生物仿制药afliberept SDZ-AFL的研制

IF 1.5 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Current Therapeutic Research-clinical and Experimental Pub Date : 2025-01-01 DOI:10.1016/j.curtheres.2025.100812

Francis Dodeller PhD , Peter Alliger PhD , Jens Heyn MD , Dragan Urosevic MD , Lisa Allmannsberger PhD , Cornelia Wersig PhD , Rufino Silva MD, PhD

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引用次数: 0

摘要

目的：aflibercept是一种重组融合蛋白，与血管内皮生长因子a （VEGF-A）和其他生长因子具有高亲和力，可减少病理性新生血管和异常血管通透性。afliberept被批准作为几种视网膜疾病的一线治疗药物，包括新生血管性年龄相关性黄斑变性（nAMD）；然而，这些生物制剂的高成本可能阻碍患者获得。2024年，山德士生物仿制药aflibercept （SDZ-AFL; SOK583A1, Enzeevu/Afqlir）被美国食品和药物管理局和欧洲药品管理局批准为参比生物仿制药aflibercept （Ref-AFL; Eylea，拜耳公司和美国Regeneron制药公司的商标）。方法本综述总结了SDZ-AFL和Ref-AFL生物相似性的所有证据，包括体外分析研究的理化和生物学特性数据、家兔眼药代动力学（PK）研究结果、临床疗效、安全性、免疫原性和III期临床研究的全身PK数据。结果分析评价表明，SDZ-AFL与Ref-AFL具有结构同源性，包括相同的氨基酸序列、难以区分的高阶结构和高度相似的结构变异水平。SDZ-AFL和Ref-AFL也表现出高度相似的体外生物活性，包括靶标结合亲和力和VEGF-A的中和效力。在兔单剂量眼PK研究中，SDZ-AFL和Ref-AFL在玻璃体内给药后的玻璃体暴露具有可比性。一项为期52周的III期临床研究（Mylight）在484名nAMD患者中评估了SDZ-AFL和reff - afl的有效性、安全性、免疫原性和全身PK。主要终点是最佳矫正视力（BCVA）从基线到第8周的平均变化：SDZ-AFL组和Ref-AFL组在该终点的差异为-0.3个字母（90% CI为- 1.5至1.0），符合预定的生物等效性界限。在整个52周的研究中，SDZ-AFL和Ref-AFL的次要疗效终点，包括BCVA和中央亚野中央凹厚度从基线的变化，也相似。随后的两项“使用中”研究证实了SDZ-AFL在小瓶试剂盒或预填充注射器中的安全使用。结论综合证据表明，SDZ-AFL与Ref-AFL在理化和生物学特性上具有相似性，在临床疗效、安全性、免疫原性等方面具有相似性。预计afliberept生物类似药的上市将减少准入障碍，可能会增加从这种生物疗法中受益的视网膜疾病患者的数量。

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Development of Biosimilar Aflibercept SDZ-AFL

Purpose

Aflibercept is a recombinant fusion protein that binds with high affinity to vascular endothelial growth factor A (VEGF-A), and other growth factors, reducing pathological neovascularization and abnormal vascular permeability. Aflibercept is approved as a first-line treatment for several retinal diseases, including neovascular age-related macular degeneration (nAMD); however, the high costs of these biologic agents can impede patient access. In 2024, Sandoz biosimilar aflibercept (SDZ-AFL; SOK583A1, Enzeevu/Afqlir) was approved by the US Food and Drug Administration and the European Medicines Agency as a biosimilar of reference aflibercept (Ref-AFL; Eylea, a trademark of Bayer AG and in the US of Regeneron Pharmaceuticals, Inc) based on a comprehensive package of data.

Methods

This narrative review summarizes the totality of evidence demonstrating biosimilarity between SDZ-AFL and Ref-AFL, including physicochemical and biological characterization data from analytical in vitro studies, results of an ocular pharmacokinetic (PK) study in rabbits, and clinical efficacy, safety, immunogenicity, and systemic PK data from Phase III clinical studies.

Results

Analytical evaluation demonstrated that SDZ-AFL has structural homology with Ref-AFL, including identical amino acid sequences, indistinguishable higher-order structures, and highly similar levels of structural variants. SDZ-AFL and Ref-AFL also demonstrated highly similar in vitro biologic activities, including target binding affinity, and potency in terms of neutralization of VEGF-A. In a single-dose ocular PK study in rabbits, vitreal exposure was comparable between SDZ-AFL and Ref-AFL after intravitreal administration. A 52-week Phase III clinical study (Mylight) evaluated the efficacy, safety, immunogenicity, and systemic PK of SDZ-AFL and Ref-AFL in 484 participants with nAMD. The primary endpoint was mean change from baseline to week 8 in best corrected visual acuity (BCVA): the difference between the SDZ-AFL and Ref-AFL groups in this endpoint was –0.3 letters (90% CI −1.5 to 1.0), which met predefined bioequivalence margins. Secondary efficacy endpoints, including changes from baseline in BCVA and central subfield foveal thickness over the whole 52-week study, were also similar for SDZ-AFL and Ref-AFL. Two subsequent “in-use” studies confirmed the safe use of SDZ-AFL provided in either a vial kit or a prefilled syringe.

Conclusion

This comprehensive totality of evidence has established biosimilarity between SDZ-AFL and Ref-AFL based on comparable physicochemical and biological characteristics, as well as similarity in clinical efficacy, safety, and immunogenicity. The introduction of aflibercept biosimilars to the market is anticipated to reduce barriers to access, potentially increasing the number of appropriate patients with retinal diseases benefiting from this biologic therapy.

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来源期刊

Current Therapeutic Research-clinical and Experimental 医学-药学

CiteScore

3.50

自引率

0.00%

发文量

审稿时长

3 months

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