Efficacy and Safety of Sirolimus in LAM

Summary

Lymphangioleiomyomatosis (LAM) is a rare lung disease of women that is caused by genetic mutations. It results in the uncontrolled growth of an unusual type of smooth muscle cell in the lung. These cells invade lung tissue, including the airways, blood vessels, and lymph vessels, and restrict the flow of air, blood, and lymph, respectively. Respiratory failure, lung collapse (pneumothorax), and pleural effusions (chylothorax) are hallmarks of the disease. This study will evaluate the safety and effectiveness of sirolimus, an inhibitor of the mTOR pathway, in stabilizing or improving lung function in people with LAM.

Timeline

Start

2006-12

Primary completion

2010-09

Completion

2011-02

Publications

• Background McCarthy C, Gupta N, Johnson SR, Yu JJ, McCormack FX. Lymphangioleiomyomatosis: pathogenesis, clinical features, diagnosis, and management. Lancet Respir Med. 2021 Nov;9(11):1313-1327. doi: 10.1016/S2213-2600(21)00228-9. Epub 2021 Aug 27.
• Background Gupta N, Lee HS, Ryu JH, Taveira-DaSilva AM, Beck GJ, Lee JC, McCarthy K, Finlay GA, Brown KK, Ruoss SJ, Avila NA, Moss J, McCormack FX; NHLBI LAM Registry Group. The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis. Chest. 2019 Feb;155(2):288-296. doi: 10.1016/j.chest.2018.06.016. Epub 2018 Jun 22.
• Background Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Decastro RM, Jacobs SS, Stylianou M, Fanburg BL; NHLBI LAM Registry Group. The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med. 2006 Jan 1;173(1):105-11. doi: 10.1164/rccm.200409-1298OC. Epub 2005 Oct 6.
• Background Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis Diagnosis and Management: High-Resolution Chest Computed Tomography, Transbronchial Lung Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017 Nov 15;196(10):1337-1348. doi: 10.1164/rccm.201709-1965ST.
• Background McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016 Sep 15;194(6):748-61. doi: 10.1164/rccm.201607-1384ST.
• Results McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 2011 Apr 28;364(17):1595-606. doi: 10.1056/NEJMoa1100391. Epub 2011 Mar 16.
• Results Argula RG, Kokosi M, Lo P, Kim HJ, Ravenel JG, Meyer C, Goldin J, Lee HS, Strange C, McCormack FX; MILES Study Investigators. A Novel Quantitative Computed Tomographic Analysis Suggests How Sirolimus Stabilizes Progressive Air Trapping in Lymphangioleiomyomatosis. Ann Am Thorac Soc. 2016 Mar;13(3):342-9. doi: 10.1513/AnnalsATS.201509-631OC.
• Results Gupta N, Lee HS, Young LR, Strange C, Moss J, Singer LG, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Downey GP, Taveira-DaSilva AM, Krischer JP, Setchell K, Trapnell BC, Inoue Y, McCormack FX; NIH Rare Lung Disease Consortium. Analysis of the MILES cohort reveals determinants of disease progression and treatment response in lymphangioleiomyomatosis. Eur Respir J. 2019 Apr 4;53(4):1802066. doi: 10.1183/13993003.02066-2018. Print 2019 Apr.
• Results Young L, Lee HS, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch JP 3rd, Goldberg HJ, Downey GP, Swigris JJ, Taveira-DaSilva AM, Krischer JP, Trapnell BC, McCormack FX; MILES Trial Group. Serum VEGF-D a concentration as a biomarker of lymphangioleiomyomatosis severity and treatment response: a prospective analysis of the Multicenter International Lymphangioleiomyomatosis Efficacy of Sirolimus (MILES) trial. Lancet Respir Med. 2013 Aug;1(6):445-52. doi: 10.1016/S2213-2600(13)70090-0.
• Results Lo P, Brown MS, Kim H, Kim H, Argula R, Strange C, Goldin JG. Cyst-based measurements for assessing lymphangioleiomyomatosis in computed tomography. Med Phys. 2015 May;42(5):2287-95. doi: 10.1118/1.4916655.
• Harun N, Gupta N, McCormack FX, Macaluso M. Dynamic use of historical controls in clinical trials for rare disease research: A re-evaluation of the MILES trial. Clin Trials. 2023 Jun;20(3):223-234. doi: 10.1177/17407745231158906. Epub 2023 Mar 17.
• Xu KF, Wang L, Tian XL, Gui YS, Peng M, Cai BQ, Zhu YJ. The St. George's Respiratory Questionnaire in lymphangioleiomyomatosis. Chin Med Sci J. 2010 Sep;25(3):140-5. doi: 10.1016/s1001-9294(10)60038-7.

Drugs

Indications