部分中文盐酸盐米加司他处方资料（仅供参考）

英文名：Migalastat Hydrochloride

商标名：GALAFOLD Capsules

中文名：盐酸盐米加司他

生产商：大冢制药

药品简介
法布里病是一种X连锁的显性遗传性溶酶体贮积症，是由于GLA基因突变导致α-半乳糖苷酶A（α-Gal A）缺陷所致，该酶的主要生物学功能是降解溶酶体中的特定脂质，包括GL-3（又名Gb3）。
Galafold的活性药物成分为migalastat，这是一种α-半乳糖苷酶A（α-Gal A）的口服药理学“分子伴侣”，能够选择性、可逆性地结合特定突变类型的α-Gal A酶，稳定这些功能失调的酶，促进其运输至溶酶体清除积累的疾病底物，从而发挥治疗作用。
 ガラフォルドカプセル123mg 

药物分类名称

法布里疾病的补救措施

批准日期：2018年5月

商標名

GALAFOLD Capsules 123mg

一般名：ミガーラスタット塩酸塩

Migalastat Hydrochloride（JAN）

化学名：（2R,3S,4R,5S）-2-（Hydroxymethyl）piperidine-3,4,5-triol monohydrochloride

分子式：C6H13NO4・HCl

分子量：199.63

構造式 

性状 

白色至浅棕色晶体

它易溶于溶解度为1.2至7.5的水溶液中。 易溶于盐酸或水，微溶于二甲基亚砜，难溶于甲醇，难溶于乙醇或乙腈。

熔点约244℃

批准条件

·制定药品风险管理计划并适当实施。

·由于日本的临床试验案例非常有限，因此在制造和销售后的复审期间对所有管理案例进行使用结果调查，掌握了使用该药物的患者的背景信息。 此外，尽快收集有关该药物安全性和有效性的数据，并采取必要措施正确使用该药物。

药用药理学

1.作用机制

通过GLA基因的突变的α-Gal的A的法布里病活性降低，并且衬底被累积，如GL-3，造成肾功能衰竭，心肌病，组织损伤如脑血管疾病。特定GLA基因突变，有时不稳定的α-Gal的甲走寻常的构象被生成的，但23，祢咖落统计充当所述α-Gal的药理陪伴分子，内质网选择性地和可逆地结合特定突变体α-Gal A以促进向溶酶体的正确转运。在溶酶体内，Migallastat解离并显示释放的α-Gal A积累的GL-3的降解作用。

2.药理作用

缺陷小鼠的α-Gal的A基因，在法布里病小鼠模型口服给药时宓咖啦STAT所表达的人突变的α-Gal的转基因，皮肤，心脏，肾脏，脑和α-的等离子体Gal A活性显着增加且剂量依赖性，并且GL-3浓度降低。此外，与每日给药方案相比，在间歇给药方案（例如每隔一天给药）中观察到更高的间质GL-3浓度降低作用。

适应症

法布里病与GLA基因突变对Migallastat有反应

用法与用量

通常，16岁或以上的患者每隔一天口服一次123mg，作为Migarastat。 此外，应在饭前和饭后2小时避免使用。

临床结果

1.法布里病患者从酶替代疗法转换的国际联合III期临床试验

该试验是一项随机，开放标记，活性对照研究，以评估这种药物和酶替代疗法（阿加糖酶α或β）的功效和安全性。 18-72岁男性和女性患者的法布里57例包括日本正在进行的酶替代疗法（男性25例，女性32，EGFR≧30毫升/分钟/1.73平方米）靶向，祢咖垃STAT 123mg 18每月间隔日口服给药或酶替代疗法通过静脉内输注每2周一次给药18个月。随后，在12个月的开放标签连续给药期间，每隔一天口服给予123mg Migalastat。分析了52名受试者（该药物组中的34名患者（5名日本病例）和18名患有酶替代治疗组（1名日本病例）且具有对该药物具有反应性的GLA基因突变的患者。作为主要终点，直至给药18个月的肾小球滤过量的年度变化的结果如下表所示，其相当于该药物组中的酶替代疗法组。

（见表6）

另外，左心室重量系数和血浆溶血 - Gb3浓度结果如下表所示。

（见表7）

在该药物组中，给药18个月后出现综合临床结果*（肾脏事件，心脏事件，脑血管事件或死亡）的受试者比例为29％（10/34例），44 ％（18个案例中的8个）。

服用该药物30个月的受试者中eGFRCKD-EPI和mGFRiohexol的年变化为-1.72 [-2.65，-0.78] mL / min / 1.73 m 2（31例）和-2.75 [-4.81，-0.68]mL/min/1.73m2（30例患者），左心室重量系数变化为-3.8 [ - 8.9,1.3] g / m 2（28名受试者），合并临床结果的受试者比例为32％（10 / 31例）。

*综合临床结果包括肾脏事件，心脏事件，脑血管事件和死亡，每个事件的定义如下。

肾脏事件：

（1）eGFRCKD-EPI下降15 mL/min/1.73m2或更高，eGFRCKD-EPI低于90 mL / min / 1.73 m 2，或

（2）24小时尿蛋白比基线增加33％或更多，24小时尿蛋白定义为300毫克或更多。

心脏事件：心肌梗塞，不稳定性心绞痛，新的症状性心律失常（需要服用抗心律失常药，DC除颤，起搏器或植入式除颤器），或纽约心脏病协会分类III或IV 它被定义为充血性心力衰竭。

