Anja Holm, Marianne Bengtson Løvendorf and Sakari Kauppinen
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Due to the recent progress in liver-targeted delivery of siRNA therapeutics , many biopharmaceutical companies have established extensive pipelines focused on the treatment of liver-related diseases. There are currently 27 siRNA drugs in clinical trials for treating liver diseases such as hypercholesterolemia, hemophilia, hepatic porphyria, amyloidosis, and primary hyperoxaluria (Table 1). Three pharmaceutical companies, Dicerna Pharmaceuticals, Arrowhead Pharmaceuticals, and Alnylam Pharmaceuticals, have GalNAc-conjugated siRNA drugs for liver diseases in phase II/III and phase III trials. Dicerna has three siRNA drugs in clinical trials, including a phase III study of nedosiran (formerly known as DCR-PHXC) for the treatment of all three known types of primary hyperoxaluria (PH). The three known genetic types of PH result from mutations in three different genes, AGXT, GRHPR, and HOGA1, respectively, in the glyoxylate metabolism pathway, resulting in overproduction of oxalate. Nedosiran is a GalNAc-siRNA conjugate targeting the lactate dehydrogenase enzyme, which catalyzes the final common step of the glyoxylate metabolism pathway, and thereby prevents overproduction of oxalate. Knockdown of LDH occurs specifically in hepatocytes due to the GalNAc ligand in nedosiran. Data from a phase III study showed a mean reduction in urinary oxalate of 48% (range: 28–59%) among participants with PH1 receiving a single 1.5 mg/kg dose, which led to normalization or near-normalization in the participants, whereas patients with PH2 showed a mean reduction of 24-h urinary oxalate of 42% (range: 22–66%). Nedosiran was generally well tolerated with mild or moderate injection site reactions.
由于 siRNA 治疗靶向肝脏递送的最新进展，许多生物制药公司已建立了专注于治疗肝脏相关疾病的广泛管线。目前有 27 种 siRNA 药物正在临床试验中，用于治疗高胆固醇血症、血友病、肝性卟啉病、淀粉样病和原发性高草酸尿症等肝脏疾病（见表 1）。Dicerna Pharmaceuticals、Arrowhead Pharmaceuticals 和 Alnylam Pharmaceuticals 三家制药公司在 II/III 期和 III 期试验中，开发了针对肝脏疾病的 GalNAc 缀合 siRNA 药物。Dicerna 在临床试验中有三种 siRNA 药物，包括 nedosiran（曾用名 DCR-PHXC）的 III 期研究，用于治疗所有三种已知的原发性高草酸尿症（PH）。这三种已知的 PH 遗传类型分别由三个不同的基因 AGXT、GRHPR 和 HOGA1 的突变引起，在乙醛酸代谢途径中导致草酸过度生产。Nedosiran 是一个 GalNAc-siRNA 共轭物，靶向乳酸脱氢酶酶，该酶催化乙醛酸代谢途径的最后共同步骤，从而防止草酸的过度生成。由于 nedosiran 中的 GalNAc 配体，LDH 的沉默特异性发生在肝细胞中。来自 III 期研究的数据显示，接受单剂量为 1.5 mg/kg 的 PH1 患者，尿草酸平均减少 48%（范围：28-59%），使得参与者的尿草酸正常或接近正常水平，而 PH2 患者显示尿草酸 24 小时平均减少 42%（范围：22-66%）。Nedosiran 通常耐受良好，仅有轻度或中度的注射部位反应。
Arrowhead Pharmaceuticals has six GalNAc-siRNA conjugates in clinical trials, which includes an ongoing phase II/III study of ARO-AAT for the treatment of the genetic disorder Alpha-1 antitrypsin deficiency (AATD). The most common AATD disease variant, the Z mutant, has a single amino acid substitution that results in accumulation of the mutant protein in globules inside the hepatocytes leading to fibrosis, cirrhosis, and an increased risk of hepatocellular carcinoma. ARO-AAT is a cholesterol-conjugated UNA-modified (chol-UNA) siRNA drug targeting the mutant alpha-1 antitrypsin (Z-AAT) for suppressing the liver disease associated with AATD. This siRNA drug is administered concomitantly with the delivery excipient ARC-EX1 containing hepatocyte-targeted GalNAc-conjugated melittin-like peptide, which does not form a complex with the siRNA drug. Results from clinical trial phase I reported a 76.1% reduction in serum AAT 4 weeks after a single 4 mg/kg ARO-AAT dose. No severe adverse events were reported, whereas mild adverse effects included chills in 75% of ARO-AAT group likely related to the infusion of ARC-AAT. The study is currently in phase II/III, where ARO-AAT is administered on day 1, 29, and 113, and every 84 days thereafter in a total of 120 AAT patients.
