A Phase III Randomized Trial Comparing Efficacy, Safety, and Immunogenicity of ZRC-3285 vs. Eylea^® in Patients with Wet Age-Related Macular Degeneration

Abstract

Introduction

This study aims to evaluate the efficacy, safety, and immunogenicity of ZRC-3285 (aflibercept biosimilar) with Eylea^® (aflibercept) in patients with neovascular (wet) age-related macular degeneration (nAMD).

Methods

This phase III, multicenter, double-blind study was conducted across 27 sites in India and randomized (2:1) patients with nAMD into either the test aflibercept (ZRC-3285, Zydus Lifesciences Ltd.) or Eylea^® (Regeneron Pharmaceuticals, Inc.) groups. All 184 enrolled patients (122 and 62 in the ZRC-3285 and Eylea^® groups, respectively) were included in the modified intend-to-treat (mITT) population. ZRC-3285 or Eylea^® was administered by intravitreal injection at a dose of 2 mg (0.05 mL) on days 1, 29, and 57. The primary objective was to assess non-inferiority of ZRC-3285 versus Eylea^® in treating nAMD and was evaluated by determining the proportion of patients who lose fewer than 15 letters from baseline visual acuity over 12 weeks using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Secondary objectives included comparison of additional efficacy outcomes, immunogenicity, and safety.

Results

Over 12 weeks, all patients in the ZRC-3285 (122, 100%) and Eylea^® (62, 100%) groups showed loss of fewer than 15 letters, demonstrating non-inferiority [95% confidence interval (CI) not evaluable (NE); p = NE)] of ZRC-3285 to Eylea^®. The proportion of patients who gained more than 15 letters in best corrected visual acuity (BCVA) over 12 weeks and the mean changes in BCVA, choroidal neovascularization (CNV), and central retinal thickness (CRT) were similar in both arms.

Conclusion

Efficacy, immunogenicity, and safety profiles of ZRC-3285 were found to be similar to those of Eylea^®.

Trial Registration

Clinical trial Registry of India (CTRI): CTRI/2023/09/057655 [Registered on 14/09/2023].

Supplementary Information

The online version contains supplementary material available at 10.1007/s40123-025-01299-5.

Key Summary Points

Why carry out this study?

(Wet) neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss globally, with limited access to costly anti-vascular endothelial growth factor (anti-VEGF) therapies in regions like India.

Aflibercept biosimilars can improve affordability and accessibility while maintaining efficacy and safety standards and reduce economic burden in such regions, enabling broader patient access to this therapeutic option.

This phase III randomized trial compared the efficacy, safety, and immunogenicity of ZRC-3285 with Eylea® in patients with wet AMD using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol and a non-inferiority margin of − 10 letters.

What was learned from the study?

The study demonstrated that ZRC-3285, an aflibercept biosimilar, is clinically comparable to Eylea® in terms of efficacy, safety, and immunogenicity for treating neovascular (wet) AMD.

All patients maintained visual acuity, and secondary outcomes—including best corrected visual acuity (BCVA) gain, choroidal neovascularization (CNV) leakage reduction, and central retinal thickness (CRT) improvement—were statistically similar between groups.

The biosimilar showed favorable safety profile, supporting its potential as a cost-effective alternative to Eylea® in resource-limited settings.

Introduction

Age-related macular degeneration (AMD) accounts for approximately 8.7% of global blindness and is the leading cause of vision loss in developed nations [1]. The global burden of AMD is rising, with projections estimating 288 million affected individuals by 2040, including 113 million in Asia due to its large population base [1, 2]. From 1990 to 2010, the incidence of blindness and visual impairment caused by AMD increased [3]. In India, the prevalence of AMD ranges from 1.4% to 3.1%, with advanced age (particularly individuals over 65 years) being the most significant demographic factor associated with increased prevalence [4].

