The next breakthrough in LAM clinical trials may be their design: challenges in design and execution of future LAM clinical trials

Abstract

The past decade has resulted in stunning progress in the pathogenesis and therapy of lymphangioleiomyomatosis (LAM), culminating in the pivotal ‘MILES’ trial, the first-ever randomized, placebo-controlled trial in LAM, demonstrating the efficacy of sirolimus in 2011. Here, we review clinical progress since 2011, focusing on new therapeutic and observational trials. These trials include the second randomized, placebo-controlled trial, a 2-year study of doxycycline effectiveness in LAM. Other clinical studies have addressed lower-dose sirolimus and treatment of pulmonary hypertension. An improved understanding of LAM pathogenesis is essential to future therapeutic breakthroughs. Critical questions that remain to be addressed include the role of estrogen and lymphangiogenesis in LAM pathogenesis and therapy, mechanisms of cystic lung destruction, the role of autophagy and pro-survival pathways in LAM cell survival. Ultimately, achieving future ‘breakthroughs’ in LAM will require continued rigorous basic and preclinical investigation, innovative clinical trial design and robust biomarkers.

Keywords:

• biomarkers
• clinical trials
• design
• doxycycline
• end points
• lymphangioleiomyomatosis
• mTOR inhibitors
• Rheb
• sirolimus
• tuberous sclerosis complex

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues.

• Lymphangioleiomyomatosis is a cystic lung disease caused by mutations in the TSC1 or TSC2 genes, which leads to activation of the mTOR pathway.

• The MILES trial has established the effectiveness of sirolimus (an mTOR inhibitor) to halt lung function decline.

• There is a need for continuous use of sirolimus; therefore, additional therapies are needed.

• Therapies are needed for women who do not respond or cannot tolerate mTOR inhibitors.

• Therapies that can be discontinued.

• The difficulty in conducting a Phase II–III clinical trial in a rare disease with an existing therapy.

• Future drugs or combination of drugs could perhaps be first tested in patients with known rates of decline in lung function. This would allow each patient in essence to serve as their own control, reducing the numbers needed to enroll.

• Biomarkers for disease activity are needed that would allow their use as end points, therefore reducing the numbers needed to enroll.