Arrowhead Pharmaceuticals 公司拥有六款 GalNAc-siRNA 缀合物正在进行临床试验，其中包括一项针对遗传性疾病 Alpha-1 抗胰蛋白酶缺乏症 (AATD) 的 ARO-AAT 的 II/III 期临床试验。最常见的 AATD 疾病变体 Z 型突变具有单个氨基酸替换，导致突变蛋白在肝细胞内聚集形成球状体，并进一步导致肝纤维化、肝硬化和肝细胞癌风险增加。ARO-AAT 是一种胆固醇缀合的 UNA 修饰 (chol-UNA) siRNA 药物，靶向突变的 alpha-1 抗胰蛋白酶 (Z-AAT)，用于抑制与 AATD 相关的肝脏疾病。该 siRNA 药物与递送载体 ARC-EX1 联合给药，ARC-EX1 含有肝细胞靶向的 GalNAc 缀合的蜂毒素样肽，但不与 siRNA 药物形成复合物。I 期临床试验结果显示，单剂量 4 mg/kg ARO-AAT 治疗后 4 周，血清 AAT 减少 76.1%。未报告严重不良事件，轻度不良事件包括 ARO-AAT 组 75% 的患者出现寒战，这可能与 ARC-AAT 的输注有关。该研究目前处于 II/III 期，ARO-AAT 在第 1、29 和 113 天以及此后每 84 天共对 120 名 AAT 患者进行给药。
Alnylam Pharmaceuticals has currently 12 siRNA drugs in its clinical development pipeline, of which 11 are GalNAc-siRNA conjugates for a wide variety of liver diseases. Inclisiran (ALN-PCSsc) is based on Alnylam’s ESC-GalNAc drug platform and targets the pro-protein convertase subtilisin-kexin type 9 (PCSK-9) for the treatment of patients with hypercholesterolemia by providing sustained reductions in low-density lipoprotein (LDL) cholesterol levels upon infrequent dosing. Inclisiran has completed three large double-blind, randomized, placebo-controlled phase III studies (ORION-9, ORION-10 and ORION-11), in which 300 mg of the drug was administered subcutaneously on day 1, day 90, followed by s.c. injections every 6 months, leading to a 51% reduction in LDL cholesterol after 1 year. The adverse effects were generally similar in the inclisiran group compared to the placebo group. However, more injection-site reactions (ISRs) occurred in the inclisiran treatment group compared to placebo, but all ISRs were mild and resolved over time. By comparison, hypercholesterolemia patients currently taking statins to lower their LDL cholesterol levels are required to dose every day. Inclisiran is being developed by The Medicines Company and is expected to achieve regulatory approval in the USA and Europe in 2020.