In AMD, the most severe vision loss occurs as a result of choroidal neovascularization (CNV), which defines the neovascular or wet form of the disease. CNV is commonly associated with the development of fibrosis and atrophic changes in the retinal pigment epithelium and photoreceptors within the macular area. These pathological alterations often result in profound central vision loss, impairing essential daily activities such as reading, driving, and recognizing faces. Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis and vascular permeability, plays a central role in the pathogenesis of CNV secondary to AMD. Therapeutic inhibition of VEGF signaling has proven to be highly effective in mitigating disease progression and preserving visual function [5]. Therefore, VEGF remains the principal therapeutic target in the treatment of nAMD, and several anti-VEGF agents such as pegaptanib sodium, ranibizumab, aflibercept, brolucizumab, faricimab, and conbercept are approved for treatment for neovascular AMD (nAMD) [6, 7]. The approval of ranibizumab biosimilars marked a significant advancement in enhancing global accessibility to ranibizumab by reducing treatment costs. Aflibercept is widely used in high-income regions, while bevacizumab predominates in the USA and low-income countries because of cost; anti-VEGF agents show similar efficacy, with no evidence of superior outcomes at lower aflibercept doses [8, 9].

Aflibercept is a recombinant fusion protein comprising VEGFR-1 and VEGFR-2 extracellular domains fused to the Fc region of human IgG1, formulated for intravitreal use and produced in Chinese hamster ovary (CHO) cells. It functions as a soluble decoy receptor, binding VEGF-A, VEGF-B, and placental growth factor (PIGF) with high affinity, thereby inhibiting VEGF receptor activation and pathological angiogenesis [10–12].

Aflibercept (Eylea^®) was approved by the US Food and Drug Administration (FDA) in 2011 for clinical use to treat patients with wet (neovascular) AMD, a leading cause of vision loss and blindness in the American population aged 60 and older.

According to data from the life sciences consultancy Spherix Global Insights, aflibercept (Eylea) currently holds a 43.4% share of the anti-VEGF market in the USA, followed by bevacizumab (Avastin, Genentech/Roche) at 34%, ranibizumab (Lucentis) at 9.4%, and faricimab (Vabysmo) at 7.6%. These figures highlight the potential impact of Eylea biosimilars in alleviating the financial burden on healthcare systems. Although Eylea dominates the US market, there are many countries, such as India, where Eylea has the least market share due to poor affordability [13]. The availability of aflibercept biosimilars may enhance affordability, increase accessibility, maintain high efficacy and safety, and reduce economic burden in such regions, enabling broader patient access to this therapeutic option [13].

To allow accessibility and affordability of aflibercept in India, a biosimilar of aflibercept (ZRC-3285) was developed by Zydus Lifesciences Ltd. The extensive physicochemical and biological comparability data showed similarity between ZRC-3285 and Eylea^®. To obtain regulatory approval of ZRC-3285 in India, a phase III, randomized, double-blind trial was performed to compare the efficacy, safety, and immunogenicity of ZRC-3285 with Eylea^® in patients with neovascular (wet) AMD.

Methods

Study Design and Participants

This randomized, double-blind, parallel group, multicenter study was conducted from March 2024 to October 2024 at 27 different sites in India and compared the efficacy, safety, and immunogenicity of ZRC-3285 with those of Eylea^®. The following key criteria were used for the inclusion: (1) aged ≥ 50 years with newly diagnosed, angiographically documented patients with primary or recurrent, active subfoveal (including juxtafoveal) CNV lesion secondary to neovascular (wet) AMD in the study eye, (2) area of CNV (classic plus occult component) must be ≥ 50% of the total lesion area in the study eye, with total lesion area < 12 disc areas (DA) in size (including blood, scars, and neovascularization) as assessed by fluorescein angiography (FA) in the study eye, (3) best corrected visual acuity (BCVA) between 20/40 and 20/320 (Snellen equivalent) using Early Treatment Diabetic Retinopathy Study (ETDRS) chart testing in the study eye at screening and baseline. Participants were excluded if central subfield of the study eye was affected by fibrosis or geographic atrophy assessed by color fundus photography, total area of subfoveal fibrosis, atrophy or scarring ≥ 50%, subretinal hemorrhage that is either 50% or more of the total lesion area (see Supplementary Material, Methods for detailed list of exclusion criteria and details of patient visits).

ZRC-3285 and Eylea^® were administered by intravitreal injection at a dose of 2 mg (0.05 mL) on days 1, 29, and 57.

