Definition
Similarity to reference product: No clinically meaningful differences in safety, purity, and potency
Manufacturing specificity: Produced using living cells. Reproduction of an identical molecule is impossible
Biosimilars in Ophthalmology
Key Points at a Glance
Section titled “Key Points at a Glance”1. What is a biosimilar?
Section titled “1. What is a biosimilar?”A biosimilar is a biological product that is highly similar to an already approved biologic (reference product) and has no clinically meaningful differences in safety, purity, and potency 7).
There are essential differences from generic drugs manufactured by chemical synthesis. Biosimilars are produced using living cells (E. coli, yeast, Chinese hamster ovary cells, etc.), so they have large molecular weights and complex structures. It is impossible to reproduce a molecule completely identical to the reference product, and they are positioned as highly similar products. While the development of a reference product requires 10-15 years and 1.2-2.5 billion dollars, the development period for a biosimilar is about 8-10 years and the cost is about one-tenth.
The most important biosimilars in ophthalmology are anti-VEGF (vascular endothelial growth factor) biosimilars used for age-related macular degeneration (nAMD), diabetic macular edema, retinal vein occlusion, etc.
Differences from generics
Molecular complexity: Unlike small-molecule drugs, large and complex protein molecules
Production method: Requires living cells, not chemical synthesis
Development cost
Reference product: 10-15 years, 1.2-2.5 billion dollars
Biosimilar: 8-10 years, cost about one-tenth
Extrapolation of indications
Principle of extrapolation: Indications for which clinical trials have not been conducted may be approved for the same indications as the reference product.
Q
What is the difference between a biosimilar and a generic drug?
A
While generic drugs have the same chemical formula as the reference product, biosimilars are complex protein molecules produced in living cells that are highly similar but not identical to the reference product. Due to the complexity of the manufacturing process, development costs are higher, and the requirements for clinical trials needed for approval differ from those for generics.
2. Approval Process and Regulatory Framework
Section titled “2. Approval Process and Regulatory Framework”In the United States, the Biologics Price Competition and Innovation Act (BPCIA) was enacted in 2009, establishing approval standards for biosimilars. For the approval of ophthalmic biosimilars, while the reference product typically requires two comparative clinical trials, a single adequate comparative clinical trial may suffice for a biosimilar 7).
Approval trials for ophthalmic biosimilars targeting nAMD require a follow-up period of at least 9 months to demonstrate equivalence in safety and efficacy with the reference product 8).
Interchangeable Product
Section titled “Interchangeable Product”An interchangeable product is a biosimilar that has been granted a special status allowing it to be substituted for the reference product at the pharmacy without the intervention of the prescribing physician. To obtain interchangeability designation, additional data are required to demonstrate that safety and efficacy are maintained even after multiple switches between the reference product and the biosimilar, and vice versa.
Q
What does "interchangeable product" mean?
A
It refers to a product that can be substituted for the reference product at the pharmacy at the pharmacist’s discretion without a change in prescription by the physician. Cimerli (ranibizumab-eqrn) has been designated as interchangeable for all five indications, and Byooviz has also obtained interchangeable status 7). The designation of interchangeable products plays an important role in promoting the use of biosimilars and reducing healthcare costs.
3. Approved Ophthalmic Biosimilars
Section titled “3. Approved Ophthalmic Biosimilars”Ranibizumab Biosimilars
Section titled “Ranibizumab Biosimilars”Biosimilars of ranibizumab (reference product: Lucentis) have been approved in several countries, including the United States and Japan.
The following are the main ranibizumab biosimilars.
| Product Name | Generic Name (INN suffix) | Year of Approval (US) |
|---|---|---|
| Byooviz | ranibizumab-nuna (SB11) | 2021 |
| Cimerli | ranibizumab-eqrn (FYB201) | 2022 |
| RBZ BS (Japan) | Ranibizumab BS | September 2021 |
Byooviz (ranibizumab-nuna, SB11): Approved by the FDA in 2021, it is the first ophthalmic biosimilar in the United States 7). In a phase 3 RCT involving 705 patients with nAMD, the difference in best-corrected visual acuity (BCVA) compared to the reference ranibizumab was only −0.8 letters, confirming equivalence at one year 2),4). Immunogenicity analysis showed that the incidence of anti-drug antibodies (ADA) was similar between SB11 and the reference product, with no impact on PK or safety 3). Byooviz subsequently obtained interchangeable status 7).