Alnylam Pharmaceuticals 目前在其临床开发管线中有 12 种 siRNA 药物，其中 11 种是 GalNAc-siRNA 共轭物，用于治疗各种肝病。Inclisiran（ALN-PCSsc）基于 Alnylam 的 ESC-GalNAc 药物平台，靶向前蛋白转化酶枯草杆菌蛋白酶/ kexin 9 型（PCSK-9），用于治疗高胆固醇血症患者，通过间断给药持续降低低密度脂蛋白（LDL）胆固醇水平。Inclisiran 已完成三项大型双盲、随机、安慰剂对照的 III 期研究（ORION-9、ORION-10 和 ORION-11），在这些研究中，药物在第 1 天和第 90 天皮下注射 300 mg，之后每 6 个月注射一次，导致 1 年后 LDL 胆固醇降低了 51%。不良反应在 Inclisiran 组与安慰剂组相比通常相似。然而，与安慰剂相比，Inclisiran 治疗组的注射部位反应（ISRs）更多，但所有 ISRs 均为轻度，并随时间解决。相比之下，目前服用他汀类药物治疗高胆固醇血症患者需要每天服药。Inclisiran 由 The Medicines Company 开发，预计将于 2020 年在美国和欧洲获得监管批准。（注：该药物已经获得批准）
Lumasiran (ALN-GO1) is an investigational, s.c.-administered GalNAc-conjugated siRNA drug targeting hydroxyacid oxidase 1 (HAO1) for the treatment of Primary Hyperoxaluria Type 1 (PH1). PH1 is a rare disease, which leads to the formation of painful and recurrent kidney stones and nephrocalcinosis caused by excessive oxalate production resulting in the deposition of calcium oxalate crystals in the kidneys and urinary tract. Renal damage is caused by a combination of tubular toxicity from oxalate, calcium oxalate deposition in the kidneys, and urinary obstruction by calcium oxalate stones. Although a small subset of patients manages the disease with vitamin B6 treatment, the only effective treatment is a combined liver-kidney transplant, which requires life-long immune suppression and carries a significant mortality risk. Results from the ILLUMINATE A phase III study showed significant reduction of oxalate after monthly doses of lumasiran (3 mg/kg) for 3 months followed by quarterly maintenance doses. There were no severe adverse events in the study, and lumasiran was generally well tolerated. Alnylam is also conducting ILLUMINATE B and C, which are studies of lumasiran given to PH1 patients less than 6 years of age and PH1 patients of all ages with advanced renal disease, respectively. Results are expected in 2020 and 2021. Earlier this year, Alnylam Pharmaceuticals and Dicerna announced that they have executed a cross-license agreement of their respective intellectual property for lumasiran and nedosiran investigational programs. Moreover, the two companies have decided to form a development and commercialization collaboration on siRNA drugs for the treatment of alpha-1 liver diseases.
Lumasiran (ALN-GO1) 是一种正在研究中的皮下注射 GalNAc 缀合 siRNA 药物，靶向羟基酸氧化酶 1 (HAO1)，用于治疗原发性高草酸尿症 1 型 (PH1)。PH1 是一种罕见疾病，由于过量草酸盐生成导致肾脏和尿路中草酸钙晶体沉积，从而形成疼痛性复发性肾结石和肾钙质沉着症。肾脏损伤是由草酸盐对肾小管的毒性、肾脏中草酸钙沉积以及草酸钙结石引起尿路梗阻共同造成的。虽然一小部分患者可以通过维生素 B6 治疗控制病情，但唯一有效的治疗方法是联合肝肾移植，该手术需要终身免疫抑制治疗，并伴有显着的死亡风险。III 期临床研究 ILLUMINATE A 的结果显示，每月剂量 (3 mg/kg) 的 lumasiran 连续使用 3 个月，然后按季度进行维持剂量治疗，可以显著降低尿液草酸盐水平。该研究中没有出现严重不良事件，lu masiran 耐受性良好。Alnylam 公司还在进行 ILLUMINATE B 和 C 研究，分别评估 lumasiran 在 6 岁以下 PH1 患者和所有年龄段晚期肾病 PH1 患者中的安全性及疗效。研究结果预计分别于 2020 年和 2021 年公布。今年年初，Alnylam Pharmaceuticals 和 Dicerna 公司宣布，双方就各自的 lumasiran 和 nedosiran 研究项目知识产权达成交叉许可协议。此外，两家公司决定合作开发和商业化用于治疗 alpha-1 肝脏疾病的 siRNA 药物。
Vutrisiran (ALN-TTRsc02) is a s.c.-administered, investigational GalNAc-siRNA conjugate targeting transthyretin (TTR) for the treatment of transthyretin-mediated (ATTR) amyloidosis. Vutrisiran is similar to the already approved patisiran, but utilizes the GalNAc delivery platform instead of LNPs. Data from clinical phase I showed a TTR knockdown of 83% after a single 25 mg dose of vutrisiran, and a good safety profile with no severe adverse events. The safety and efficacy of vutrisiran are currently being evaluated in the HELIOS Phase III clinical program. Patients will receive either s.c.-administered vutrisiran (total dose of 25 mg every 3 months) (n = 120) or intravenously (i.v.) administered patisiran (0.3 mg/kg every 3 weeks) (n = 40) during a treatment period of 18 months. Results from the vutrisiran study will be evaluated with the placebo arm from the APOLLO study for most endpoints, which evaluated the efficacy and safety of patisiran in patients with hATTR amyloidosis with polyneuropathy.
