1. Risks and Benefits of Drug Therapy for LAM Robert M. Kotloff, M.D. Chairman, Department of Pulmonary Medicine Respiratory Institute Cleveland Clinic

2. Where We Were Not Too Long Ago “There are no well designed studies upon which to base therapeutic decisions in LAM and there is no consensus regarding optimal treatment” (Murray and Nadel, 5 th ed, 2010) “Thus far, treatment regimens have been unsatisfactory.” (Fishman, 4 th ed, 2008)

3. LAM Timeline 1919 1 st case described in literature 1966 1st case series 1995 LAM Foundation established NIH Registry 1997 1998 TSC2 mutation in LAM Akt signaling pathway 2001 2003 Cinn. sirolimus trial MILES trial 2005 2011 1 st effective drug 1994

4. Medications Used to Treat LAM Medroxyprogesterone Tamoxifen Plaquenil Letrozole Rapamycin (sirolimus) Simvastatin

5. Control of Cell Growth mTOR TSC1TSC2

6. LAM Smooth Muscle Cell Proliferation Bronchi: airflow obstruction Lymphatics: chylous effusions Blood vessels: hemoptysis Kidney: angiomyolipomas

7. Renal Angiomyolipomas

9. Development of Cysts MMPs

10. Appearance of LAM Cysts on CT

11. Rapamycin (sirolimus) Discovered on Easter Island (Rapa Nui) Originally developed as anti- fungal agent Subsequently found to have immunosuppressive properties; used as anti-rejection drug after transplant Also inhibits proliferation of cells; has anti-tumor effects

12. Rapamycin (sirolimus) mTOR TSC1TSC2 rapamycin

13. Effect of Sirolimus on Lung Function: MILES Trial McCormack FX et al. N Engl J Med 2011;364:1595-1606

14. Bissler J et al. N Engl J Med 2008;358:140-151 Effect of Sirolimus on AML Volume

15. Common Side Effects of Rapamycin Mouth ulcers (66%) Elevated cholesterol (27%) Diarrhea (52%) Acne (61%) Leg swelling (45%) NIH series, CHEST 2015

16. Frequency of Oligoamenorrhea

17. Frequency of Ovarian Cysts

18. Uncommon but Serious Side Effects Delayed wound healing Pneumonitis Pericardial effusion

19. FDA Black Box Warning Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, use in these patients is not recommended.

20. A Current Dilemma: The LAM Patient Awaiting Lung Transplant Stop rapamycin Continue rapamycin Switch to everolimus

21. Uncommon but Serious Side Effects Delayed wound healing Pneumonitis Pericardial effusion J Postgrad Med. 2006 Oct-Dec;52(4):329.

22. Uncommon but Serious Side Effects Delayed wound healing Pneumonitis Pericardial effusion www.cardiachealth.org

23. Immunosuppression “Increased susceptibility to infection and development of lymphoma may result from immunosuppression.” No difference in infection rates between treatment and placebo groups in MILES trial

24. Rapamycin Drug Interactions Antifungals: fluconazole (Diflucan), voriconazole Anti-HTN: verapamil, diltiazem Macrolide antibiotics: erythromycin, clarithromycin (Biaxin) Anti-seizure meds: Dilantin, phenobarbitol Grapefruit juice

25. Rapamycin Despite many potential side effects, generally well tolerated Tending to use lower doses Requires monitoring of trough blood levels Use VEGF-D blood levels to predict response and determine dosing?

26. Decrease in VEGF-D and Response to Rapa

27. Simvastatin Developed as a cholesterol- lowering drug Numerous other effects described: Inhibit smooth muscle cell growth Inhibit release of MMPs Inhibit platelet aggregation (clumping) Anti-inflammatory

28. Simvastatin simvastatin Rheb

29. LAM Mouse Model: Nodules and Cysts E. A. Goncharova et al., Sci Transl Med 2012;4:154ra134 Nodules Cysts

30. Effect of Rapamycin and Simvastatin on Mouse Lung Cell Proliferation and Cyst Size E. A. Goncharova et al., Sci Transl Med 2012;4:154ra134 Rapa Sim Rapa+Sim No treatment Sim Rapa+Sim No treatment Rapa

31. Limited Experience with Rapa vs. Rapa + Simvastatin Taveira-DaSilva, Chest 2015 Rapa + Sim (n=14) Rapa (n=44)

32. Simvastatin: Side Effects Muscle pain (35%) Joint pain (60%) Elevated LFTs (30%, but similar to rapa) No evidence for increased side effects in group taking both rapa and simvastatin NIH Series, CHEST 2015

33. Take Home Points Rapamycin represents the first effective treatment for LAM Despite potential for many side effects, rapa generally well tolerated Commonly used drugs can alter rapa levels Safety of simvastatin/rapa combination currently being investigated (SOS trial) Benefit of simvastatin either alone or in combination with rapa is uncertain