Cimerli (ranibizumab-eqrn, FYB201): Approved by the FDA in 2022 7). In the COLUMBUS-AMD study (477 patients), the mean improvement in best-corrected visual acuity was +7.8 letters in the FYB201 group and +8.0 letters in the reference group, confirming equivalence 5). It received interchangeable designation for all five approved indications of ranibizumab 7). The product was granted biosimilar approval based on phase 3 trial data 5).
Ranibizumab BS in Japan: Approved in September 2021 for myopic choroidal neovascularization (CNV) 1). A pre-approval RCT involving 351 patients confirmed equivalence with the reference product, with zero cases of iritis 1). A systematic review of multiple biosimilars also showed outcomes equivalent to the reference product 6).
Aflibercept Biosimilars
Section titled “Aflibercept Biosimilars”In 2024, five aflibercept (reference product: Eylea) biosimilars received FDA approval 8),9). All are 2 mg intravitreal injection formulations, and their adverse event profiles are consistent with the reference aflibercept 7).
The approved aflibercept biosimilars are listed below.
| Product Name | Generic Name (INN suffix) | Manufacturer |
|---|---|---|
| Yesafili | aflibercept-jbvf | Biogen/Samsung Bioepis |
| Opuviz | aflibercept-yszy | Regeneron/Mylan |
| Ahzantive | aflibercept-mrbb | Coherus BioSciences |
| Enzeevu | aflibercept-abzv | Amgen |
| Pavblu | aflibercept-ayyh | Pfizer |
4. Evidence of Efficacy and Safety
Section titled “4. Evidence of Efficacy and Safety”Efficacy
Section titled “Efficacy”Multiple large phase 3 RCTs have confirmed that the efficacy of ranibizumab biosimilars is equivalent to that of the reference product2),4),5).
In the phase 3 RCT by Woo et al. (2021) (nAMD, 705 patients), the change in best-corrected visual acuity at 52 weeks was equivalent between SB11 (Byooviz) and reference ranibizumab (difference: −0.8 letters), meeting the criteria for statistical equivalence2).
In the COLUMBUS-AMD trial by Holz et al. (2022) (nAMD, 477 patients), the mean visual acuity improvement was +7.8 letters in the FYB201 (Cimerli) group and +8.0 letters in the reference product group, confirming that it was within the pre-specified equivalence margin5).
On the other hand, long-term prospective data remain limited, and accumulation of evidence on long-term follow-up of 5 years or more is considered a future challenge7).
Safety and Immunogenicity
Section titled “Safety and Immunogenicity”Immunogenicity is a particularly important item in the safety evaluation of biosimilars.
Bressler et al. (2023) reported in a post hoc analysis of SB11 that the incidence of anti-drug antibodies (ADA) was comparable between SB11 and reference ranibizumab, and that the presence or absence of ADA did not significantly affect PK, visual acuity, or safety3).
It should be noted that if the composition of excipients (additives) differs from that of the reference product, it may affect the safety profile8).
Post-injection non-infectious intraocular inflammation: A rarely reported adverse event is non-infectious anterior chamber inflammation after biosimilar administration.
Tetsumoto et al. (2024) reported a case of a 74-year-old man who developed acute non-infectious anterior chamber inflammation after intravitreal injection of ranibizumab BS1). The patient received the injection 2 days after COVID-19 vaccination, and within 24 hours, anterior chamber cells 3+ and flare 2+ appeared. Symptoms were reduced by day 4 with betamethasone eye drops.
As a mechanism for sterile intraocular inflammation, it is hypothesized that foreign epitopes unique to biosimilars are recognized by antigen-presenting cells, leading to immune activation 1). It has also been suggested that immune activation after COVID-19 vaccination may have synergistically enhanced inflammation 1). Currently, it is recommended to allow at least 2 weeks between COVID-19 vaccination and anti-VEGF intravitreal injection 1).
Endophthalmitis (infectious 0.02–0.14%, sterile 0.005–4.4%) is a known adverse event even with original anti-VEGF drugs 1) and is not a risk unique to biosimilars.
Q
Is the efficacy of biosimilars the same as the original product?
A
Multiple phase 3 RCTs have confirmed that visual acuity improvement is statistically equivalent to the original product 2),4),5). However, long-term (over 5 years) prospective data are still limited 7), and continued data collection is important.