The study protocol was duly approved by the institutional ethics committees (IECs) of the respective study sites and by the Central Drugs Standard Control Organization (CDSCO), in compliance with the New Drugs and Clinical Trials Rules, 2019. A detailed list of study sites along with their respective IECs is provided in the Supplementary Material. The study was conducted in accordance with the ethical principles of Declaration of Helsinki, Good Clinical Practice (GCP) guidelines of CDSCO, Ethical guidelines for Biomedical Research on Human Participants by the Indian Council of Medical Research (ICMR), and other relevant regulatory guidelines. Written informed consent was obtained from all participants prior to enrolment.

Objectives and Endpoints

The primary endpoint was proportion of patients who lose fewer than 15 letters (approximately 3 lines) from BCVA over 12 weeks. The secondary outcomes included the assessment of mean change in BCVA, proportion of patients who gain more than 15 letters (approximately 3 lines) from baseline visual acuity, change in the total size of choroidal neovascular leakage area in the study eye, and change in the central retinal thickness (CRT) in the study eye between the two groups.

Safety Evaluation

All reported terms for adverse events (AEs) [ocular and systemic (non-ocular)] were coded using the Medical Dictionary for Regulatory Activities (MedDRA^®, Version 27.0). Safety assessment includes vital signs and physical examinations, ophthalmic examination, laboratory assessment, and post-injection assessment.

Statistical Analysis

Statistical analysis was performed using SAS^® (Version 9.4) software (SAS Institute Inc., USA). Considering the response rate of 96%, at least 156 patients were required to demonstrate the non-inferiority of ZRC-3285 to Eylea^® with non-inferiority margin of − 10 at 85% power and 2.5% level of significance (one sided). Considering the randomization ratio of 2:1 and a dropout rate up to 15%, 184 patients (ZRC-3285 group, 122; Eylea^® group, 62) were required to be enrolled in the study.

Results

Patient Disposition and Baseline Characteristics

Figure 1 shows the Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition (see Table 1 for patient demographics and baseline characteristics). Of 211 screened patients, 184 were randomized (2:1) to receive either ZRC-3285 or Eylea^®, and of these, 5 (2.72%) participants discontinued the study; 3 and 2 in the ZRC-3285 and Eylea^® groups, respectively, with consent withdrawal (1.09%) and lost to follow-up (1.63%) being the primary reasons. Importantly, the discontinuation rate was comparable between the ZRC-3285 (2.46%) and Eylea^® (3.23%) groups. The baseline characteristics of patients in the two study groups were comparable (Table 1).

Fig. 1.

The CONSORT diagram. mITT modified intended-to-treat, PP per-protocol

Table 1.

Demographic details and baseline characteristics of participants

Parameter/Characteristic	Statistics	ZRC-3285/Biosimilar (N = 122)	Eylea®/Reference (N = 62)	Total (N = 184)
Gender
Male	n (%)	69 (56.56)	36 (58.06)	105 (57.07)
Female	n (%)	53 (43.44)	26 (41.94)	79 (42.93)
Age (years)	Mean ± SD	70.28 ± 9.16	69.61 ± 9.27	70.05 ± 9.18
Height (cm)	Mean ± SD	160.32 ± 9.94	159.07 ± 11.58	159.90 ± 10.51
Weight (kg)	Mean ± SD	64.21 ± 10.39	64.69 ± 9.12	64.37 ± 9.96
Baseline ETDRS BCVA (Letter score for study eye)	Mean ± SD	48.25 ± 10.56	49.58 ± 9.94	48.70 ± 10.35
Central retinal thickness (CRT) in μm	Mean ± SD	323.56 ± 123.13	309.18 ± 93.22	318.71 ± 113.87
Area of CNV (For study eye) in mm2	Mean ± SD	6.98 ± 5.29	8.89 ± 7.40	7.63 ± 6.13
Visual acuity (approximate Snellen equivalent) (For study eye)
20/200 or worse	n (%)	29 (23.77)	15 (24.19)	44 (23.91)
Better than 20/200 but worse than 20/40	n (%)	93 (76.23)	46 (74.19)	139 (75.54)
20/40 or better	n (%)	–	1 (1.61)	1 (0.54)
Type of lesion (For study eye)
Minimally Classic	n (%)	23 (18.85)	12 (19.35)	35 (19.02)
Occult with No Classic	n (%)	31 (25.41)	14 (22.58)	45 (24.46)
Predominantly Classic	n (%)	68 (55.74)	36 (58.06)	104 (56.52)
Total Lesion size (in Disc Area for study eye)	Mean ± SD	4.26 ± 2.98	4.60 ± 3.04	4.37 ± 3.00
Total Area (in mm2 for study eye)	Mean ± SD	11.61 ± 9.37	14.51 ± 12.83	12.59 ± 10.71

