Repurposing Sodium Cromoglycate For Lymphangioleiomyomatosis (LAM): An Open Label, Proof Of Concept And Feasibility Study

Lymphangioleiomyomatosis (LAM) is a rare, incurable, disease of women which causes lung damage leading to progressive loss of lung function, respiratory failure and sometimes death. Mutations in the tuberous sclerosis complex genes leads to activation of the mTOR pathway, a regulator of cell growth and metabolism, in turn causing increased growth and survival of 'LAM cells' which invade the lungs and attract other cell types to form nodules in the lungs which cause lung damage. Drugs that inhibit the mTOR pathway suppress disease activity but require lifelong use and lung function loss continues albeit more slowly than before treatment. To control the disease fully and prevent disability, additional well tolerated long term treatments targeting the recruited cells that are not dependent on mTOR activation are required. Our laboratory has used cell culture and animal models of LAM to show that nodules of LAM cells and fibroblasts attract mast cells, a circulating cell normally associated with the allergic response. We found that LAM nodules activate these mast cells which then release tryptase, a protein which caused the growth of cells in LAM nodules. We then showed that by using sodium cromoglycate, a drug used in asthma and allergic diseases, we could block the release of tryptase from mast cells, reducing the growth of LAM nodules and lung damage. Sodium cromoglycate has been used for decades as an asthma treatment where it has been shown to be safe in long term treatment and is inexpensive, meaning it could be quickly applied to women with LAM. As our laboratory studies show that sodium cromoglycate acts on cells that are not dependent upon activation of the mTOR pathway, the drug could be helpful both alone and when used with mTOR inhibitors to reduce the residual decline in lung function in mTOR inhibitor treated patients. We plan to perform a clinical trial in which 21 women with LAM who are also treated with an mTOR inhibitor and 21 not treated with an mTOR inhibitor will be treated with a sodium cromoglycate inhaler for 28 weeks. We will use reduction in the blood level of a protein marker of disease extent and activity in LAM, vascular endothelial growth factor-D, to determine if sodium cromoglycate may be helpful in LAM. The study will run through the National LAM Centre and Biomedical Research Centre in Nottingham where most UK LAM patients receive care. Working with LAM action, UK LAM patient charity we have designed the study to make it easier for patients to take part, by performing the reseach study visits at the patients' clinical visits and test the use of home lung function monitoring technology, meaning no extra visits to the centre will be required for patients. We will also measure standard lung function and quality of life. LAM is a rare disease and women with LAM have to travel long distances to the LAM Centre for their care, we hope by using this 'patient friendly' study design with no study visits above clinical care, we can reduce paient inconvenience and make it easy for people to participate. If sodium cromoglycate looks like it may be effective, we will use the results of the study to plan a larger study to see if sodium cromoglycate reduces the loss of lung function in LAM. The use of home lung function monitoring in this study will be evaluated as an outcome measure for rare lung disease trials.

Lymphangioleiomyomatosis (LAM) is a rare, incurable, disease of women which causes progressive lung function loss, respiratory failure and sometimes death. Loss of TSC gene function in 'LAM cells' causes mTOR hyperactivation, recruitment of wild type cells and lung damage. Whilst mTOR inhibitors partially suppress disease activity, they require lifelong use and lung function loss continues albeit more slowly. To control the disease fully, additional, well tolerated long term interventions targeting mTOR independent wild type cells are required. Using pre-clinical models, our group have shown that nodules of LAM cells and fibroblasts attract mast cells, which release tryptase, driving LAM nodule growth and that mast cell stabilisation using sodium cromoglycate (SCG) reduces LAM spheroid growth in vitro and lung damage in vivo. We hypothesise that repurposing inhaled SCG will reduce disease progression in women with LAM. SCG is cheap with decades of human safety data and as the effect of SCG is independent of mTOR, could act both alone and as an adjunct to mTOR inhibitors. We will conduct a open label biomarker study to generate efficacy and safety data of the effect of SCG in women with LAM stratified by mTOR inhibitor treatment. The study will run through the National LAM Centre and the Nottingham BRC where most UK patients receive care and to maximise recruitment and retention will align with clinical visits and use remote monitoring. 42 patients will be treated with inhaled SCG for 28 weeks in an open label proof of efficacy biomarker study, stratified by mTOR inhibitor use. The primary endpoint will be reduction in serum vascular endothelial growth factor-D (VEGF-D), a biomarker of disease activity. We will also measure standard lung function, quality of life and the feasibility of using remote monitoring for clinical trials in a rare disease centre. The data will inform design of a definitive randomised trial examining the effect of SCG on lung function in LAM.