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In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f).

ABSTRACT: Recombinant human follicle-stimulating hormone (r-hFSH) is widely used in fertility treatment. Although biosimilar versions of r-hFSH (follitropin alfa) are currently on the market, given their structural complexity and manufacturing process, it is important to thoroughly evaluate them in comparison with the reference product. This evaluation should focus on how they differ (e.g., active component molecular characteristics, impurities and potency), as this could be associated with clinical outcome. This study compared the site-specific glycosylation profile and batch-to-batch variability of the in-vivo bioactivity of Bemfola, a biosimilar follitropin alfa, with its reference medicinal product GONAL-f. The focus of this analysis was the site-specific glycosylation at asparagine (Asn) 52 of the ?-subunit of FSH, owing to the pivotal role of Asn52 glycosylation in FSH receptor (FSHR) activation/signalling. Overall, Bemfola had bulkier glycan structures and greater sialylation than GONAL-f. The nominal specific activity for both Bemfola and GONAL-f is 13,636 IU/mg. Taking into account both the determined potency and the nominal amount the average specific activity of Bemfola was 14,522 IU/mg (105.6% of the nominal value), which was greater than the average specific activity observed for GONAL-f (13,159 IU/mg; 97.3% of the nominal value; p = 0.0048), although this was within the range stated in the product label. A higher batch-to-batch variability was also observed for Bemfola versus GONAL-f (coefficient of variation: 8.3% vs 5.8%). A different glycan profile was observed at Asn52 in Bemfola compared with GONAL-f (a lower proportion of bi-antennary structures [~53% vs ~77%], and a higher proportion of tri-antennary [~41% vs ~23%] and tetra-antennary structures [~5% vs <1%]). These differences in the Asn52 glycan profile might potentially lead to differences in FSHR activation. This, together with the greater bioactivity and higher batch-to-batch variability of Bemfola, could partly explain the reported differences in clinical outcomes. The clinical relevance of the differences observed between GONAL-f and Bemfola should be further investigated.

SUBMITTER: Mastrangeli R

PROVIDER: S-EPMC5589168 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f).

Mastrangeli Renato R Satwekar Abhijeet A Cutillo Francesca F Ciampolillo Cinzia C Palinsky Wolf W Longobardi Salvatore S

PloS one 20170907 9

Recombinant human follicle-stimulating hormone (r-hFSH) is widely used in fertility treatment. Although biosimilar versions of r-hFSH (follitropin alfa) are currently on the market, given their structural complexity and manufacturing process, it is important to thoroughly evaluate them in comparison with the reference product. This evaluation should focus on how they differ (e.g., active component molecular characteristics, impurities and potency), as this could be associated with clinical outco ...[more]

PMID: 28880909

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Project description:BackgroundLive birth has increasingly been identified as the standard clinical approach to measure the success of medically assisted reproduction (MAR). However, previous analyses comparing biosimilar preparations of follitropin alfa versus the reference product (GONAL-f®, Merck KGaA, Darmstadt, Germany or GONAL-f® RFF; EMD Serono, Inc., Rockland, MA), have had insufficient power to detect differences in clinically meaningful outcomes such as live birth.MethodsMedline, Embase, the Cochrane Library, Web of Science and clinical trial registries were searched for randomised controlled trials (RCTs) and conference abstracts comparing biosimilar follitropin alfa versus the reference product in controlled ovarian stimulation (COS) cycles published before 31 October 2020. Only studies in humans and publications in English were included. Retrieved studies were screened independently by two authors based on titles and abstracts, and then by full text.Inclusion criteriaRCTs comparing follitropin alfa biosimilar preparations with the reference product in infertile patients of any age, with any type of infertility for any duration, undergoing COS for the purposes of MAR treatment (including frozen cycles). The primary outcome was live birth. Combined data for biosimilar preparations were analysed using a fixed-effects model.ResultsFrom 292 unique records identified, 17 studies were included in the systematic review, representing five unique RCTs that were included in the meta-analysis. Rates of live birth (RR = 0.83, 95% CI 0.71, 0.97; 4 RCTs, n = 1881, I2 = 0%), clinical pregnancy (RR = 0.82, 95% CI 0.72, 0.94; 4 RCTs, n = 2222, I2 = 0%) and ongoing pregnancy (RR = 0.81, 95% CI 0.68, 0.96; 4 RCTs, n = 1232, I2 = 0%) were significantly lower with biosimilar preparations versus the reference product. Rates of cumulative live birth and cumulative clinical pregnancy were also significantly lower with biosimilars versus the reference product. There was high risk of publication bias.ConclusionsThis meta-analysis included data from RCTs evaluating the efficacy and safety of the biosimilar follitropin alfa preparations and demonstrated lower probability of live birth and pregnancy (ongoing and clinical) in couples treated with biosimilar preparations compared with the reference product. This study provides more insight into the differences between biosimilar r-hFSH preparations and the reference product than previously reported.Trial registrationRegistration number: CRD42019121992 .

Dataset Information

In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f).

Publications

In-vivo biological activity and glycosylation analysis of a biosimilar recombinant human follicle-stimulating hormone product (Bemfola) compared with its reference medicinal product (GONAL-f).

Similar Datasets

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