months (n = 101) 25-36 months (n = 77) 37-48 months (n = 18) Stomatitis46 (41.1)9 (8.9)2 (2.6)0 (0.0) Nasopharyngitis36 (32.1)19 (18.8)14 (18.2)5 (27.8) Acne28 (25.0)8 (7.9)3 (3.9)0 (0.0) Headache26 (23.2)11 (10.9)3 (3.9)0 (0.0) Hypercholesterolaemia25 (22.3)9 (8.9)6 (7.8)3 (16.7) Aphthous stomatitis21 (18.8)14 (13.9)6 (7.8)1 (5.6) Fatigue19 (17.0)2 (2.0)2 (2.6)0 (0.0) Cough18 (16.1)4 (4.0)4 (5.2)0 (0.0) Diarrhea17 (15.2)6 (5.9)3 (3.9)0 (0.0) Nausea17 (15.2)5 (5.0)0 (0.0)2 (11.1) Mouth ulceration17 (15.2)3 (3.0)2 (2.6)0 (0.0) Urinary tract infection16 (14.3)14 (13.9)6 (7.8)1 (5.6) Vomiting15 (13.4)7 (6.9)1 (1.3)1 (5.6) Hypertension14 (12.5)3 (3.0)3 (3.9)1 (5.6) Edema peripheral12 (10.7)8 (7.9)4 (5.2)0 (0.0) Amenorrhoea12 (10.7)7 (6.9)3 (3.9)0 (0.0) Leukopenia12 (10.7)6 (5.9)0 (0.0) Back pain12 (10.7)5 (5.0)2 (2.6)1 (5.6) Blood lactate dehydrogenase increased12 (10.7)2 (2.0)1 (1.3)0 (0.0) Hypophosphataemia11 (9.8)5 (5.0)4 (5.2)2 (11.1)

25. The effects of mTOR inhibitors in TSC Rescue therapy Enlarging brain growths - SEGA Kidney growths - AML Lung Skin Epilepsy (Exist-3) TRON

26. New Directions Other Treatments – Statins, Metformin, MAP-kinase inhibitors Neural Crest Origin www.epistop.eu TSCure

27. Future hopes A cure for tomorrow? What a cure might look like? o Early diagnosis o Treatment regime that prevents manifestations of TSC

28. London September 2015 TSC International Research Conference 11-13 th September 2015 TS C URE

29. Never Give Up Hope “It is a genetic disease, there is no point in research” Care for today – A CURE for tomorrow

30. Questions?

31. What About the NHS? Where is the care? When will we get treatment?

32. TSC clinic Network London – St Georges / Brighton – GOSH / UCL Birmingham Bath Cambridge Leeds / York Manchester Liverpool Newcastle

33. The Service Specification Clinic Coordinator Clinical Geneticist Paediatric Neurologist Adult neurologist Neuroradiologist Neurosurgeon Paediatric Nephrologist Adult Nephrologist Paediatric Urologist Adult Urologist Interventional radiologist Clinical Psychologist Dermatologist Cardiologist Chest Physician

34. Cohort Funding Bid Cost efficiency Cost Everolimus – Year 1 £1.7 million – Year 2 £ 5 million – Year 3 £10 million – Then cheaper Efficiency – We have the answer

35. Cohort Funding Bid Cost efficiency Sussex Kidney Unit – £20 million – £ 10 million on dialysis – £1.5 million on EPO Cancer drug fund – £200 million 2014-5 – £280 million 2015-6

36. TS Campaign #Fight4treatment Your MP Your local media Simon Stevens (CEO NHS) Chief / deputy chief medical officer https://www.gov.uk/government/organisations/department- of-health https://www.gov.uk/government/organisations/department- of-health Cc TSA Friends / Family

37. The Walk of Remembrance? Hand in a letter at 79 Whitehall London Lay a flower in St James Park

39. Size AMLs (cm) v Age St Georges Kingswood J C, et al Abstract ERA-EDTA Congress 2012 AGE IN YEARS S I Z E In C M

40. 40 UK Gen. Pop (95% CI) TSC (95% CI)** Figure 4. Prevalence of CKD in the Overall TSC Population by Age Compared to the UK General Population (Dec 1998 – Nov 2003 as reported by Stevens P et al. 2007 ) Patient Age (Years) *If a CKD (stage 3-5) record/identifier was observed prior to 1998 in a TSC patient, this patient was still considered to have a CKD case in the observational period (i.e. Dec 1998-Nov 2003). 18-2425-3435-4445-5455-6465-7475-84≥85 3251281712000 0.1-16.22.2-18.98.3-41.018.4-67.19.9-65.1--- 0.1-0.20.4-0.61.5-1.82.7-3.29.5-10.422.3-23.737.3-39.245.9-49.2 TSC (N)

41. 41 EXIST-1/2: Mean Glomerular Filtration Rate During Extended Everolimus Treatment (Safety Sets)

42. MILES Study McCormack, F. et al NEJM 2011