Vutrisiran (ALN-TTRsc02) 是一种皮下注射的正在研究中的 GalNAc-siRNA 缀合物，靶向转甲状蛋白 (TTR) 用于治疗转甲状蛋白介导的 (ATTR) 淀粉样变性病。Vutrisiran 与已经获批的 patisiran 相似，但使用 GalNAc 递送平台替代脂质纳米颗粒 (LNPs)。I 期临床试验数据显示，单剂量 25mg 的 vutrisiran 可使 TTR 敲除 83%，安全性良好，无严重不良事件。vutrisiran 的安全性和有效性目前正在 HELIOS III 期临床项目中评估。患者将在 18 个月的治疗期间接受皮下注射 vutrisiran (总剂量 25mg，每 3 个月一次) (n = 120) 或静脉注射 patisiran (0.3mg/kg，每 3 周一次) (n = 40)。vutrisiran 研究的大多数终点将与 APOLLO 研究的安慰剂组进行评估，APOLLO 研究评估了 patisiran 在患有 hATTR 淀粉样变性多发性神经病变的患者中的疗效和安全性。
Fitusiran (ALN-AT3sc) targets anti-thrombin 3 (AT3) to enhance thrombin generation (TG) and rebalance hemostasis in patients with hemophilia A (HA) or hemophilia B (HB) with or without inhibitors for the treatment of hemophilia and rare bleeding disorders. Hemophilia is caused by a mutation in the F8 and F9 genes encoding the coagulation factors VIII (FVIII:C) and IX (FIX:C), respectively. Anti-thrombin (AT) is the naturally occurring inhibitor of thrombin, and patients with AT deficiency exhibit a clinically hypercoagulable state leading to thromboembolic events. Moreover, hemophilia patients with a concomitant AT deficiency have less severe bleeding phenotypes compared to patients with normal levels of AT. Fitusiran is administered s.c. once a month, and Phase I and II data showed dose-dependent lowering of AT (20%), increased TG, and a decrease in the frequency of spontaneous and traumatic bleeds. Fitusiran is currently in clinical phase III studies and is being developed by Sanofi Genzyme deploying Alnylam’s ESC-GalNAc siRNA drug platform.
