The introduction of anti-VEGF therapy has radically improved the visual and anatomical outcomes of patients with neovascular age-related macular degeneration (AMD).1-3 These anti-VEGF therapies are considered biologics, which are therapeutic agents containing proteins derived from living organisms. Examples of biologics include macromolecules such as proteins, peptides, aptamers, SiRNA, and antibodies.4 A large fraction of currently available medications already fall under this category, and it is estimated that within 10 years, about half of drugs in production will be biologics.5
The first anti-VEGF medication to enter the ophthalmology arena for neovascular AMD was pegaptanib sodium (Macugen; Eyetech Pharamceuticals).6 Subsequently, 3 other anti-VEGF medications emerged and are currently most commonly used agents for the treatment of neovascular AMD. They include the off-label bevacizumab (Avastin; Genentech), and the on-label ranibizumab (Lucentis; Genentech) and aflibercept (Eylea; Regeneron).7 Most recently, brolucizumab (Beovu; Novartis) was approved by FDA.8 Avastin is a humanized, recombinant full-sized monoclonal antibody against VEGF-A. Lucentis is a humanized antibody fragment that also acts against VEGF-A. Eylea is a recombinant fusion protein of the human VEGF receptor 1 and 2 combined to human IgG1, which enables it to act against VEGF-A, -B, and placental growth factor (PlGF). Brolucizumab is a single chain antibody fragment, which also targets VEGF-A.8
While these treatment methods have provided significant stabilization, and in some cases, improvement, in the visual acuity of patients with neovascular AMD, the financial and frequent visit burden often plays a factor in patient compliance. This is a concern, because various studies have linked undertreatment to a decline in visual acuity.9 In a review of clinical trials published between 2013 to 2018 using bevacizumab, ranibizumab, or aflibercept, initial visual acuity improvements were maintained throughout follow-up so long as the patients were maintained on treatment.9 The most commonly followed trial protocol required monthly injections of bevacizumab and ranibizumab and every-2-month dosing of aflibercept after initial loading doses. The authors reported that visual acuity did correlate with the frequency of injections, and that as-needed treatment was more often correlated with visual decline.9
To combat the sometimes significant financial burden associated with current anti-VEGF therapies, biosimilar medications have arisen as a potential alternative. While it remains to be seen what the price point will be of these medications, reports estimate that biosimilars may bring up to a 30% reduction in costs.7
In addition to alleviating financial burden, biosimilars might also become a treatment option as the patents for ranibizumab and aflibercept expire in the future.7 This allows for the entrance of alternative therapies into the marketplace. In general, treatment alternatives to any existing biologics include generic medications as well as biosimilars. Biosimilars are not generic medications; it is important to note that biosimilar medications do not copy the molecular structure of existing biological medications, but instead aim to mimic their therapeutic endpoint. These medications are complex end products from cell lines, requiring extensive modification to produce a different molecule entirely from their reference biologic, but with a similar efficacy and safety profile.10 Because manufacturers do not reveal the exact production process of original biologic medications, the generation of these biosimilar agents requires reverse engineering and information already present in the market. Moreover, given the process by which biosimilars are produced, immunological reactions are of concern, as is lack of stability compared to generic medications.7 Additionally, because biosimilars are cultivated from living cell lines, there can be a small amount of variation in their end product.7 Overall, the goal of producing a biosimilar results in a different end molecule that shares similar pharmacokinetics, safety, and efficacy to the original medication.7,10,11 While the exact regulations of biosimilars vary based on location, in the United States, the Food and Drug Administration (FDA) approves a biosimilar medication if it shows no meaningful difference clinically from the already approved biologic.12
On the other hand, generic medications have the same structure to the already established original molecule and have a shorter review process in general.10 The FDA allows for the expedited review and approval of generics through an abbreviated new drug application (ANDA). Because the generic medication uses the same active ingredient that is already present in the original biologic, manufacturers do not have to prove safety. Instead, they are only required to prove the same pharmacologic efficacy and bioavailability as the reference medication.13
While they are difficult to produce, biosimilars offer an advantage, because they are cheaper to manufacture than biologics and have a shorter development period.7,10,14 Given the different production process and end molecule, there is also a theoretical increased efficacy of the biosimilar product compared to the original medication.7 Additionally, there is less of a burden on the manufacturers of biosimilars to enroll in clinical trials. Instead, they are required to prove similar pharmacokinetics and efficacy through fewer trials.7 Once proven effective, a biosimilar can be approved for all the indications that its original biological medication has. Various biosimilars are under development throughout the world for the treatment of neovascular AMD, and their release and availability rely largely on the regulation and approval of their respective drug administrations.