Values are presented as n (%) or mean ± standard deviation

BMI body mass index, N number of participants in each treatment group, ETDRS Early Treatment Diabetic Retinopathy Study, BCVA best corrected visual acuity, CRT central retinal thickness, CNV choroidal neovascularization

^aBiosimilar = aflibercept (test product, ZRC-3285, Zydus Lifesciences Ltd.)

^bReference = aflibercept (reference product, Eylea^®, Regeneron Pharmaceuticals Inc.)

^cFor the study eye

Efficacy Analysis

In the mITT population, over 12 weeks, all patients in the ZRC-3285 (122, 100%) and Eylea^® (62, 100%) groups showed loss of fewer than 15 letters (approximately 3 lines) from baseline visual acuity, demonstrating no difference (95% CI not evaluable (NE); p = NE) between the two groups. This result suggested that the efficacy of ZRC-3285 is non-inferior to that of Eylea^® (Table 2).

Table 2.

Efficacy analysis results

Endpoints	Testa (N = 122) n (%)	Referenceb (N = 62) n (%)	Difference (95% CI)	P value
Proportion of patients who lose fewer than 15 letters from baseline visual acuity over 12 weeks	122 (100.00)	62 (100.00)	0 (NE)	NE
Proportion of patients who gain more than 15 letters from baseline visual acuity over 12 weeks	32 (26.23)	16 (25.81)	0.42 (− 13.00, 13.85)	0.951
Change in the total size of choroidal neovascular leakage area (mm2)	− 3.49 ± 3.68	− 3.51 ± 3.91	0.02 (− 1.13, 1.18)	0.969
CRT (μm)	− 90.43 ± 115.15	− 73.23 ± 74.83	− 17.2 (mean difference)	0.224

95% confidence interval was intended to be evaluated using two-proportion Z test and p value was intended to be tested using the chi-square or Fisher's exact test

Percentage is calculated on the basis of total number of patients for each treatment

NE not evaluable, CRT central retinal thickness, N number of patients enrolled in each treatment, n number of patients in respective category

^aTest = aflibercept (test product, ZRC-3285)

^bReference = aflibercept (reference product Eylea^®, Regeneron Pharmaceuticals, Inc.)

The proportion of patients who gain more than 15 letters (approximately 3 lines) from baseline visual acuity over 12 weeks was 32 (26.23%) in the ZRC-3285 group and 16 (25.81%) in the Eylea^® group. This result suggests no significant difference (0.42 [95% CI − 13.00 to 13.85; p = 0.951]) between the two groups (Table 2).

The mean of change in CNV leakage area from baseline to week 12 was − 3.49 ± 3.68 mm² in the ZRC-3285 group and − 3.51 ± 3.91 mm² in the Eylea^® group. Furthermore, the mean difference (95% CI) in change in CNV leakage area from baseline to week 12 was 0.02 mm² (− 1.13 to 1.18). This result suggested that there was no significant difference (p = 0.969) between the two groups in terms of mean of change in CNV leakage area (Table 2).

The mean ± SD change in the CRT at 12 weeks compared to baseline was − 90.43 ± 115.15 μm for the ZRC-3285 group and − 73.23 ± 74.83 μm for the Eylea^® group; the corresponding mean difference was – 17.2 μm (p = 0.224). Hence there was no significant difference between the two groups in mean change in the CRT at week 12 (Table 2).

The mean BCVA changes from baseline to week 12 were 9.32 ± 8.13 letters in the ZRC-3285 group and 10.16 ± 8.35 letters in the Eylea^® group, indicating no significant difference (least squares mean (LSM) difference − 0.96 letters [95% CI − 3.48 to 1.56; p = 0.454]) between the two groups (Table 3). Comparable outcomes for all parameters listed above were observed in the per-protocol (PP) population.