Fitusiran (ALN-AT3sc) 是一种靶向抗凝血酶 III 型 (AT3) 的 siRNA 药物，通过皮下注射给药，每月一次。该药物的作用原理是增强凝血酶生成 (TG)，从而重建血友病 A (HA) 或血友病 B (HB) 患者 (无论伴有或不伴有抑制物) 的止血平衡，用于治疗血友病和罕见出血性疾病。血友病是一种遗传性出血性疾病，由 F8 和 F9 基因突变引起，这两种基因分别编码凝血因子 VIII (FVIII:C) 和 IX (FIX:C)。抗凝血酶 (AT) 是人体内的一种天然凝血酶抑制物，AT 缺乏的患者会出现异常的高凝状态，容易形成血栓。而对于血友病患者来说，如果同时伴有 AT 缺乏，出血症状反而会轻一些。Fitusiran 的 I 期和 II 期临床试验数据显示，该药物可以剂量依赖性地降低 AT 水平 (约 20%)，同时增加凝血酶生成，并减少患者自发性出血和外伤性出血的发生频率。Fitusiran 目前正处于 III 期临床研究阶段，由赛诺菲基因泰克公司开发，并采用了 Alnylam 公司的 ESC-GalNAc siRNA 药物平台。
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There are currently two FD-approved siRNA drugs on the market, patisiran (ONPATTRO™) for the treatment of hereditary transthyretin amyloidosis (hATTR) and givosiran (GIVLAARI™) for the treatment of acute hepatic porphyria (AHP), respectively (Fig. 3). Patisiran was approved in 2018 by the FDA for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis and is the first FDA-approved siRNA drug. It is an LNP-encapsulated siRNA targeting transthyretin (TTR) for the treatment of hATTR. hATTR is an autosomal dominant, progressive, life-threatening multisystem disease caused by mutations in the gene encoding TTR. Both mutant and wild-type transthyretin deposit as amyloids in peripheral nerves and the heart, kidney, and gastrointestinal tract, resulting in polyneuropathy and cardiomyopathy. TTR is mainly produced in the liver and forms homotetramers that transport retinol, thyroxine, and vitamin A. The absence of this protein results in vitamin A deficiency, and thus vitamin A is required as a daily supplement. However, if the protein is present, but misfolded, as occurs subsequent to its mutation in hATTR patients, it generates amyloid fibrils, which deposit in various organs. Treatment options for hATTR prior to the approval of patisiran included orthotopic liver transplantation or the administration of TTR tetramer stabilizing drugs such as tafamidis or diflunisal. However, many patients continue to have disease progression.
目前已经有两种 siRNA 药物获批上市，分别为：治疗遗传性转甲状蛋白淀粉样变性病 (hATTR) 的 patisiran (商品名：ONPATTRO™) 和治疗急性肝卟啉病 (AHP) 的 givosiran (商品名：GIVLAARI™) (见图 3)。Patisiran 是史上首个获得 FDA 批准上市的 siRNA 药物，获批时间为 2018 年，用于治疗由遗传性转甲状蛋白介导的周围神经病变。Patisiran 是一种利用脂质纳米颗粒 (LNP) 递送的 siRNA 药物，靶向转甲状蛋白 (TTR)，用于治疗 hATTR。hATTR 是一种常染色体显性遗传病，由编码转甲状蛋白的基因突变引起，是一种进行性、危及生命的全身性疾病。hATTR 患者体内会产生突变型和野生型的转甲状蛋白，这些蛋白异常折叠并沉积为淀粉样蛋白，主要累积于周围神经、心脏、肾脏和胃肠道，导致多发性神经病变和心肌病。转甲状蛋白主要由肝脏产生，并以同源四聚体的形式运载视黄醇、甲状腺素和维生素 A。hATTR 患者由于转甲状蛋白异常，会出现维生素 A 缺乏，因此需要每日补充维生素 A。以往，hATTR 的治疗方案主要包括原位肝移植或使用稳定 TTR 四聚体的药物，例如 tafamidis 或 diflunisal。然而，这些传统疗法并不能阻止疾病的进展。
Fig. 3 Schematic illustration of the secondary structures of patisiran and givosiran. (a) Patisiran is an LNP-encapsulated siRNA (ALN-TTR02) targeting transthyretin (TTR) for the treatment of hereditary transthyretin amyloidosis (hATTR). All of the pyrimidines in the sense strand and two of the uridines in the antisense strand of patisiran contain 2′-O-Me-modified sugars, and both strands contain 2′-deoxythymidine (dT) dinucleotide overhangs at their 3′-ends. (b) Givosiran (ALN-AS1) is a GalNAc-conjugated siRNA drug targeting aminolevulinate synthase 1 (ALAS1) for the treatment of acute hepatic porphyria (AHP). The nucleotides are all chemically modified with either 2′-O-Me or 2′-F and the 3′ end of the sense strand is covalently linked to GalNAc to enable specific delivery of the siRNA drug to hepatocytes patisiran 和 givosiran 二级结构示意图。