1. From bench to bedside: Current clinical trials in LAM Souheil El-Chemaly, MD, MPH 2013 EPILEPSY CONFERENCE NYU Langone Medical Center May 5 th 2013 HARVARD MEDICAL SCHOOL BRIGHAM AND WOMEN’S HOSPITAL

2. Disclosures No conflict of interest

3. TSC and LAM Incidence of LAM in TSC - The risk of LAM was age-dependent, rising by about 8% per year. - Prevalence of LAM was 27% in subjects 40 years. Clinically significant LAM in TSC - 63% developed pulmonary symptoms - 12.5% died due to LAM. Young et al. Chest. In press

4. Rapalogues Bissler et al. NEJM 2008; 358:140-151

5. The MILES trial McCormack FX et al. NEJM 2011364(17):1595-606

6. How do we preserve lung function?

7. Different approaches Disease suppression Remission induction Henske EP et al. J Clin Invest. 2012;122(11):3807–3816 McCormack et al. AJRCCM 2012; 186 (12):1210-1212.

8. Disease suppression Taveira-DaSilva et al. Ann Intern Med 2011 154 (12):797-805

9. From bench to bedside 1- Autophagy inhibition

10. Autophagy “Self-eating” Garbage disposal for cells, which use the breakdown products to fuel energy production and to replenish building blocks for proteins and other essential molecules Increased autophagy can lead to cell survival mTORC1 is a known inhibitor of autophagy

11. Inhibition of mTORC1 and autophagy Parkhitko et al. PNAS (2011); 108:12455-60

12. TORC1 Cell Proliferation Autophagy Sirolimus + + - - - - - + - Untreated Sirolimus Hydroxychloroquine LAM/TSC

13. SAIL trial

14. Sirolimus and Autophagy Inhibition in LAM Phase I dose escalation study - Sirolimus (same doses used in MILES). - Hydroxychloroquine (dose escalation) Clinicaltrials.gov NCT01687179 NCT01687179 Sponsored by the Department of Defense

15. 1/3 DLT’s >1/3 DLT’s 0/3 DLT’s Add 3 patients to dose level 1/6 DLT’s >1/6 DLT’s Escalate to dose level i+1 Stop and declare dose level i-1 as the MTD Enter 3 patients at dose level i Dose escalation scheme

16. Objectives Primary endpoint -Safety and tolerability of HCQ+Sirolimus Secondary endpoint - To evaluate lung function,6MWT, AML size, and quality of life. Exploratory endpoint - Metabolomics, cytokines and circulating LAM cells

17. Inclusion criteria Female age 18 or older Diagnosis of LAM –CT chest compatible with LAM and a biopsy or cytology consistent with LAM. –CT chest consistent with LAM in the setting of tuberous sclerosis, renal AML, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen or serum VEGF-D > 800 pg/uL. Post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted

18. Exclusion criteria Use of an investigational drug within 30 days Recent pneumothorax within 8 weeks History of malignancy in the last 2 years other than basal cell skin cancer Currently taking doxycycline, metformin, lupron or simvastatin Use of estrogen containing medication within 30 days

19. Study visits Week Baseline3816243648 Visit number1234567 Drug Administration RecordXXXXX Liver, renal, glucose, cholesterolXXXXXX EKGXXX Urine pregnancyXXXXX CBC diffXXXXX Sirolimus levelsXXXX Chest CTX CXRXXXX MRI abdomenXXX Full PFTXXX 6 MWTXXX SpirometryX St George ’ s questionnaire XXXX Ophthalmology examXX

20. From bench to bedside 2- Estrogen in LAM

21. Role of estrogen in LAM Yu J et al. PNAS 2009 106 (8) 2635-2640 Li C et al. AJRCMB 2013 In Press Faslodex (estrogen receptor antagonist)

22. TRAIL Trial of Aromatase Inhibition in LAM Phase 2 trial - Letrozole nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) 2.5mg po daily OR - Placebo Clinicaltrials.gov NCT01353209NCT01353209

23. Inclusion criteria Post menopausal female Diagnosis of LAM –CT chest compatible with LAM and a biopsy or cytology consistent with LAM. –CT chest consistent with LAM in the setting of tuberous sclerosis, renal AML, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen or serum VEGF-D > 800 pg/uL. Post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted

24. Exclusion criteria Known allergy to letrozole Inability to comply with pulmonary function tests or follow up visits. Treatment with investigational agents within 30 days Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration Medical or psychiatric conditions that would interfere with the ability to provide informed consent.

25. Objectives -Primary Outcome Measures: - Effect on FEV1 at 12 months -Secondary Outcome Measures: -Effects on FVC, DLCO, TLC,RV, FRC, 6MWT at 12 months -Effects on quality of life measures (QoL, dyspnea, fatigue, functional performance -Serum VEGF-D level

26. Future direction in therapy Henske EP et al. J Clin Invest. 2012;122(11):3807–3816.

27. Summary Molecular insights have lead to targeted therapies in LAM. Rapalogues alone are not sufficient. Additional drugs are needed Currently 2 clinical trials are recruiting in the US: – SAIL (Sirolimus and Hydroxychloroquine) –TRAIL (aromatase inhibitor)

28. SAIL Trial Team BWH LAM teamNIH Intramural Program Elizabeth HenskeJoel Moss Ivan RosasAngelo Taveira-Dasilva Hilary GoldbergMary Haughey Danielle Morse Matt Hunninghake Phil Camp Betsy Peters Melissa Smith Funding: Department of Defense

29. Contact info Souheil El-Chemaly, MD, MPH sel-chemaly@partners.org Betsy Peters RN 617-525-9331 epeters2@partners.org