Table 3.

Best corrected visual acuity (BCVA) results (full analysis set)

Endpoints	Testa (N = 122) n (%)	Referenceb (N = 62) n (%)	Least square mean difference	95% CI	P value
Change in BCVA from baseline at week 12, letters	9.32 ± 8.13	10.16 ± 8.35	− 0.96	(− 3.48, 1.56)	0.454

P value obtained using independent t test

SD standard deviation, N number of patients enrolled in each treatment

^aTest = aflibercept (test product, ZRC-3285)

^bReference = aflibercept (reference product Eylea^®, Regeneron Pharmaceuticals, Inc.)

Immunogenicity

The majority of patients in both study groups did not exhibit immune responses to the therapy at evaluated time intervals (Supplementary Material, Table S1). In the ZRC-3285 group, nine participants showed a positive anti-drug antibody (ADA) test at any one time point during the duration of the study, with all these patients showing ADA positivity on visit 5 [day 85, end of study (EOS)] but with very low titers (2–8). In this group, two patients showed a positive ADA test at visit 2 (day 1, baseline). In contrast, seven patients had a positive ADA test in the Eylea^® group (one patient at visit 2 (day 1, baseline) and the remaining patients showing ADA positivity on visit 5 (day 85, EOS). Overall, very low immunogenicity levels (barely detectable titer values) were observed in both groups, indicating similar immunogenic profiles of both ZRC-3285 and Eylea^®.

Safety

The incidence, causality, and severity of treatment-emergent adverse events (TEAEs) were comparable between the two treatment groups. Among the total of 55 reported AEs, 36 occurred in the ZRC-3285 and 19 in the Eylea^® group. When analyzed by patient incidence, 26 patients (21.31%) in the ZRC-3285 and 10 patients (16.13%) in the Eylea^® group had ocular AEs. Ten patients (8.20%) in the ZRC-3285 and nine patients (14.52%) in the Eylea^® group had non-ocular AEs. There was no significant difference observed between the occurrence of ocular AEs and non-ocular AEs (p = 0.146). The most frequently reported TEAEs (reported in > 3% of patients in either treatment group) by System Organ Class (SOC) were conjunctival hemorrhage (4 patients [3.28%, 4 events] in the ZRC-3285 group and 1 patient [1.61%, 1 event] in the Eylea^® group), eye irritation (5 patients [4.10%, 6 events] in the ZRC-3285 group and 2 patients [3.23%, 2 events] in the Eylea^® group), eye pain (2 patients [1.64%, 3 events] in the ZRC-3285 group and 2 patients [3.23%, 2 events] in the Eylea^® group), ocular hyperemia (8 patients [6.56%, 8 events] in the ZRC-3285 group and 2 patients [3.23%, 2 events] in the Eylea^® group), pyrexia (2 patients [3.23%, 3 events] in the Eylea^® group), and headache (3 patients [2.46%, 3 events] in the ZRC-3285 group and 3 [4.84%, 3 events] in the Eylea^® group). The majority of AEs were mild in severity in both treatment groups. In terms of causality, most AEs were either possible or unlikely related to study medication. All the AEs were resolved/recovered during the study (Table 4). No serious AEs (SAEs) were observed in the study. The results of blood chemistry parameters, hematological parameters, urinalysis, vital signs, and physical examination were comparable between the two treatment groups during the study.

Table 4.

Summary of treatment emergent adverse events by severity (safety population)

	ZRC-3285	Eylea®	Total
	(N = 122)	(N = 62)	(N = 184)
	n (%) E	n (%) E	n (%) E
Total number of adverse events	36	19	55
Number of patients with at least one TEAE	26 (21.31) 36	13 (20.97) 17	39 (21.20) 53
Adverse events by severity grade	26 (21.31) 36	13 (20.97) 17	39 (21.20) 53
Mild	25 (20.49) 35	12 (19.35) 16	37 (20.11) 51
Moderate	1 (0.82) 1	1 (1.61) 1	2 (1.09) 2
Adverse events by causality	26 (21.31) 36	13 (20.97) 17	39 (21.20) 53
Possible	21 (17.21) 28	7 (11.29) 9	28 (15.22) 37
Unlikely	7 (5.74) 8	7 (11.29) 8	14 (7.61) 16
Adverse events by outcome	26 (21.31) 36	13 (20.97) 17	39 (21.20) 53
Resolved/recovered	26 (21.31) 36	13 (20.97) 17	39 (21.20) 53
Unknown	0 (0.00) 0	0 (0.00) 0	0 (0.00) 0

