D N Franz1, K Budde2, J C Kingswood3, E Belousova4, S Sparagana5, P J de Vries6, N Berkowitz7, A Ridolfi8, J J Bissler9. 1. Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 2. Charité Universitätsmedizin, Berlin, Germany. 3. Royal Sussex County Hospital, Brighton, UK. 4. Moscow Research Institute of Pediatrics & Pediatric Surgery, Moscow, Russia. 5. Texas Scottish Rite Hospital for Children, Dallas, TX, USA. 6. Division of Child and Adolescent Psychiatry, University of Cape Town, Cape Town, South Africa. 7. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. 8. Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France. 9. St. Jude Children's Research Hospital and Le Bonheur Children's Hospital, Memphis, TN, USA.
Abstract
BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS:Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION:Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.
RCT Entities:
BACKGROUND:Tuberous sclerosis complex (TSC) is a genetic disorder associated with tumour growth in various organs, including the brain, kidneys, heart and skin. Cutaneous lesions are prevalent manifestations of TSC, occurring in up to 90% of patients. Oral mammalian target of rapamycin inhibitors, such as everolimus, is believed to be effective for treatment of TSC-associated lesions because they act on the underlying disease pathophysiology. OBJECTIVE: We evaluated the long-term effect of oral everolimus on TSC-associated skin lesions as a secondary objective in the phase III studies EXIST-1 (NCT00789828) and EXIST-2 (NCT00790400) after approximately 4 years of treatment. MATERIALS AND METHODS:Everolimus was dosed 4.5 mg/m2 /day (titrated to trough 5-15 ng/mL) in patients with TSC-associated subependymal giant cell astrocytoma in EXIST-1, and 10 mg/day initially in adult patients with TSC- or sporadic lymphangioleiomyomatosis-associated renal angiomyolipoma in EXIST-2. Following positive results from the core phase, remaining patients were offered open-label everolimus in an extension. Skin lesion response rate was the proportion of patients achieving complete or partial clinical response. RESULTS: A total of 105 patients in EXIST-1 and 107 in EXIST-2 received everolimus and had ≥1 skin lesion at baseline. Skin lesion response rate (95% confidence interval) was 58.1% (48.1-67.7%) in EXIST-1 and 68.2% (58.5-76.9%) in EXIST-2; most were partial responses. At week 192 (EXIST-1: n = 55; EXIST-2: n = 56), 69% and 66% had a response. Most common drug-related adverse event was stomatitis (41-45%). CONCLUSION: Oral everolimus improved TSC-related skin lesions, with responses sustained over 4 years of treatment in EXIST-1 and EXIST-2.
Authors: John J Bissler; Fahad Zadjali; Dave Bridges; Aristotelis Astrinidis; Sharon Barone; Ying Yao; JeAnna R Redd; Brian J Siroky; Yanqing Wang; Joel T Finley; Michael E Rusiniak; Heinz Baumann; Kamyar Zahedi; Kenneth W Gross; Manoocher Soleimani Journal: Physiol Rep Date: 2019-01
Authors: Laurent M Willems; Felix Rosenow; Susanne Schubert-Bast; Gerhard Kurlemann; Johann Philipp Zöllner; Thomas Bast; Astrid Bertsche; Ulrich Bettendorf; Daniel Ebrahimi-Fakhari; Janina Grau; Andreas Hahn; Hans Hartmann; Christoph Hertzberg; Frauke Hornemann; Ilka Immisch; Julia Jacobs; Karl Martin Klein; Kerstin A Klotz; Gerhard Kluger; Susanne Knake; Markus Knuf; Klaus Marquard; Thomas Mayer; Sascha Meyer; Hiltrud Muhle; Karen Müller-Schlüter; Felix von Podewils; Susanne Ruf; Matthias Sauter; Hannah Schäfer; Jan-Ulrich Schlump; Steffen Syrbe; Charlotte Thiels; Regina Trollmann; Adelheid Wiemer-Kruel; Bernd Wilken; Bianca Zukunft; Adam Strzelczyk Journal: CNS Drugs Date: 2021-07-17 Impact factor: 5.749