Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis — NEJM

Original Article

Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis
Francis X. McCormack, M.D., Yoshikazu Inoue, M.D., Ph.D., Joel Moss, M.D., Ph.D., Lianne G. Singer, M.D., Charlie Strange, M.D., Koh Nakata, M.D., Ph.D., Alan F. Barker, M.D., Jeffrey T. Chapman, M.D., Mark L. Brantly, M.D., James M. Stocks, M.D., Kevin K. Brown, M.D., Joseph P. Lynch, III, M.D., Hilary J. Goldberg, M.D., Lisa R. Young, M.D., Brent W. Kinder, M.D., Gregory P. Downey, M.D., Eugene J. Sullivan, M.D., Thomas V. Colby, M.D., Roy T. McKay, Ph.D., Marsha M. Cohen, M.D., Leslie Korbee, B.S., Angelo M. Taveira-DaSilva, M.D., Ph.D., Hye-Seung Lee, Ph.D., Jeffrey P. Krischer, Ph.D., and Bruce C. Trapnell, M.D. for the National Institutes of Health Rare Lung Diseases Consortium and the MILES Trial Group

March 16, 2011 (10.1056/NEJMoa1100391)

Comments open through March 23, 2011

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 (FEV1).


Results
During the treatment period, the FEV1 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 FEV1 during the treatment period was 153 ml, or approximately 11% of the mean FEV1 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.) see here please: Efficacy and Safety of Sirolimus in Lymphangioleiomyomatosis — NEJM