Current clinical trials in LAM - Tuberous Sclerosis Alliance目前的临床试验中，结核结节性硬化症联盟.pptVIP

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Current clinical trials in LAM - Tuberous Sclerosis Alliance目前的临床试验中，结核结节性硬化症联盟.ppt

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Current clinical trials in LAM - Tuberous Sclerosis Alliance目前的临床试验中，结核结节性硬化症联盟.ppt

From bench to bedside: Current clinical trials in LAM Souheil El-Chemaly, MD, MPH 2013 EPILEPSY CONFERENCE NYU Langone Medical Center May 5th 2013 HARVARD MEDICAL SCHOOL BRIGHAM AND WOMEN’S HOSPITAL Disclosures No conflict of interest TSC and LAM Incidence of LAM in TSC - The risk of LAM was age-dependent, rising by about 8% per year. - Prevalence of LAM was 27% in subjects 21 years and 81% in subjects 40 years. Clinically significant LAM in TSC - 63% developed pulmonary symptoms - 12.5% died due to LAM. Young et al. Chest. In press Rapalogues Bissler et al. NEJM 2008; 358:140-151 The MILES trial McCormack FX et al. NEJM 2011364(17):1595-606 How do we preserve lung function? Different approaches Disease suppression Remission induction Henske EP et al. J Clin Invest. 2012;122(11):3807–3816 McCormack et al. AJRCCM 2012; 186 (12):1210-1212. Disease suppression Taveira-DaSilva et al. Ann Intern Med 2011 154 (12):797-805 From bench to bedside1- Autophagy inhibition Autophagy “Self-eating” Garbage disposal for cells, which use the breakdown products to fuel energy production and to replenish building blocks for proteins and other essential molecules Increased autophagy can lead to cell survival mTORC1 is a known inhibitor of autophagy Inhibition of mTORC1 and autophagy Parkhitko et al. PNAS (2011); 108:12455-60 TORC1 Cell Proliferation Autophagy Sirolimus + + - - - - - + - Untreated Sirolimus Hydroxychloroquine LAM/TSC SAIL trial SAIL trial Sirolimus and Autophagy Inhibition in LAM Phase I dose escalation study - Sirolimus (same doses used in MILES). - Hydroxychloroquine (dose escalation) Clinicaltrials.gov NC? Sponsored by the Department of Defense 1/3 DLT’s 1/3 DLT’s 0/3 DLT’s Add 3 patients to dose level 1/6 DLT’s 1/6 DLT’s Escalate to dose level i+1 Stop and declare dose level i-1 as the MTD Enter 3 patients at dose level i Dose escalation scheme Objectives Primary endpoint -Safety and tolerability of HCQ+Siro