（a）Patisiran 是一种 LNP 封装的 siRNA（ALN-TTR02），靶向转甲状腺素蛋白（TTR），用于治疗遗传性转甲状腺素蛋白淀粉样变性（hATTR）。patisiran 的正义链中的所有嘧啶和反义链中的两个尿苷都含有 2′-O-Me 修饰的糖，并且两条链在其 3′ 端都含有 2′-脱氧胸苷 (dT) 二核苷酸悬垂。（b）Givosiran (ALN-AS1) 是一种 GalNAc 结合的 siRNA 药物，靶向氨基乙酰丙酸合酶 1 (ALAS1)，用于治疗急性肝卟啉症 (AHP)。所有核苷酸均经过 2′-O-Me 或 2′-F 化学修饰，正义链的 3′ 端与 GalNAc 共价连接，从而能够将 siRNA 药物特异性递送至肝细胞
Patisiran targets a conserved sequence in the 3′ untranslated region of both mutant and wild-type TTR mRNA, leading to its degradation and a 86.8% reduction in serum TTR protein levels and tissue TTR deposits primarily in the liver. Patisiran (ALN-TTR02) is formulated as a 100 nm LNP composed of the siRNA (ALN-18328) and four lipid components of which two are constituents of other approved drugs (DSPC [1,2-distearoyl-sn-glycero-3-phosphocholine] and cholesterol), and two novel lipid components (DLin-MC3-DMA [(6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate] and PEG2000-C-DMG [α-(3′-{[1,2-di(myristyloxy)proponoxy] carbonylamino}propyl)-ω-methozy,polyoxyethylene]). All of the pyrimidines in the sense strand and two of the uridines in the antisense strand of patisiran contain 2′-O-methyl modified sugars with the remaining being unmodified ribonucleotides. Both guide and passenger strands contain 2′-deoxythymidine dinucleotide overhangs at their respective 3′-ends. All internucleotide linkages are natural, unmodified phosphodiester linkages (Fig. 3a).
Patisiran (ALN-TTR02) 靶向转甲状蛋白 (TTR) mRNA 3' 非翻译区 (UTR) 的保守序列，导致其降解，从而使血清 TTR 蛋白水平降低 86.8%，并主要降低肝脏组织中的 TTR 沉积。Patisiran 是一种由 100 nm 的脂质纳米颗粒 (LNP) 递送的 siRNA 药物。该 LNP 由 siRNA (ALN-18328) 和四种脂质成分组成，其中两种为其他获批药物的成分 (DSPC [1,2-distearoyl-sn-glycero-3-磷酸胆碱] 和胆固醇)，另外两种为新型脂质成分 (DLin-MC3-DMA [(6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl-4-(dimethylamino)butanoate] 和 PEG2000-C-DMG [α-(3′-{[1,2-di(myristyloxy)proponoxy] carbonylamino}propyl)-ω-methoxy,polyoxyethylene])。Patisiran 的正义链中的所有嘧啶核苷和反义链中的两个尿苷都含有 2′-O-甲基修饰的糖基，其余为未修饰的核糖核苷酸。引导链和乘客链在各自的 3′端含有 2′-脱氧胸腺苷二核苷酸悬垂。所有核苷酸之间的磷酸二酯键均为自然未修饰的磷酸二酯键（见图 3a）。
The chemical design of patisiran protects the siRNA and allows passive uptake into hepatocytes upon systemic delivery by i.v. infusion at a dose of 0.3 mg/kg every 3 weeks. Disease progression was halted or reversed with patisiran treatment, which included a transition from assisted to unassisted walking. More importantly, cardiac manifestations of hATTR were also improved. The adverse effects are mostly mild and infusion-related. However, seven patients (5%) in the patisiran group died compared to six patients (8%) in the placebo group in phase III clinical trial. The causes of death were primarily cardiovascular in nature and consistent with those expected in patients with hATTR.
