Dickey Amy K, Leaf Rebecca K
Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA.
Harvard Medical School, Boston, MA.
Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):426-433. doi: 10.1182/hematology.2024000663.
The acute hepatic porphyrias (AHPs) are a family of rare genetic diseases associated with attacks of abdominal pain, vomiting, weakness, neuropathy, and other neurovisceral symptoms. Pathogenic variants in 1 of 4 enzymes of heme synthesis are necessary for the development of AHP, and the onset of acute attacks also requires the induction of δ-aminolevulinic acid synthase 1 (ALAS1), the first and rate-limiting step of heme synthesis in the liver. Givosiran is an RNA interference medication that inhibits hepatic ALAS1 and was designed to treat AHP. In 2019 the US Food and Drug Administration approved givosiran for AHP based on positive results from a phase 3 clinical trial of 94 patients with AHP who demonstrated a marked improvement in AHP attacks and a substantial decrease in δ-aminolevulinic acid and porphobilinogen, the primary disease markers of AHP. A long-term follow-up study demonstrated continued improvement in AHP attack rates, biochemical measures of disease, and quality of life. Real-world studies have also confirmed these results. Common side effects include injection site reactions, hyperhomocysteinemia, and abnormalities of liver and renal biochemistries. This article reviews the studies that led to givosiran approval, discusses real-world clinical data, and highlights remaining questions in the treatment of AHP.
急性肝卟啉病（AHPs）是一类罕见的遗传性疾病，与腹痛、呕吐、虚弱、神经病变及其他神经内脏症状发作相关。血红素合成的4种酶中任何一种发生致病性变异都是AHPs发病所必需的，而急性发作的发生还需要诱导δ-氨基乙酰丙酸合酶1（ALAS1），这是肝脏中血红素合成的第一步且为限速步骤。吉沃西坦是一种抑制肝脏ALAS1的RNA干扰药物，旨在治疗AHPs。2019年，基于一项针对94例AHPs患者的3期临床试验的阳性结果，美国食品药品监督管理局批准吉沃西坦用于治疗AHPs，这些患者在AHPs发作方面有显著改善，且作为AHPs主要疾病标志物的δ-氨基乙酰丙酸和卟胆原大幅减少。一项长期随访研究表明，AHPs发作率、疾病生化指标及生活质量持续改善。真实世界研究也证实了这些结果。常见副作用包括注射部位反应、高同型半胱氨酸血症以及肝肾功能生化指标异常。本文回顾了促使吉沃西坦获批的研究，讨论了真实世界临床数据，并突出了AHPs治疗中尚存的问题。
