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Efficacy and safety of sirolimus in lymphangioleiomyomatosis
Francis X McCormack1, Yoshikazu Inoue, Joel Moss
1University of Cincinnati, Cincinnati, OH, USA. frank.mccormack@uc.edu
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.).
Insights
Sirolimus stabilized lung function in women with lymphangioleiomyomatosis (LAM), a rare lung disease. This mTOR inhibitor improved quality of life and reduced VEGF-D, offering a potential therapy for selected LAM patients.
Area of Science:
- Pulmonology
- Oncology
- Pharmacology
Background:
- Lymphangioleiomyomatosis (LAM) is a progressive, cystic lung disease in women.
- It is characterized by the inappropriate activation of mammalian target of rapamycin (mTOR) signaling.
- Sirolimus (rapamycin) inhibits mTOR and has shown promise in preliminary trials for LAM.
Purpose of the Study:
- To evaluate the efficacy of sirolimus in patients with LAM.
- To assess the effect of sirolimus on lung function decline.
- To investigate the impact of sirolimus on quality of life and biomarkers in LAM patients.
Main Methods:
- A two-stage trial involving 89 patients with LAM and moderate lung impairment.
- A 12-month randomized, double-blind comparison of sirolimus versus placebo.
- The primary endpoint was the rate of change in forced expiratory volume in 1 second (FEV1).
Main Results:
- Sirolimus treatment stabilized lung function (FEV1 slope of 1±2 ml/month) compared to placebo (-12±2 ml/month; P<0.001).
- Improvements were observed in forced vital capacity, functional residual capacity, serum VEGF-D, and quality of life with sirolimus.
- Lung function declined similarly in both groups after sirolimus discontinuation; adverse events were more frequent with sirolimus.
Conclusions:
- Sirolimus stabilized lung function in LAM patients, reduced VEGF-D levels, and improved quality of life and functional performance.
- Therapy with sirolimus may be beneficial for selected patients with LAM.
- Further research is warranted to optimize sirolimus therapy in LAM.
