监管新闻:西帕糖苷酶α-atga(Pombiliti)与米格鲁司他(Opfolda)联合用于晚发型庞贝氏症成人患者。

IF 4.2 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Daniela V. Luquetti, Linda J. B. Jeng, Kathleen M. Donohue, Janet W. Maynard, the Review Team
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The two forms of PD present differently: infantile-onset PD (IOPD) is a rapidly progressive disease associated with severe left ventricular hypertrophy and high mortality within the first year of life, whereas late-onset PD (LOPD) is a slower progressive disease associated with motor impairment and respiratory muscle weakness; respiratory failure is the most common cause of death.<span><sup>1</sup></span> Currently, the approved therapies for PD are recombinant human acid alpha-glucosidases, alglucosidase alfa and avalglucosidase alfa-ngpt. Although alglucosidase alfa results in stabilization or improvement of symptoms for many patients, some patients continue to decline during treatment. 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引用次数: 0

摘要

庞贝病(PD)又称糖原贮积病 II 型、酸性麦芽糖酶缺乏症和糖原病 II 型,是一种罕见的严重溶酶体疾病,由酸性α-葡萄糖苷酶(GAA)基因的常染色体隐性变异引起。GAA 酶缺乏会导致糖原在不同组织的溶酶体内堆积。两种类型的帕金森病表现不同:婴儿型帕金森病(IOPD)进展迅速,伴有严重的左心室肥大,出生后第一年内死亡率高;而晚发型帕金森病(LOPD)进展较慢,伴有运动障碍和呼吸肌无力;呼吸衰竭是最常见的死亡原因。尽管阿糖苷酶α能使许多患者的症状得到稳定或改善,但有些患者的症状在治疗过程中仍在继续减轻。2-4 因此,治疗和治愈帕金森病仍然是尚未满足的需求。Cipaglucosidase alfa-atga 与内源性 GAA 酶的氨基酸序列相同,但含有复合型 N-聚糖结构,在同一聚糖上有两个甘露糖-6-磷酸(M6P)分子,可与细胞表面的 M6P 受体结合。米格鲁司他与cipaglucosidase alfa-atga合用,是一种N-烷基化亚氨基糖(D-葡萄糖的合成类似物),也是Zavesca的活性成分。米格司他能与西帕糖苷酶α-atga结合,稳定并减少输注后血液中西帕糖苷酶α-atga的失活。在本文中,我们提供了FDA对西帕糖苷酶α-atga的生物制品许可申请(BLA)和米格司他的新药申请(NDA)的审查摘要,这两种药物被批准联合用于治疗在目前的酶替代疗法(ERT)下病情未见好转的LOPD成年患者。通过一项具有确证证据(CE)的充分且良好对照的试验数据,我们确立了西帕糖苷酶α-atga与米格司他联合用药治疗LOPD受试者的实质性有效性证据。一项针对 18 岁及以上 LOPD 受试者的单项试验显示,与使用一种未获美国批准的阿糖苷酶 alfa 产品与安慰剂联合用药治疗相比,该药在运动功能和肺功能方面的数值改善具有临床意义。这种疾病的病因已得到充分证实,疗法的作用机制以及 Gaa 基因敲除小鼠的数据显示组织中糖原减少、肌肉功能改善,这些都为 CE 提供了强有力的机理支持。虽然这些数据足以证明对目前 ERT 治疗效果不佳的有治疗经验的受试者具有实质性疗效,但鉴于缺乏统计学意义的优越性以及两种产品比一种产品固有的风险增加,这些数据不足以支持将其用作一线疗法。根据对151名LOPD受试者的评估,西帕糖苷酶α-atga与米格鲁司他联合用药的安全性似乎与目前可用的疗法相似:阿糖苷酶α、阿瓦糖苷酶α和米格鲁司他。总之,美国食品药品管理局认为,西帕糖苷酶α-atga与米格鲁司他联合用药对肺功能(LOPD患者药物治疗的一个重要目标)的益处大于其风险,如果按照商定的标签使用的话。西帕糖苷酶α-阿特加与米格鲁司他联合用药的上市,为体重≥40公斤、目前的ERT治疗效果不佳的LOPD成年患者提供了二线ERT治疗。凯瑟琳-多诺霍(Kathleen M. Donohue)和珍妮特-梅纳德(Janet W. Maynard)指导了手稿的策划和撰写。Daniela V. Luquetti、Linda J. B. Jeng、Kathleen M. Donohue和Janet W. Maynard声明他们有利益冲突。本文不包含任何作者进行的以人类或动物为对象的研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Regulatory news: Cipaglucosidase alfa-atga (Pombiliti) coadministered with Miglustat (Opfolda) for adults with late-onset Pompe disease

