Bashir Aamir, Tiwari Pramil, Duseja Ajay
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, India.
Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Sector 67, Rupnagar, Punjab, 160062, India.
Ther Adv Rare Dis. 2021 Jul 18;2:26330040211026928. doi: 10.1177/26330040211026928. eCollection 2021 Jan-Dec.
Lysosomal acid lipase deficiency (LAL-D) is a very rare genetic abnormality caused by LIPA gene mutation. The disease has two distinct clinical variants in humans: Wolman disease in infants and cholesteryl ester storage disease in children and adults. Both conditions are characterized by elevated serum transaminases, dyslipidaemia, severe liver steatosis and accelerated fibrosis or cirrhosis, contributing to its high rate of early mortality. Recently sebelipase alfa (recombinant human LAL) was launched to address its underlying pathology. This systematic review evaluates the safety and efficacy of sebelipase alfa for LAL-D.
This systematic review was performed following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Clinical trial records were systematically searched in , and up to September 2020. Records that have reported at least one of the included outcomes were included. Baseline and endpoint mean and standard deviation (SD) for all outcomes were recorded. For safety, frequency and overall distribution of different adverse events were included.
A total of seven records from five individual studies with 110 LAL-D patients were included into this study. The mean age ranged from 2.57 months in infants to 31.6 years among adults. Serum transaminases (alanine aminotransferase and aspartate aminotransferase), serum lipids (total cholesterol, triglycerides, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol), gamma-glutamyl transferase and liver volume were included as efficacy outcomes. Final pooled results were synthesized as a change from baseline to end of the treatment. A significant effect on both serum transaminases and other serum lipid was achieved ( < 0.01), while non-significant differences were seen for GGT and liver volume as = 0.35 and = 0.08 was observed. Mostly the adverse events related to the infusions were infrequent and mild-to-moderate in severity.
Sebelipase alfa as an enzyme replacement provides an effective, safe and well tolerated treatment in both variants of LAL-D.
Lysosomal acid lipase deficiency (LAL-D) is a rare, progressive, genetic disorder caused by functional mutations in the LIPA gene, which encodes LAL enzyme. This enzyme maintains lipid homeostasis by hydrolysing the cholesterol esters and triglycerides. Patients with deficient LAL activity are seen with abnormal liver functions which keep them at a high risk of early mortality. Clinical diagnosis of this disease is very challenging due to both its low prevalence and low awareness among patients/clinicians and additionally due to its overlap with other liver/lipid disorders. Also, owing to lack of safe and effective treatment, dietary modifications and some lipid modifying drugs are usually used to control the LAL-D manifestations. Recently, recombinant human LAL named as sebelipase alfa (Kanuma™, Alexion Pharmaceuticals, Inc., New Haven, Connecticut, USA) was approved in 2015 for the European Union and subsequently in the United States as an enzyme replacement therapy for LAL deficiency. The initial clinical trial data indicate that sebelipase alfa produces a significant improvement in all of the wide range of LAL-D manifestations. However, the cumulative evidence is not reported regarding its safety and effective use. Therefore, a systematic literature review of all the clinical trial records by following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines was undertaken. From all of the available clinical trial records, 110 LAL-D patients treated with sebelipase alfa were included. Serum transaminases, serum lipids, gamma-glutamyl transferase (GGT) and liver volume were included as efficacy outcomes. Final pooled results were synthesized as a change from baseline to end of the treatment. A significant effect on both serum transaminases and other serum lipids was achieved ( < 0.01), while non-significant differences were observed for GGT and liver volume, with = 0.35 and = 0.08 respectively. Mostly the adverse events related to the infusions were infrequent and mild-to-moderate in severity. The enzyme replacement provides an effective, safe and well tolerated treatment in both variants of LAL-D.
溶酶体酸性脂肪酶缺乏症（LAL-D）是一种由LIPA基因突变引起的非常罕见的基因异常疾病。该疾病在人类中有两种不同的临床变体：婴儿型沃尔曼病以及儿童和成人型胆固醇酯贮积病。这两种病症的特征均为血清转氨酶升高、血脂异常、严重肝脂肪变性以及纤维化或肝硬化加速，导致其早期死亡率较高。最近， sebelipase alfa（重组人LAL）被用于解决其潜在病理问题。本系统评价评估了sebelipase alfa治疗LAL-D的安全性和有效性。
本系统评价按照系统评价和Meta分析的首选报告项目指南进行。截至2020年9月，在 、 和 中系统检索临床试验记录。纳入报告了至少一项纳入结局的记录。记录所有结局的基线和终点均值及标准差（SD）。对于安全性，纳入不同不良事件的发生频率和总体分布情况。
本研究共纳入了来自五项个体研究的七份记录，涉及110例LAL-D患者。平均年龄范围从婴儿的2.57个月到成人的31.6岁。疗效结局包括血清转氨酶（丙氨酸转氨酶和天冬氨酸转氨酶）、血脂（总胆固醇、甘油三酯、高密度脂蛋白胆固醇和低密度脂蛋白胆固醇）、γ-谷氨酰转移酶和肝脏体积。最终汇总结果以从基线到治疗结束的变化形式呈现。血清转氨酶和其他血脂均取得了显著效果（ ＜0.01），而γ-谷氨酰转移酶和肝脏体积差异无统计学意义，分别为 ＝0.35和 ＝0.08。大多数与输注相关的不良事件发生频率低，严重程度为轻至中度。
作为一种酶替代疗法，sebelipase alfa在LAL-D的两种变体中均提供了有效、安全且耐受性良好的治疗。
溶酶体酸性脂肪酶缺乏症（LAL-D）是一种罕见的、进行性的基因疾病，由编码LAL酶的LIPA基因功能突变引起。该酶通过水解胆固醇酯和甘油三酯来维持脂质稳态。LAL活性缺乏的患者肝功能异常，使其面临较高的早期死亡风险。由于该疾病患病率低、患者/临床医生认知度低，且与其他肝脏/脂质疾病存在重叠，其临床诊断极具挑战性。此外，由于缺乏安全有效的治疗方法，通常采用饮食调整和一些脂质调节药物来控制LAL-D的表现。最近，名为sebelipase alfa（Kanuma™，Alexion Pharmaceuticals，Inc.，美国康涅狄格州纽黑文）的重组人LAL于2015年在欧盟获批，随后在美国获批作为LAL缺乏症的酶替代疗法。初步临床试验数据表明，sebelipase alfa在所有广泛的LAL-D表现方面均产生了显著改善。然而，尚未报告其安全有效使用的累积证据。因此，按照系统评价和Meta分析的首选报告项目指南对所有临床试验记录进行了系统文献综述。从所有可用的临床试验记录中，纳入了110例接受sebelipase alfa治疗的LAL-D患者。疗效结局包括血清转氨酶、血脂、γ-谷氨酰转移酶（GGT）和肝脏体积。最终汇总结果以从基线到治疗结束的变化形式呈现。血清转氨酶和其他血脂均取得了显著效果（ ＜0.01），而GGT和肝脏体积差异无统计学意义，分别为 ＝0.35和 ＝0.08。大多数与输注相关的不良事件发生频率低，严重程度为轻至中度。酶替代疗法在LAL-D的两种变体中均提供了有效、安全且耐受性良好的治疗。