Only one biosimilar medication, Razumab (Intas Pharmaceuticals), a humanized, monoclonal IgG antibody fragment, has been approved as a biosimilar alternative to ranibizumab.7 The medication was approved in 2015 after a retrospective multicenter clinical trial demonstrated efficacy in 103 patients with neovascular AMD.7 The study endpoints included change in best-corrected visual acuity (BCVA) from baseline to monthly time points until 6 months, or 24 weeks, as well as weeks 30, 36, and 48.15 Moreover, central subfield thickness (CST) and intraocular pressure were measured. There was a significant improvement in BCVA from baseline to all time points measured, and a significant reduction in CST. There was not a significant change in intraocular pressure between visits. Additionally, the RE-ENACT study, which was a retrospective, multicenter analysis of 561 Indian patients with AMD, retinal vein occlusions and diabetic macular edema showed favorable visual acuity gains and central thickness reduction on OCTs.16,17 Currently, the mediation is available in the Indian market.7
The biosimilar FYB 201 (Formycon and Bioeq) is on the horizon, with a planned launch in 2021 in the United States and in 2022 in the European Union.7 A phase 3 randomized controlled trial, COLUMBUS-AMD (NCT02611778), met its primary endpoint of visual acuity change after 8 weeks of treatment in patients with neovascular AMD.18 Samsung Bioepis recently completed a phase 3 randomized controlled clinical trial to compare the efficacy and safety of the biosimilar SB11 to ranibizumab (NCT03150589). The primary endpoint of this study was change in BCVA from baseline to week 8 and reduction in CST on OCT between baseline and week 4; the results are still pending. Xlucane (Xbrane Biopharma) is a biosimilar that is being studied in a phase 3 randomized clinical trial (XPLORE; NCT03805100) to confirm efficacy, safety, and immunogenicity compared to ranibizumab. The primary endpoint will be visual acuity at the 8-week point, with follow-up for 12 months. The study plans to enroll 600 patients in 16 countries. Pfenex has completed a phase 1/2 randomized clinical trial of PF582, which enrolled 25 patients with neovascular AMD, with patients receiving 3 monthly injections. There was no difference in intraocular or systemic safety in patients receiving the biosimilar vs ranibizumab. There was also no significant difference in visual acuity between the 2 medications.19 CHS3551 (Coherus Biosciences) also has a biosimilar currently in the preclinical stages.20
Currently, there are no medications approved and released as an aflibercept biosimilar.7 The development of FYB203 (Formycon and Bioeq) is currently under way, and the product is expected to be available in the United States in 2023.21 A phase 1 randomized clinical trial of ALT-L9 (Alteogen) will be conducted in 5 hospitals in Korea.22 A phase 3 randomized clinical trial is currently enrolling to study MYL1710 (Momenta Pharmaceuticals and Mylan; NCT03610646). Preclinical development is under way for CHS-2020 (Coherus Biosciences).20
The compounding process required for use of bevacizumab may limit its use particularly in countries outside of the United States, thus allowing for the biosimilar bevacizumab market to grow.7 However, given that bevacizumab is already a cost-effective, generally trusted off-label treatment option in the United States, it may be difficult to convince clinicians to opt for a biosimilar instead. Currently, in the oncology realm, the biosimilar Mvasi (bevacizumab-awwb, Amgen and Allergan), is approved by the FDA for oncologic indications, as is Zirabev (bevacizumab-bvzr; Pfizer). A phase 3 randomized clinical trial is under way studying ONS-510 (Outlook Therapeutics), to evaluate the biosimilar against bevacizumab (NCT03834753).
Biosimilars might come to play a bigger role in treatment of retinal diseases and in particular neovascular AMD. It is important for retina specialists to be educated on what differentiates biologics, biosimilars, and generic medications. The clinical trials conducted around the world will provide new information about safety and efficacy of these new agents. RP
- Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
- Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
- Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.
