Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients’ Perspectives,CNS Drugs

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Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients’ Perspectives
CNS Drugs ( IF 7.4 ) Pub Date : 2021-07-17 , DOI: 10.1007/s40263-021-00839-4
Laurent M Willems _{1,

2} , Felix Rosenow _{1,

2} , Susanne Schubert-Bast _{1,

2,

3} , Gerhard Kurlemann ₄ , Johann Philipp Zöllner _{1,

2} , Thomas Bast ₅ , Astrid Bertsche ₆ , Ulrich Bettendorf ₇ , Daniel Ebrahimi-Fakhari ₈ , Janina Grau _{1,

2} , Andreas Hahn ₉ , Hans Hartmann ₁₀ , Christoph Hertzberg ₁₁ , Frauke Hornemann ₁₂ , Ilka Immisch ₁₃ , Julia Jacobs _{14,

15} , Karl Martin Klein _{1,

2,

16} , Kerstin A Klotz _{14,

17} , Gerhard Kluger _{18,

19} , Susanne Knake ₁₃ , Markus Knuf _{20,

21} , Klaus Marquard ₂₂ , Thomas Mayer ₂₃ , Sascha Meyer ₂₄ , Hiltrud Muhle ₂₅ , Karen Müller-Schlüter ₂₆ , Felix von Podewils ₂₇ , Susanne Ruf ₂₈ , Matthias Sauter ₂₉ , Hannah Schäfer _{30,

31} , Jan-Ulrich Schlump ₃₂ , Steffen Syrbe ₃₃ , Charlotte Thiels ₃₄ , Regina Trollmann ₃₅ , Adelheid Wiemer-Kruel ₅ , Bernd Wilken ₃₆ , Bianca Zukunft ₃₇ , Adam Strzelczyk _{1,

2,

13}

Affiliation

Epilepsy Center Frankfurt Rhine-Main and Department of Neurology, Goethe-University Frankfurt, Schleusenweg 2-16 (Haus 95), 60528, Frankfurt am Main, Germany.
LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany.
Department of Neuropediatrics, Goethe-University Frankfurt, Frankfurt am Main, Germany.
St. Bonifatius Hospital, Lingen, Germany.
Epilepsy Center Kork, Clinic for Children and Adolescents, Kehl-Kork, Germany.
Department of Neuropediatrics, University Hospital for Children and Adolescents, Rostock, Germany.
Neuropediatric Practice, Hirschaid, Germany.
Department of General Pediatrics, Division of Neuropediatrics, University Hospital Münster, Münster, Germany.
Department of Neuropediatrics, Justus-Liebig-University Gießen, Gießen, Germany.
Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
Department of Neuropediatrics, Vivantes Klinikum Neukölln, Berlin, Germany.
Department of Neuropediatrics, Leipzig University Hospital for Children and Adolescents, Leipzig, Germany.
Epilepsy Center Hessen and Department of Neurology, Philipps-University Marburg, Marburg (Lahn), Germany.
Department of Neuropediatrics and Muscle Disorders, Center for Pediatrics, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
Department of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.
Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
Research Institute, Rehabilitation, Transition and Palliation, PMU Salzburg, Salzburg, Austria.
Department of Pediatrics, Klinikum Worms, Worms, Germany.
Department of Pediatrics, University Medicine Mainz, Mainz, Germany.
Department of Pediatric Neurology, Psychosomatics and Pain Management, Klinikum Stuttgart, Stuttgart, Germany.
Epilepsy Center Kleinwachau, Radeberg, Germany.
Department of Neuropediatrics, University Children´s Hospital of Saarland, Homburg, Germany.
Department of Neuropediatrics, Christian-Albrechts-University Kiel and University Hospital Schleswig-Holstein, Kiel, Germany.
Epilepsy Center for Children, University Hospital Neuruppin, Brandenburg Medical School, Neuruppin, Germany.
Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.
Department of Neuropediatrics, University Hospital Tübingen, Tübingen, Germany.
Klinikum Kempten, Klinikverbund Allgäu, Kempten/Allgäu, Germany.
Division of Nephrology, Medizinische Klinik und Poliklinik IV, Klinikum der LMU München - Innenstadt, München, Germany.
Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Department of Neuropediatrics, University of Witten/Herdecke, Herdecke, Germany.
Division of Pediatric Epileptology, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Department of Neuropediatrics and Social Pediatrics, St. Josef-Hospital, University Hospital of Pediatrics and Adolescent Medicine, Ruhr-University Bochum, Bochum, Germany.
Department of Neuropediatrics, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
Department of Neuropediatrics, Klinikum Kassel, Kassel, Germany.
Department of Nephrology and Internal Intensive Care, Charité - University Medicine Berlin, Berlin, Germany.