Patisiran 的化学设计能够保护 siRNA，并允许其在通过静脉输注 (i.v.) 以 0.3 mg/kg 的剂量进行全身递送后被动地被肝细胞摄取。帕替沙兰治疗可阻断或逆转疾病进展，例如一位患者能够从使用辅助行走工具转变为无需辅助即可行走。更重要的是，hATTR 的心脏症状也得到改善。帕替沙兰治疗耐受性良好，不良反应大多轻微且与输注相关。然而，在 III 期临床试验中，帕替沙兰组有 7 名患者 (5%) 死亡，安慰剂组有 6 名患者 (8%) 死亡。死亡原因主要为心血管方面的原因，与 hATTR 患者的预期情况一致。
Givosiran is a GalNAc-conjugated siRNA drug targeting aminolevulinate synthase 1 (ALAS1) for the treatment of AHP. AHP comprises four genetic disorders each caused by distinct enzyme defects in the heme biosynthesis pathway in the liver, leading to abnormal accumulation of toxic heme precursors, such as δ-aminolevulinic acid (ALA) and porphobilinogen (PBG). This causes acute porphyria attacks that primarily manifest as neurovisceral symptoms such as abdominal pain (cardinal symptom), acute neuropathy, and psychiatric symptoms, such as hallucinations, anxiety and paranoia. Most symptomatic patients have few attacks in their lifetime; however, up to 5% of patients will have recurrent attacks (≥4 attacks per year). The estimated prevalence of AHP is 5.4 per million individuals.
Givosiran 是一种靶向 δ-氨基乙酰丙酸合酶 1 (ALAS1) 的 GalNAc 缀合 siRNA 药物，用于治疗急性肝卟啉病 (AHP)。AHP 包括四种遗传性疾病，每种疾病均由肝脏血红素生物合成途径中不同酶缺陷引起，导致毒性血红素前体物质 (例如 δ-氨基乙酰丙酸 (ALA) 和尿卟啉原 (PBG)) 异常积累。这会导致急性卟啉症发作，主要表现为神经内脏症状，例如腹痛 (主要症状)、急性神经病变以及精神症状 (如幻觉、焦虑和偏执妄想)。大多数有症状的患者一生中发病次数较少；然而，多达 5% 的患者会出现复发性发作 (每年 ≥ 4 次发作)。AHP 的估计患病率为百万分之一 5.4。
Givosiran is chemically modified with PS backbone linkages, and 2′-OMe and 2′-F sugars, and covalently linked to GalNAc to enable specific delivery of the siRNA drug to hepatocytes (Fig. 3b). This results in knockdown of the liver-expressed ALAS1 mRNA preventing accumulation of neurotoxic ALA and PBG levels that are associated with acute porphyria attacks. Clinical phase III study showed that administration of givosiran by s.c. injections at 2.5 mg/kg once monthly results in dose-dependent knockdown of ALAS1 mRNA (up to 86% knockdown), 91% reduction of the ALA protein and 96% reduction in PBG in the liver, urine, and serum samples. These reductions prevent ALA formation, decrease 5-ALA levels and prevent the production of porphyrins and hemes, such as PBG. After a 6-month treatment, mean ALA and PBG levels were reduced from baseline by 77% and 76%, respectively, and more importantly, the median annual attack rate was significantly decreased by 90% in the givosiran treatment group. In November 2019, givosiran was approved by the FDA for the treatment of adults with AHP based on the positive results from the multinational, phase III ENVISION trial. In the EU, givosiran received a positive opinion in January 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.