- Joseph M, Trinh HM, Cholkar K, Pal D, Mitra AK. Recent perspectives on the delivery of biologics to back of the eye. Expert Opin Drug Deliv. 2017;14(5):631-645.
- Sharma A, Kumar N, Bandello F, Loewenstein A, Kuppermann BD. Need of education on biosimilars amongst ophthalmologists: combating the nocebo effect. Eye (Lond). November 29, 2019. [Epub ahead of print]
- Gragoudas ES, Adamis AP, Cunningham ET Jr., Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805-2816.
- Sharma A, Reddy P, Kuppermann BD, Bandello F, Lowenstein A. Biosimilars in ophthalmology: “is there a big change on the horizon?” Clin Ophthalmol. 2018;12:2137-2143.
- Khanna S, Komati R, Eichenbaum DA, Hariprasad I, Ciulla TA, Hariprasad SM. Current and upcoming anti-VEGF therapies and dosing strategies for the treatment of neovascular AMD: a comparative review. BMJ Open Ophthalmol. 2019;4(1):e000398.
- Mones J, Singh RP, Bandello F, Souied E, Liu X, Gale R. Undertreatment of neovascular age-related macular degeneration after 10 years of anti-vascular endothelial growth factor therapy in the real world: the need for a change of mindset. Ophthalmologica. 2020;243(1):1-8.
- Sharma A, Kumar N, Kuppermann BD, Bandello F, Loewenstein A. Understanding biosimilars and its regulatory aspects across the globe: an ophthalmology perspective. Br J Ophthalmol. 2020;104(1):2-7.
- Casadevall N, Edwards IR, Felix T, et al. Pharmacovigilance and biosimilars: considerations, needs and challenges. Expert Opin Biol Ther. 2013;13(7):1039-1047.
- FDA. Biosimilar product regulatory review and approval. Available at: https://www.fda.gov/files/drugs/published/Biosimilar-Product-Regulatory-Review-and-Approval.pdf . Accessed February 14, 2020.
- Hornecker JR. Generic drugs: history, approval process, and current challenges. Available at: https://www.uspharmacist.com/article/generic-drugs-history-approval-process-and-current-challenges . Accessed February 14, 2020.
- DiMasi JA, Grabowski HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. J Health Econ. 2016;47:20-33.
- Sharma S, Khan M, Chaturvedi A; RE-ENACT 2 Study Investigators Group. A multicenter, retrospective study (RE-ENACT 2) on the use of razumab (world’s first biosimilar ranibizumab) in wet age-related macular degeneration. Ophthalmol Ther. 2020;9(1):103-114.
- Sharma S, Khan MA, Chaturvedi A, RE-ENACT Study Investigators Group. Real-life clinical effectiveness of razumab (world’s first biosimilar ranibizumab) in wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion: a retrospective pooled analysis. Int J Oph thalmol Eye Res. 2018;6(4):377-383.
- Sharma S, Khan MA, Chaturvedi A, RE-ENACT Study Investigators Group. Real-life clinical effectiveness of razumab (the world’s first biosimilar of ranibizumab) in retinal vein occlusion: a subgroup analysis of the pooled retrospective RE-ENACT study. 2019;241(1):24-31.
- Edison Investment Research Limited. FY18 results: FYB201 launch on track for 2021. Accessed February 14, 2020. Available at: https://www.edisongroup.com/publication/fy18-results-fyb201-launch-on-track-for-2021/24222
- Pfenex. Pfenex to regain full rights to PF582 and announces phase 1/2 results. Available at: https://www.prnewswire.com/news-releases/pfenex-to-regain-full-rights-to-pf582-and-announces-phase-12-results-300310159.html . Accessed February 14, 2020.
- Coherus Biosciences. Addressing important unmet needs. Available at: https://www.coherus.com/products-and-pipeline/ . Accessed February 14, 2020.
- Bioeq. FYB203. 2018. Accessed January 1, 2020. Available at: https://www.bioeq.com/development-programs/fyb203
- Biosimilar Development. Alteogen Inc. gets IND approval for a clinical study in Korea for Eylea biosimilar (ALT-L9). Available at: https://www.biosimilardevelopment.com/doc/alteogen-inc-gets-ind-approval-for-a-clinical-study-in-korea-for-eylea-biosimilar-alt-l-0001 . Accessed February 14, 2020.