脑血管事件：中风或短暂性脑缺血发作。

2.未经治疗的法布里病患者的III期海外试验

本研究是一项随机，双盲，安慰剂对照研究，旨在评估该药物的疗效和安全性。尚未进行酶替代疗法或6个月尚未执行了超过16至74岁的外国男人和女人法布里病患者67例（男性24例，43名妇女，EGFR≧30毫升/分钟/1.73平方米）定位，因此弥Galastat 123mg或安慰剂以6个月的间隔日口服给药。随后，在18个月的开放标签连续给药期间，每隔一天口服给予123mg Migalastat。 50例GLA基因突变在这种药物是反应性的（安慰剂组22，在药物组28名受试者），如下表所示有在每肾间质的毛细管GL-3夹杂物的变化是的。

（见表8）

eGFRCKD-EPI年变化的受试者中这种药物施用18-24个月是-0.30 [-1.65,1.04]毫升/分钟/1.73平方米（41例），左心室质量指数的变化量为-7.7[-15.4， -0.0]g/m2（27例）。

包装

7粒胶囊1片PTP

制造供应商

Amicus Therapeutics Co.Ltd。

完整资料附件：http://www.info.pmda.go.jp/go/pack/3999045M1028_1_01/

GALAFOLD®treatment regimen for nationally designated intractable disease · Fabry disease acquired domestic manufacture and market approval

Amikas Therapeutics Co., Ltd. (Headquarters: Otemachi, Chiyoda-ku, Tokyo) announced on March 23 that Falbury's oral therapeutic agent "Garaforud® capsule 123 mg (generic name: Migarastat hydrochloride) We announced that we acquired manufacturing and marketing authorization.

"Garaforud ® capsule 123 mg" is the first oral therapeutic agent for Fabry disease

Fabry disease (FD) is one of the diseases classified as "lysosomal disease (about 31 types)" that the country designates as intractable disease (specific disease) -

Mutation of the GLA (α-galactosidase A) gene present on the X chromosome causes the normal GLA protein to not be produced in vivo, and the glycolipid which GLA should originally decompose by intracellular lysosomes is not degraded It accumulates in the disease.

* Glycolipids such as globotriosylceramide (GL-3 or Gb 3) accumulate in the intracellular lysosome, which causes various symptoms such as renal disorder, cardiomyopathy, cerebrovascular disease, etc. It is an inborn error of metabolism . (▲ Ministry of Health, Labor and Welfare Policy Research Project for Refractory Diseases, etc. Lysosomal Disease Research Group / ▲ National Research and Development Center National Development and Medical Research Center)

Fabry disease is a sharp limb pain (extremity end pain) that occurs after infancy and school days, sweat-free (hypohidrosis or anhidrosis), red-purple rash in the buttocks and genitalia ), Symptoms such as frequent abdominal pain and diarrhea (ischemic enteritis).

Pains in the hands and feet, in particular, are caused by stress, high temperature and fatigue, and can not be exercised due to pain, or it can become a school refusal.

If you leave these symptoms neglected, you will be able to see the corneal turbidity (swirl shape) of the eye, renal symptoms (proteinuria in the early stage, renal failure), cardiovascular symptoms (heart , Arrhythmia, valvular disease, ischemic heart disease), cerebrovascular symptoms (cerebral infarction, cerebral hemorrhage, headache) appear and symptoms become severe with age.

In addition, hearing loss, tinnitus, lower limb lymphedema and psychiatric symptoms will be recognized.

Fabry disease is an X chromosome recessive inherited form, most of the patients are male, but in women who are heterozygotes, females may also develop due to inactivation bias of the X chromosome.

It is said that the incidence of Fabry disease is one in 40,000 to 11.7 million people, but the actual number of patients is thought to be more than the conventional estimate, and the estimated number of domestic patients is 315 It is reported that ~ 760 people.

Diagnosis of Fabry disease (lysosomal disease) is done based on clinical symptoms, clinical examination, but definite diagnosis is "α-galactosidase A (α-galactosidase A; α-Gal A in leukocytes or cultured fibroblasts ) And the presence or absence of gene mutation of α-galactosidase by genetic analysis "and examined.

"GALAFOLD ® capsule 123 mg" is an analogue of terminal galactose of sphingoglycolipid (GSL = glycosphingolipid) which is a substrate of α-galactosidase (α-GAL-A = a type of hydrolase).

By binding to mutant α-GAL-A, a pharmacological chaperone (which functions as a correct functioning protein (ie, a protein that functions properly), which acts to activate the function of the original enzyme by normalizing the glycolipid transport in the target cell = Chaperone).

GALAFOLD ® product overview

Product name: Galafold ® (Galafold) capsule 123 mg

Common name: Migarastat hydrochloride (migalastat)

Indication/effect: Fabry disease accompanied by GLA gene mutation reactive to Migaratstat

Dosage/Dosage: Usually, oral administration of 123 mg once a day as a Migalastat to patients over the age of 16 years. In addition, it should be avoided 2 hours before and after meals.

Approval acquisition date: March 23, Heisei 30

Approval condition: RMP, all cases immediately after marketing survey

"Fabrazyme intravenous drip infusion" and "Repregall intravenous drip infusion" are on sale in Japan as a treatment for Fabry disease, but "Garaforud ® capsule 123 mg" is the first therapeutic agent by oral administration Yes, it is a subject of Fabry disease who has a different mechanism of action from that of existing enzyme replacement therapy (ERT) formulation and is accompanied by genetic mutation reactive with this drug, and is one of the new treatment options for such patients.