Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.
Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease.
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DOI：
10.1002/hep.26289
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发表时间：
2013-09
期刊：
影响因子：
13.5
通讯作者：
Quinn, Anthony G.
中科院分区：
文献类型：
--
作者：
Balwani, Manisha;Breen, Catherine;Enns, Gregory M.;Deegan, Patrick B.;Honzik, Tomas;Jones, Simon;Kane, John P.;Malinova, Vera;Sharma, Reena;Stock, Eveline O.;Valayannopoulos, Vassili;Wraith, J. Edmond;Burg, Jennifer;Eckert, Stephen;Schneider, Eugene;Quinn, Anthony G.
胆固醇酯贮积病是一种溶酶体酸性脂肪酶的遗传性缺乏症，是一种未得到充分认识的进行性肝病病因，目前尚无批准的治疗方法。其表现特征包括血脂异常、转氨酶升高和肝肿大。
为了评估重组人溶酶体酸性脂肪酶塞利帕酶α的临床效果和安全性，9名患者在LAL - CL01研究中接受了4次每周一次的输注（0.35、1或3 mg·kg⁻¹），这是对该研究药物的首次人体研究。完成LAL - CL01研究的患者有资格参加扩展研究（LAL - CL04），在该研究中，他们在过渡到长期隔周输注（1或3 mg·kg⁻¹）之前，再次接受4次每周一次的塞利帕酶α输注（0.35、1或3 mg·kg⁻¹）。
塞利帕酶α耐受性良好，大多数不良事件为轻度且与塞利帕酶α无关。未检测到抗药物抗体。LAL - CL01研究中的患者转氨酶下降，而在不同研究阶段之间转氨酶升高。在LAL - CL04研究中接受持续塞利帕酶α治疗的7名患者，与LAL - CL01研究中的基线值相比，第12周时丙氨酸转氨酶和天冬氨酸转氨酶的平均±标准差下降分别为46±21 U/L（-52%）和21±14 U/L（-36%）（p<0.05）。在LAL - CL04研究的第12周，这7名患者的总胆固醇较基线平均下降44±41 mg/dL（-22%；p = 0.047），低密度脂蛋白胆固醇下降29±31 mg/dL（-27%；p = 0.078），甘油三酯下降50±38 mg/dL（-28%，p = 0.016），高密度脂蛋白胆固醇升高5 mg/dL（15%；p = 0.016）。
这些数据表明，在胆固醇酯贮积病患者中，研究性的酶替代药物塞利帕酶α耐受性良好，能迅速降低血清转氨酶，且这些改善在长期给药时得以维持，同时伴有血脂谱的改善。
Cholesteryl Ester Storage Disease, an inherited deficiency of lysosomal acid lipase, is an underappreciated cause of progressive liver disease with no approved therapy. Presenting features include dyslipidemia, elevated transaminases, and hepatomegaly. To assess the clinical effects and safety of the recombinant human lysosomal acid lipase, sebelipase alfa, 9 patients received 4 once-weekly infusions (0.35, 1, or 3 mg·kg−1) in LAL-CL01 which is the first human study of this investigational agent. Patients completing LAL-CL01 were eligible to enroll in the extension study (LAL-CL04) in which they again received 4 once-weekly infusions of sebelipase alfa (0.35, 1, or 3 mg·kg−1) before transitioning to long term every other week infusions (1 or 3 mg·kg−1). Sebelipase alfa was well-tolerated with mostly mild adverse events unrelated sebelipase alfa. No anti-drug antibodies were detected. Transaminases decreased in patients in LAL-CL01 and increased between studies. In 7 patients receiving ongoing sebelipase alfa treatment in LAL-CL04, mean±SD decreases for alanine transaminase and aspartate aminotransferase at week 12 compared to the baseline values in LAL-CL01 were 46±21U/L (-52%) and 21±14U/L (-36%), respectively (p<0.05). Through week 12 of LAL-CL04, these 7 patients also showed mean decreases from baseline in total cholesterol of 44±41mg/dL (-22%; p=0.047), low density lipoprotein-cholesterol of 29±31mg/dL (-27%; p=0.078), and triglycerides of 50±38mg/dL (-28%, p=0.016) and increases in high density lipoprotein-cholesterol of 5mg/dL (15%; p=0.016). These data establish that sebelipase alfa, an investigational enzyme replacement, in patients with Cholesteryl Ester Storage Disease is well tolerated, rapidly decreases serum transaminases and that these improvements are sustained with long term dosing and are accompanied by improvements in serum lipid profile.
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影响因子：
2.2
作者：
Mire-Sluis, AR;Barrett, YC;Zuckerman, LA
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