SB15 Biosimilar Demonstrates High Similarity to Reference Product Aflibercept

The physicochemical and biological properties of SB15, a biosimilar product referencing aflibercept (Eylea), was highly similar to aflibercept reference products in the US and European Union (EU) in a study from Springer Link.¹ The findings support safe and effective use of SB15, according to the authors. 

Both the FDA and European Medicines Agency (EMA) approved aflibercept, aVEGF inhibitor, for a a range of ocular diseases such as neovascular age-related macular degeneration (nAMD), macular edema following retinal vein occlusion, diabetic macular edema, and diabetic retinopathy.

The FDA approved aflibercept in November 2011, along with Japan, Australia, Switzerland, and other countries.² However, the EMA did not approve aflibercept until the following year, in November 2012.

More recently, Samsung Bioepis developed SB15, a biosimilar to reference aflibercept.³ Earlier this year, a multi-region study proved comparable safety, efficacy, immunogenicity, and pharmacokinetics in SB15 vs reference aflibercept for first-line treatment after patients switched from aflibercept to SB15 in nAMD.⁴ Aflibercept is an anti-VEGF agent that harbors the binding domains of vascular endothelial growth factor (VEGF) receptors 1 and 2 while blocking all VEGF-A isoforms, VEGF-B, and placental growth factor.⁵ The biosimilar, SB15, is produced by a recombinant DNA technology and was developed to reference aflibercept.

An analytical panel was used to comprehensively characterize SB15 compared with the US/EU-sourced aflibercept.¹ Every sample included in the study was handled in a sterile manner in a biological safety cabinet. 

The analysis examined primary structure, higher-order structure, physicochemical properties, and functional activities. The molecular weights of SB15 and US/EU aflibercept were comparable for the deglycosylated and reduced samples.

The intact molecular weights of SB15 and US/EU aflibercept were also comparable based on single-chain molecular weight, disulfide linkage, and site-specific N-glycosylation analysis. The primary structure did not have any meaningful differences observed in biological activities.

Higher-order structural comparisons using circular dichroism and differential scanning calorimetry revealed high similarity between SB15 and the reference aflibercept products. Circular dichroism analyzes protein structure through polarized light,⁶ while differential scanning calorimetry assesses protein stability by measuring changes in heat flow.⁷

In terms of size and charge heterogeneity, there were no meaningful differences in the physicochemical properties between SB15 and its reference product.¹ The relative quantity of high molecular weight of SB15 (0.9%) were lower than US/EU aflibercept (2.4 and 2.5%, respectively). While there was a difference in charge heterogeneity, it was not associated with any changes in biological activities.

Biological activities such as mechanism of action–related binding activities, potencies, and fragment crystallizable–related biological functions were similar between SB15 and the reference product.

There were no significant differences between SB15, US aflibercept, and EU aflibercept in terms of VEGF-A 165 neutralization potencies, and all SB15 samples were within the US/EU similarity range. There were relative FcRn binding affinities for all SB15 tested samples, which were within the US/EU similarity range.

There were also no significant differences in VEGF family ligands binding activities between SB15 and US/EU aflibercept.

The authors concluded that their state-of-the-art analysis demonstrated highly similar results between SB15 and US/EU aflibercept. These results support the biosimilarity of SB15 with respect to US/EU aflibercept.

“The structural, physicochemical, and biological similarity between SB15 and US/EU aflibercept were evaluated,” the authors wrote. “Comprehensive analytical characterization of SB15 and US/EU aflibercept were implemented and the results demonstrated that SB15 and US/EU aflibercept were highly similar. The results of the analytical characterization provide the foundation for the totality of evidence to support the biosimilarity of SB15 with respect to US/EU aflibercept.”

References

1. Lee H, Huh J, Kim D, et al. Analytical characterization for similarity assessment between an aflibercept biosimilar SB15 and reference product (Eylea).Ophthalmol Ther. 2024;13(8):2209-2225. doi:10.1007/s40123-024-00977-0

2. Eylea (aflibercept) injection approved for the treatment of wet age-related macular degeneration in Europe. News release. Regeneron. November 27, 2021. Accessed August 5, 2024. https://investor.regeneron.com/news-releases/news-release-details/eylear-aflibercept-injection-approved-treatment-wet-age-0

3. Sadda SR, Bradvica M, Vajas A, et al. Biosimilar SB15 versus reference aflibercept in neovascular age-related macular degeneration: 1-year and switching results of a phase 3 clinical trial. BMJ Open Ophthalmol. 2023;8(1):e001561. doi:10.1136/bmjophth-2023-001561

4. Santoro C. SB15 effective, safe in treating nAMD, before, after switching. The Center for Biosimilars^®. February 1, 2024. Accessed August 5, 2024. https://www.centerforbiosimilars.com/view/sb15-effective-safe-in-treating-namd-before-after-switching

5. Woo SJ, Bradvica M, Vajas A, et al. Efficacy and safety of the aflibercept biosimilar SB15 in neovascular age-related macular degeneration: aphase 3 randomized clinical trial. JAMA Ophthalmol. 2023;141(7):668–676. doi:10.1001/jamaophthalmol.2023.2260

6. Hurlburt N. Circular dichroism. Chemistry LibreTexts. October 2, 2013. Accessed August 7, 2024. https://chem.libretexts.org/Bookshelves/Physical_and_Theoretical_Chemistry_Textbook_Maps/Supplemental_Modules_(Physical_and_Theoretical_Chemistry)/Spectroscopy/Electronic_Spectroscopy/Circular_Dichroism

7. Differential scanning calorimeters. TA Instruments. Accessed August 7, 2024. https://www.tainstruments.com/products/thermal-analysis/differential-scanning-calorimeters/