5. Cost and Health Economic Impact
Section titled “5. Cost and Health Economic Impact”Anti-VEGF drugs account for more than 10% of total Medicare Part B spending in the United States, with ranibizumab and aflibercept ranking among the top drugs.
The wholesale acquisition cost (WAC) of biosimilars is significantly lower than that of the original products.
| Product | Strength | WAC (per vial) |
|---|---|---|
| ranibizumab-nuna (Byooviz) | 0.5mg | $1,130 |
| ranibizumab-eqrn (Cimerli) | 0.3mg | $816 |
If all patients switch from the originator to ranibizumab biosimilar, Medicare is expected to save approximately $132 million per year, and patient out-of-pocket costs could be reduced by about $33.6 million annually.
The U.S. Inflation Reduction Act (IRA, 2022) increased the add-on payment (ASP add-on) for biosimilars from the previous 6% to 8%, providing an incentive to promote biosimilar prescribing.
Cost Reduction Effect
Medicare overall: Estimated annual savings of approximately $132 million
Patient out-of-pocket: Estimated annual reduction of approximately $33.6 million
Promotion of Price Competition
Lower WAC than originator: Byooviz $1,130, Cimerli $816 (0.5mg and 0.3mg equivalent)
Inflation Reduction Act: ASP add-on increased from 6% to 8%
Improved Access
Interchangeable products: Allows pharmacy-level substitution, improving patient access
Extrapolation of indications: Can be used for the same multiple diseases as the originator
Q
How much cost can be reduced by switching to biosimilars?
A
If all patients switch from the originator to ranibizumab biosimilar, Medicare is expected to save approximately $132 million per year, and patient out-of-pocket costs could be reduced by about $33.6 million annually. Including aflibercept biosimilar would lead to even greater savings.
6. Future Perspectives and Biosimilars Under Development
Section titled “6. Future Perspectives and Biosimilars Under Development”Biosimilars Under Development
Section titled “Biosimilars Under Development”Following ranibizumab and aflibercept, several anti-VEGF biosimilars are in development or under review. Representative candidates include CKD-701, XSB-001, Xlucane, LUBT010, and SB15 (aflibercept biosimilar).
For bevacizumab (Avastin) biosimilars, legal and regulatory issues are being discussed, and there are challenges to approval in the ophthalmology field.
Accumulation of Long-Term Data
Section titled “Accumulation of Long-Term Data”Accumulating long-term prospective safety and efficacy data is the most important issue 7). Since current phase 3 RCTs mainly have follow-up periods of 1–2 years, long-term follow-up data of 5 years or more are needed. Collection of real-world evidence (RWE) is also becoming increasingly important.
Future Challenges
Section titled “Future Challenges”- Expanding evidence on interchangeability (switching) between biosimilars
- Expansion of approved indications in each country, including Japan
- Enhancing education and information provision for patients and healthcare professionals
- Establishment of prescribing and dispensing systems (clarification of substitution rules for interchangeable products)
7. References
Section titled “7. References”- Tetsumoto R, et al. Acute noninfectious anterior ocular inflammation following ranibizumab biosimilar intravitreal injection. Cureus. 2024;16(5):e60356.
- Woo SJ, et al. Efficacy and safety of a proposed ranibizumab biosimilar product vs reference ranibizumab product for neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol. 2021;139:68-76.
- Bressler NM, et al. Immunogenicity with ranibizumab biosimilar SB11 (Byooviz) and reference product Lucentis. JAMA Ophthalmol. 2023;141:117-27.
- Bressler NM, et al. Biosimilar SB11 versus reference ranibizumab in neovascular age-related macular degeneration: 1-year phase III randomized controlled trial outcomes. Br J Ophthalmol. 2022;106:1379-85.
- Holz FG, et al. Efficacy and safety of biosimilar FYB201 compared with ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2022;129:54-63.
- Sharma A, et al. Approved biosimilar ranibizumab - a global update. Eye (Lond). 2023;37:200-2.
- American Academy of Ophthalmology. Retinal Vein Occlusions Preferred Practice Pattern. Ophthalmology. 2024.
- American Academy of Ophthalmology. Age-Related Macular Degeneration Preferred Practice Pattern. Ophthalmology. 2024.
- American Academy of Ophthalmology. Diabetic Retinopathy Preferred Practice Pattern. Ophthalmology. 2024.