Pompe disease (PD), also known as glycogen storage disease type II, acid maltase deficiency, and glycogenosis type II, is a rare and serious lysosomal disease caused by autosomal recessive variants in the acid alpha-glucosidase (GAA) gene. The resulting enzyme deficiency of GAA results in intra-lysosomal accumulation of glycogen in various tissues. The two forms of PD present differently: infantile-onset PD (IOPD) is a rapidly progressive disease associated with severe left ventricular hypertrophy and high mortality within the first year of life, whereas late-onset PD (LOPD) is a slower progressive disease associated with motor impairment and respiratory muscle weakness; respiratory failure is the most common cause of death.1 Currently, the approved therapies for PD are recombinant human acid alpha-glucosidases, alglucosidase alfa and avalglucosidase alfa-ngpt. Although alglucosidase alfa results in stabilization or improvement of symptoms for many patients, some patients continue to decline during treatment. For other patients, the improvement in muscle weakness is not sustained, and thus, patients tend to develop progressive disease, which can lead to respiratory failure.2-4 Therefore, treatment and cure of PD continue to represent unmet needs.

Cipaglucosidase alfa-atga provides an exogenous source of GAA. Cipaglucosidase alfa-atga has the same amino acid sequence as the endogenous GAA enzyme but contains complex-type N-glycan structures with two mannose-6-phosphate (M6P) moieties on the same glycan which mediates binding to M6P receptors on the cell surface. Miglustat, which is coadministered with cipaglucosidase alfa-atga, is an N-alkylated iminosugar (a synthetic analog of D-glucose) and is the active ingredient in Zavesca, which is approved for the treatment of adult patients with mild/moderate Type 1 Gaucher disease for whom ERT is not a therapeutic option. Miglustat binds with, stabilizes, and reduces the inactivation of cipaglucosidase alfa-atga in the blood after infusion. The bound miglustat is dissociated from cipaglucosidase alfa-atga after it is internalized and transported into lysosomes.

In this article, we provide the summary of FDA's review of the biologics license application (BLA) for cipaglucosidase alfa-atga and the new drug application (NDA) for miglustat, which were approved to be coadministered for the treatment of adult patients with LOPD who are not improving on their current enzyme replacement therapy (ERT).

Substantial evidence of effectiveness for cipaglucosidase alfa-atga coadministered with miglustat in subjects with LOPD was established using data from one adequate and well-controlled trial with confirmatory evidence (CE). A single trial in subjects 18 years of age and older with LOPD showed a clinically meaningful numerical improvement in motor and lung function compared with treatment with a non-US-approved alglucosidase alfa product coadministered with placebo. The well-established etiology of the disease, the mechanism of action of the therapy, and data from Gaa knockout mice showing reduced glycogen in tissues and improved muscle function provided strong mechanistic support for CE. While these data are adequate to establish substantial evidence of effectiveness for treatment-experienced subjects who are not improving on their current ERT, the data were not adequate to support use as first-line therapy given the lack of statistical significance for superiority and the inherent increased risk of two products over one.

The observed safety profile of cipaglucosidase alfa-atga coadministered with miglustat as assessed in 151 subjects with LOPD appears to be similar to that of the currently available therapies: alglucosidase alfa, avalglucosidase alfa, and miglustat. The most important safety concerns are known risks with ERTs: hypersensitivity reactions (including anaphylaxis) and infusion-associated reactions.

In summary, the FDA concluded that the benefits of cipaglucosidase alfa-atga coadministered with miglustat on lung function, an important target for drug treatment for patients with LOPD, outweigh its risks when used according to the agreed-upon labeling. The availability of cipaglucosidase alfa-atga coadministered with miglustat provides a second-line ERT for adult patients with LOPD weighing ≥40 kg who are not improving on their current ERT.

Daniela V. Luquetti and Linda J. B. Jeng contributed to the planning and writing of the manuscript. Kathleen M. Donohue and Janet W. Maynard supervised the planning and writing of the manuscript. All authors contributed to the final version of the manuscript.

The authors declare no funding.

Daniela V. Luquetti, Linda J. B. Jeng, Kathleen M. Donohue, and Janet W. Maynard declare that they have conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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来源期刊
Journal of Inherited Metabolic Disease
Journal of Inherited Metabolic Disease 医学-内分泌学与代谢
CiteScore
9.50
自引率
7.10%
发文量
117
审稿时长
4-8 weeks
期刊介绍: The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).
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