If a patient has multiple occurrences of an AE, the patient is presented only once for the corresponding AE. Percentage is calculated as (n/N) × 100

N  number of patients in the safety population, n number of patients for specific category, E event, TEAE treatment emergent adverse event

Discussion

This phase 3 clinical study evaluated the efficacy, safety, and immunogenicity of ZRC-3285 with aflibercept (Eylea^®), which is an approved drug for wet AMD. This study demonstrated non-inferiority of ZRC-3285 to Eylea^®. The results show equivalent efficacy and comparable safety and immunogenicity between ZRC-3285 and Eylea^® in nAMD. The results of all other evaluated outcomes were not significantly different between ZRC-3285 and Eylea^® groups.

The primary endpoint results for this study demonstrated equivalent proportions of patients who lost fewer than 15 letters from baseline BCVA to the end of week 12 (100% of patients in the ZRC-3285 group and 100% in the reference Eylea^® group), demonstrating no difference (95% CI NE; p = NE) between the two groups. The results obtained in this study were almost comparable to previous clinical studies (VIEW1 and VIEW2) [14] of Eylea^® as well as a biosimilar of Eylea^®. In the present study, the proportion of patients who maintained visual acuity (%) (< 15 letters of BCVA loss) was 100%; these efficacy results were consistent with those of VIEW1 and VIEW2, where 94–95% of patients maintained visual acuity after 52 weeks. A previous study evaluated changes in visual acuity after 32 weeks of treatment with another biosimilar of Eylea^®, SB15 [15]. SB15 showed efficacy results consistent with those of the present study of ZRC-3285: the maintenance of visual acuity was achieved in 97.7% patients.

The mean BCVA changes from baseline to week 12 were 9.32 letters in the ZRC-3285 group and 10.16 letters in the Eylea^® group; these are also comparable to those reported in previous studies with Eylea^® (7.9 and 8.9 letters in VIEW1 and VIEW2 studies, respectively, at week 52) [14] as well as SB15 (7.6 letters at week 32) [15]. The proportion of patients who showed improvement in BCVA by gaining > 15 letters at week 12 (26.23% in the ZRC-3285 group and 25.81% in the reference Eylea^® group) in this study are comparable to those reported for SB15 (21.9% at week 32) [15].

In terms of changes in CRT, the LSM change in CRT from baseline in the ZRC-3285 group (− 90.43 µm) is also comparable to SB15 (− 110.4 µm) at week 32.

The percent reduction in CNV leakage area observed in the present study with ZRC-3285 (− 3.49 ± 3.68 mm²) is comparable with VIEW1 (− 3.4 ± 6.0 mm²) [14]. The efficacy and safety results obtained in the present study therefore demonstrate that ZRC-3285’s efficacy and safety are similar to those reported previously with Eylea^® and another reported biosimilar SB15.

The biosimilar aflibercept (ZRC-3285) demonstrated a favorable safety and immunogenicity profile in the Indian population. Immunogenicity levels were minimal, with barely detectable antibody titers, and were comparable between the biosimilar and reference Eylea^® groups. The incidence and nature of TEAEs were similar across both groups, with most events being mild and resolving during the study. No SAEs were reported, and no significant differences were observed in ocular versus non-ocular AEs.

The strength of this study lies in its robust design—a randomized, double-blind, parallel-group trial. The study was conducted at 27 clinical sites across India. The sites included well-recognized ophthalmology centers (AIIMS, Delhi; SMS Hospital, Jaipur; LVPI, Hyderabad; Dr Agarwal’s Eye Hospital, Tirunelveli; Sankara Nethralaya, Chennai; Regional Institute of Ophthalmology Patna; Sankara and Nethra Eye Hospital, Bengaluru). Hence, the target population was representative of the actual diseased population of India. The sample size was adequately powered to demonstrate non-inferiority, and the study achieved a high completion rate of over 97%. Additionally, the endpoints were consistent with global benchmarks, reinforcing the external validity and reliability of the findings.

