[HTML][HTML] Efficacy and safety of sirolimus in lymphangioleiomyomatosis

FX McCormack, Y Inoue, J Moss… - … England Journal of …, 2011 - Mass Medical Soc
FX McCormack, Y Inoue, J Moss, LG Singer, C Strange, K Nakata, AF Barker, JT Chapman…
New England Journal of Medicine, 2011Mass Medical Soc
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 …
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.)
The New England Journal Of Medicine