Efficacy and safety of sirolimus in lymphangioleiomyomatosis

Abstract

Background: Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women; it is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling, which regulates cellular growth and lymphangiogenesis. Sirolimus (also called rapamycin) inhibits mTOR and has shown promise in phase 1-2 trials involving patients with LAM.

Methods: We conducted a two-stage trial of sirolimus involving 89 patients with LAM who had moderate lung impairment--a 12-month randomized, double-blind comparison of sirolimus with placebo, followed by a 12-month observation period. The primary end point was the difference between the groups in the rate of change (slope) in forced expiratory volume in 1 second (FEV(1)).

Results: During the treatment period, the FEV(1) slope was -12±2 ml per month in the placebo group (43 patients) and 1±2 ml per month in the sirolimus group (46 patients) (P<0.001). The absolute between-group difference in the mean change in FEV(1) during the treatment period was 153 ml, or approximately 11% of the mean FEV(1) at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.

Conclusions: In patients with LAM, sirolimus stabilized lung function, reduced serum VEGF-D levels, and was associated with a reduction in symptoms and improvement in quality of life. Therapy with sirolimus may be useful in selected patients with LAM. (Funded by the National Institutes of Health and others; MILES ClinicalTrials.gov number, NCT00414648.).

Figure 1. Screening, Randomization, and Follow-up

The treatment period was 12 months in duration and was followed by a 12-month observation period during which no patients received a study drug and all patients remained unaware of their treatment assignment. Spirometry was performed every 3 months during the treatment year and every 6 months during the observation year. Patients who were unable to undergo pulmonary-function (PF) testing at one visit could undergo testing at a subsequent visit. The reasons for withdrawal of patients from the study included a decision to use sirolimus outside the study (3 patients in the placebo group and 5 in the sirolimus group), pneumothorax (2 patients in the placebo group), infection (3 patients in each group), placement on a list for transplantation (2 patients in the placebo group), non-adherence to visits or testing (2 patients in the sirolimus group), rash (1 patient in the sirolimus group), anxiety (1 patient in the sirolimus group), and death (2 deaths in the placebo group, 1 due to stroke and 1 in a house fire). FEV₁ denotes forced expiratory volume in 1 second and LAM lymphangioleiomyomatosis.

Figure 2. Change in Lung Function during the Treatmentand Observation Phases of the Trial

Panel A shows the mean forced expiratory volume in 1 second (FEV₁) at baseline and at each follow-up visit in the placebo and sirolimus groups. The number of patients for whom FEV₁ data were available at each time point is also shown. Panel B shows the mean changes from baseline to 12 months in FEV₁ and forced vital capacity (FVC) in the 34 patients in the placebo group and the 41 patients in the sirolimus group for whom 12-month data were available. Panel C shows the frequency of FEV₁ changes, in increments or decrements of 5% of the baseline value, from baseline to 12 months. The percentage of patients who had any improvement in FEV₁ was significantly greater in the sirolimus group than in the placebo group (46% vs. 12%, P<0.001). Conversely, a significantly greater percentage of patients in the placebo group than in the sirolimus group had some worsening of FEV₁ (67% vs. 44%). In Panels A and B, T bars indicate standard errors.