This study has certain limitations: it was conducted exclusively in an Indian population, which may limit the generalizability of the findings to other ethnic or geographic populations. The relatively short duration (12 weeks) limits comparison assessment; however, this duration is consistent with other biosimilar trials [16–18]. Additionally, detailed morphological parameters such as subretinal fluid, intraretinal fluid, and subretinal hyperreflective material (SHRM), as well as responder/non-responder analysis, were not evaluated, limiting anatomical characterization. There is also plateauing of the effect after 3 months. Since aflibercept is given intravitreally, there is limited systemic absorption. Therefore, we have not evaluated the pharmacokinetics in this study.

Overall, comparable safety, efficacy, and immunogenicity along with the extensive physicochemical and biological similarity were seen between ZRC-3285 and Eylea^®.

Conclusion

The study demonstrates that ZRC-3285 is clinically comparable to Eylea^® in terms of efficacy, safety, and immunogenicity for treating wet AMD. Our biosimilar shows promise as a cost-effective alternative for patients with nAMD.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Mudit Bansal: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Punit Singh: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Ruchi K Mehta: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Rohit Sanjay Laul: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Parth Rana: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Urmil Shah: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Rajpal Vohra: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Shachi Desai: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Sharad Bhomaj: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Sourabh Patwardhan: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing Jaishri Murli Manoher: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Anjali Sapar: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Sandeep Parwal: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Ajay Kartik Amabde: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Rahul Shroff: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Sribhargava Natesh: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Rupak Kanti Biswas: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Lional Raj D: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Bibhuti P Sinha: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Minija C K: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Ekta Patel: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Ashish Kamble: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Pramod Bhende: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Sandeep Patil: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Anup Shah: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Ritesh Narula: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Bandana Kumari: Data curation, Investigation, Methodology, Project Administration, Supervision, Writing – Review & Editing. Lokesh Bathula: Data curation, Project Administration, Supervision Sandip Kirtane: Data curation, Project Administration, Supervision, Resources. Bhargav Darji: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Visualization, Writing – Review & Editing Maulik Doshi: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Resources, Supervision, Visualization, Writing – Review & Editing. Deven Parmar: Conceptualization, Investigation, Project Administration, Resources, Supervision, Visualization, Writing – Review & Editing.

Funding

This study was sponsored and funded by Zydus Lifesciences Ltd., Ahmedabad, India. The journal’s Rapid Service Fee was also funded by Zydus Lifesciences Ltd.

Data Availability

The data supporting this study’s findings are available from the corresponding author upon reasonable request.

Declarations

Conflict of Interest

Deven Parmar is an employee of Zydus Therapeutics Inc., USA. Lokesh Bathula, Sandip Kirtane, Bhargav Darji, and Maulik Doshi are employees of Zydus Lifesciences Ltd. Mudit Bansal, Punit Singh, Ruchi K Mehta, Rohit Sanjay Laul, Parth Rana, Urmil Shah, Rajpal Vohra, Shachi Desai, Sharad Bhomaj, Sourabh Patwardhan, Jaishri Murli Manoher, Anjali Sapar, Sandeep Parwal, Ajay Kartik Amabde, Rahul Shroff, Sribhargava Natesh, Rupak Kanti Biswas, Lional Raj D, Bibhuti P Sinha, Minija C K, Ekta Patel, Ashish Kamble, Pramod Bhende, Sandeep Patil, Anup Shah, Ritesh Narula, and Bandana Kumari have nothing to disclose.

Ethical Approval

The study protocol was duly approved by the institutional ethics committees (IECs) of the respective study sites and by the Central Drugs Standard Control Organization (CDSCO), in compliance with the New Drugs and Clinical Trials Rules, 2019. A detailed list of study sites along with their respective IECs is provided in the Supplementary Material. The study was conducted in accordance with the ethical principles of Declaration of Helsinki, Good Clinical Practice (GCP) guidelines of CDSCO, Ethical guidelines for Biomedical Research on Human Participants by the Indian Council of Medical Research (ICMR), and other relevant regulatory guidelines. Written informed consent was obtained from all participants prior to enrolment.