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

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)

LAM Timeline st case described in literature st case series 1995 LAM Foundation established NIH Registry TSC2 mutation in LAM Akt signaling pathway Cinn. sirolimus trial MILES trial st effective drug 1994

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

Control of Cell Growth mTOR TSC1TSC2

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

Renal Angiomyolipomas

Development of Cysts MMPs

Appearance of LAM Cysts on CT

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

Rapamycin (sirolimus) mTOR TSC1TSC2 rapamycin

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

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

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

Frequency of Oligoamenorrhea

Frequency of Ovarian Cysts

Uncommon but Serious Side Effects Delayed wound healing Pneumonitis Pericardial effusion

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.

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

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

Uncommon but Serious Side Effects Delayed wound healing Pneumonitis Pericardial effusion

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

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

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?

Decrease in VEGF-D and Response to Rapa

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

Simvastatin simvastatin Rheb

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

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

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

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

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