Background

The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder.

Objective

The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective.

Methods

A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC.

Results

Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m² (median: 5.6 mg/m², range 2.0–15.1 mg/m²) in children and adolescents and 4 ± 2.1 mg/m² (median: 3.7 mg/m², range 0.8–10.1 mg/m²) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE.

Conclusions

From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

中文翻译：

依维莫司在结节性硬化症患者中的疗效、保留率和耐受性：基于患者观点的调查研究

背景

依维莫司 (EVE) 获批用于治疗结节性硬化症 (TSC) 患者的血管平滑肌脂肪瘤 (2013)、室管膜下巨细胞星形细胞瘤 (2013) 和药物难治性癫痫 (2017) 代表了第一个可用于改善疾病的治疗选择这种罕见而复杂的遗传疾病。

客观的

本研究的目的是从患者的角度分析EVE在德国TSC患者中的使用、疗效、耐受性和治疗保留情况。

方法

2019 年 2 月至 2019 年 7 月，德国 TSC 患者权益组织在德国 26 个专门的 TSC 中心进行了结构化的跨年龄调查，招募了 TSC 的儿童、青少年和成人患者。

结果

在 365 名参与者中，36.7% ( n = 134) 报告了当前或过去的 EVE 摄入量，其中 31.5% ( n = 115) 在研究开始时服用了 EVE。儿童和青少年的平均 EVE 剂量为 6.1 ± 2.9 mg/m ²（中位数：5.6 mg/m ²，范围 2.0–15.1 mg/m ^{2 ）和 4 ± 2.1 mg/m}²（中位数：3.7 mg/m ² , 范围 0.8–10.1 mg/m ²) 在成年患者中。TSC 的早期诊断、血管平滑肌脂肪瘤的存在、药物难治性癫痫、神经精神症状、室管膜下巨细胞星形细胞瘤、心脏横纹肌瘤和整体多器官受累与使用 EVE 作为疾病缓解治疗有关。报道的血管平滑肌脂肪瘤疗效为 64.0%（成人患者为 75%），药物难治性癫痫为 66.2%，室管膜下巨细胞星形细胞瘤为 54.4%。EVE 的总体保留率为 85.8%。成人 EVE 治疗 12 个月后的保留率（93.7%）高于儿童和青少年（88.7%；24 个月后为 90.5% 对 77.4%；36 个月后为 87.3% 对 77.4%）。耐受性是可以接受的，70.9% 的患者报告了不良事件，包括口腔炎 (47.0%)、痤疮样皮疹 (7.7%)、增加对常见感染和淋巴水肿的易感性（各 6.0%），这是最常报告的症状。与未服用 EVE 的患者相比，总分为 41.7 分，而未服用 EVE 的患者为 36.8 分，目前正在接受 EVE 治疗的患者显示利物浦不良事件概况增加。在服用 EVE 的患者中更频繁地报告了可能与 EVE 典型不良反应有关的子项“疲劳”、“皮肤问题”和“口腔/牙龈问题”的明显偏差。