Givosiran 经过化学修饰，具有磷硫酸 (PS) 骨架键，2'-OMe 和 2'-F 糖基，并通过共价键连接 GalNAc 糖基，使 siRNA 药物能够特异性地递送至肝细胞 (图 3b)。这导致肝脏表达的 ALAS1 mRNA 被敲低，从而阻止神经毒性 ALA 和 PBG 水平的积累，这些代谢物与急性卟啉症发作有关。临床 III 期研究表明，每月一次皮下注射 2.5 mg/kg 的 Givosiran 剂量可使 ALAS1 mRNA 剂量依赖性敲低 (最高可达 86%)，肝脏、尿液和血清样本中 ALA 蛋白减少 91%，PBG 减少 96%。这些降低阻止了 ALA 的形成，降低了 5-ALA 水平，并阻止了卟啉和血红素 (例如 PBG) 的产生。经过 6 个月的治疗，平均 ALA 和 PBG 水平分别较基线降低了 77% 和 76%。更重要的是，Givosiran 治疗组的年发病率中位数下降了 90%。2019 年 11 月，基于来自多国 III 期 ENVISION 试验的阳性结果，吉沃西兰被 FDA 批准用于治疗成人 AHP。2020 年 1 月，欧盟批准吉沃西兰用于治疗 12 岁及以上青少年和成人 AHP。
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Since the discovery of the RNAi pathway in 1998, siRNAs have become a powerful tool for studying gene function and for the development of RNA-targeted therapeutics. Importantly, siRNA-based drugs have several advantages compared to small molecules and monoclonal antibody drugs, which include efficient knockdown of previously undruggable targets, rapid lead optimization, and readily scalable drug manufacturing process. Such features have attracted many researchers and pharmaceutical companies to develop siRNA-based therapeutics. With the emergence of new chemical modifications and improved targeting technologies, the field of RNA therapeutics is experiencing a renaissance. The clinically validated LNPs, GalNAc conjugates, and DPC delivery platforms will continue to produce many new siRNA drugs for the treatment of liver diseases, while ongoing research into new delivery strategies is focusing on effective delivery beyond the liver. Reaching the central and peripheral nervous systems (CNS, PNS), respectively, is highly important, due to the unmet medical need for several neurological pathologies. Indeed, recent efforts have shifted toward delivery to the CNS, where strategies to cross the blood-brain barrier include receptor-mediated delivery and intrathecal injections. For example, single well-tolerated intrathecal injections of an siRNA-conjugate in rodent and nonhuman primate models resulted in robust gene silencing throughout the whole CNS, as reported by Alnylam. Other specific administration routes such as intravitreal injection, intratracheal administration, and aerosol inhalation are also being developed for treating ocular and respiratory disorders, respectively. The recent regulatory approvals of ONPATTRO™ (patisiran) and GIVLLARI™ (givosiran) are success stories that will pave the way for the development of new siRNA drugs for the treatment of a wide array of diseases in the coming years.
自从 1998 年发现 RNAi 机制以来，siRNA 已经成为研究基因功能和开发 RNA 靶向治疗药物的重要工具。与小分子药物和单克隆抗体药物相比，siRNA 疗法具有诸多优势，例如能够高效抑制传统药物难以靶向的基因、快速优化先导化合物以及简便易于规模化的药物生产工艺。这些特点吸引了众多研究人员和制药公司投入到 siRNA 药物的研发之中。随着新型化学修饰方法和靶向技术不断涌现，RNA 疗法领域正经历着复兴。经过临床验证的脂质纳米颗粒 (LNP)、GalNAc 缀合物和 DPC 递送平台将继续催生大量用于治疗肝脏疾病的 siRNA 药物，同时，针对肝脏以外靶器官的递送策略也正在积极研究中。有效递送至中枢神经系统 (CNS) 和周围神经系统 (PNS) 对于治疗一系列神经系统疾病具有重要意义，因为这些疾病目前尚缺乏有效的治疗手段。近年来，研究人员将注意力转向了如何递送 siRNA 至中枢神经系统，相关策略包括受体介导递送和鞘内注射。例如，Alnylam 公司报道了在啮齿动物和非人类灵长类模型中，单次鞘内注射 siRNA 缀合物即可在整个中枢神经系统实现有效的基因沉默，且具有良好的耐受性。此外，针对眼部和呼吸系统疾病，其他特异性给药途径例如玻璃体腔内注射、气管内给药和雾化吸入等方法也在被开发之中。像 ONPATTRO™ (patisiran) 和 GIVLAARI™ (patisiran) 等 siRNA 药物的获批上市，是该领域的成功案例，并将为未来几年开发治疗各种疾病的新型 siRNA 药物铺平道路。
