A phase II clinical trial of the Safety Of Simvastatin (SOS) in patients with pulmonary lymphangioleiomyomatosis and with tuberous sclerosis complex

Inroduction: The mechanistic target of rapamycin inhibitors (mTORi) sirolimus and everolimus stabilize lung function in patients with pulmonary lymphangioleiomyomatosis (LAM) but do not induce remission. Pre-clinical studies suggest that simvastatin in combination with sirolimus induces LAM cell death. The objective of this study was to assess the safety of simvastatin with either sirolimus or everolimus in LAM patients. Methods: This was a phase II single arm trial evaluating the safety of escalating daily simvastatin (2040 mg) in LAM patients already treated with sirolimus or everolimus. Adverse events and changes in lipid panel profile, pulmonary function tests, and VEGF-D were assessed. Results: Ten LAM patients on a stable dose of mTORi for >3 months were treated with 20 mg simvastatin for two months followed by 40 mg for two months. The most common adverse events were peripheral edema (30%), cough (30%), and diarrhea (30%). No patients withdrew or had a reduction in simvastatin dose because of adverse events. Two patients required sirolumus dose reduction for supratherapeutic trough levels following simvastatin initiation. Total cholesterol and low density lipoproteins declined over the study period (-46.0 mg/dL +/- 20.8, p = 0.008; -41.9 mg/dL +/- 22.0, p = 0.01, respectively). There was also a decline in FEV1 (-82.0 mL +/- 86.4, p = 0.02) but no significant change in FVC, DLCO, or VEGF-D. Conclusions: The combination of simvastatin with mTORi in LAM patients is safe and well-tolerated from an adverse events perspective. The addition of simvastatin, however, was associated with decline in FEV1 and the efficacy of this combination should be explored in larger trials.