From bench to bedside: Current clinical trials in LAM

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

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 <21 years and 81% 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 bedside1- 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. Parkhitko et al. PNAS (2011); 108:12455-60 Inhibition of mTORC1 and autophagy

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

13. SAIL trial

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

15. Enter 3 patients at dose leveli >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 Stop and declare dose level i-1 as the MTD Escalate to dose level i+1 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

20. From bench to bedside2- Estrogen in LAM

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

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 NCT01353209

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 Henske Joel Moss Ivan Rosas Angelo Taveira-Dasilva Hilary Goldberg Mary 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