Innovator ranibizumab (IR) received the United States Food and Drug Administration (US-FDA) approval in 2006 and the European Medical Agency (EMA) approval in 2007 [1, 2]. Ranibizumab biosimilar {Razumab (RB) Intas Pharmaceuticals Ltd, India} was approved by the drug controller general of India (DGCI) in 2015 [3]. Since then, Razumab has been widely implemented in India as a cost-effective treatment option. There are multiple single-arm scientific studies that have been published related to the efficacy and safety of RB [4,5,6,7,8,9]. However, to the best of our knowledge, no comparative data on RB vs IR has been published yet. This is the first study that compares the efficacy and safety of RB vs IR in neovascular age-related macular degeneration (n-AMD).

We retrospectively reviewed charts of treatment naïve n-AMD patients who were treated with at least 2 consecutive injections at 4 weeks interval with either 0.5 mg of RB or IR between Dec 2018 and Dec 2020. We found 42 eyes in the RB group and 44 eyes in the IR group to be eligible for analysis according to the inclusion criteria. The methodology adhered to the tenets of the declaration of Helsinki. Institute’s committee on human research approved the protocol. Informed consent was taken as per the routine protocol of the institute regarding data utilization for the research purpose. A minimum of 8-week follow-up from the time of diagnosis of n-AMD was required to be included in the study. Eyes with structural changes other than n-AMD and patients with vitreo-retinal interface diseases were excluded. Furthermore, patients who were switched to another drug in any of the groups during the initial 6 months were also excluded. Each patient underwent best-corrected visual acuity (BCVA) measurement with Snellen chart {converted to Early Treatment Diabetic Retinopathy Study (ETDRS) letter score for analysis}, central subfield thickness (CST) with spectral-domain optical coherence tomography (SD-OCT) (Optovue Fremont, CA, USA) and intraocular pressure (IOP) measurement along with complete ophthalmic examination at each follow-up visit. Follow-up visit at 8 weeks was considered as the primary outcome for efficacy and safety. Further analysis of safety and efficacy was performed at 24 weeks. Efficacy was determined on the basis of comparison of BCVA and CMT. Safety was assessed on the basis of the occurrence of ocular or systemic adverse events noted at each follow-up visit. Amongst safety, predominantly clinical immunogenicity was tested and it was considered positive if the clinician (AS) had documented any anterior chamber inflammation (cells/flare) and/OR posterior chamber inflammation (vitritis/ snow banking/ snow balls/ retinitis/ retinal vasculitis) during any of the visits. Otherwise, it was considered negative. Descriptive statistics including mean, standard deviation (SD), median, and range were calculated for continuous variables. Unpaired t-test was used to measure mean differences between RB and IR. The Chi-square test was used for the comparison of categorical data. The baseline data were matched in terms of age, BCVA, and CMT.

Key outcomes

Mean age of the patient was 70.5 ± 6.8 years and 69.1 ± 5.8 in RB and IR groups respectively (p = 0.3065, 90% CI −4.106 to 1.306). Male to female ratio was 1.1 and 1.2 (p = 0.840571) in the RB and IR groups respectively. Baseline mean ETDRS letter score was 45.4 ± 9.5 and 47.3 ± 9.4 in RB and IR groups respectively. (p = 0.3539, 90% CI −2.154 to 5.954) Baseline mean CMT was 337.2 ± 25.6 and 328.4 ± 23.1 in RB and IR groups respectively. (p = 0.0976, 90% CI −19.247 to 1.647).

Mean number of injections during 24 weeks was 3.8 ± 0.7 in the RB group and 3.6 ± 0.7 in the IR group (P = 0.1579, 90% CI −0.479 to 0.079).

Efficacy

At 8-week follow-up, the mean ETDRS letter score was 76.1 ± 4.6 and 75.9 ± 4.1 in RB and IR groups respectively. (P = 0.8318, 90% CI −2.067 to 1.667).

At 24-week follow-up, the mean ETDRS letter score was 76.3 ± 6.9 and 76.7 ± 6.4 in RB and IR groups respectively. (P = 0.7810, 90% CI −2.452 to 3.252).

At 8-week follow-up, the mean CMT was 230.7 ± 14.8 and 227.4 ± 13.7 in the RB and IR groups respectively. (p = 0.2860, 90% CI −9.412 to 2.812).

At 24-week follow-up, the mean CMT was 218.5 ± 13.9 and 223.07 ± 12.3 in the RB and IR groups respectively. (P = 0.1097, 90% CI −1.0521 to 10.1921).

Safety

None of the patient’s records were documented with ocular or systemic adverse events including clinical signs of immunogenicity in both groups.

To summarize, real-world data of comparison between RB and IR shows no difference in terms of efficacy and safety in this retrospective limited series. Both medications were safe and effective in improving BCVA and CMT in the treatment naïve n-AMD cases. Recently, comparative phase 3 results of another proposed ranibizumab biosimilar (SB11, Samsung Bioepis Co. Ltd, South Korea) with IR demonstrated equivalence in terms of safety and efficacy [10]. It is interesting to see the primary end point as BCVA for FDA and CST for EMA as described in this study [10]. We have highlighted this point for further clarification in our letter to the editor [11]. Although the BIRA study was retroprospective in nature, choosing 8 weeks as the primary outcome measure in our study was according to the current regulatory recommendations for biosimilar vs originator studies. Mean change from baseline in BCVA at week 8 can detect both improvement and deterioration of the disease and give an opportunity of analysis before the efficacy plateau is reached. Hence, it is considered as a sensitive primary end point to detect differences between the two treatments [10].

The development of biosimilars is challenging because minor changes in the drug structure have the potential to modify the efficacy and safety of the drug in development [12]. Immunogenicity testing is of utmost importance and hence pharmacovigilance has been the key regulatory aspect [13, 14]. Biosimilars are new to ophthalmology and Razumab was the first biosimilar of ranibizumab to be approved and used in ophthalmology (approved only in India) [15]. Biosimilars are known to encounter the nocebo effect (negative perception) around them [16]. India is in the driving seat in this area and some takeaways can be utilized by other companies from the Indian experience [17].

There are limitations to the study due to its small sample size, retrospective design, and short follow-up. Furthermore, all the eyes were treatment naïve, and all types of macular neovascularization (MNV) were included. Hence, these results may not be directly extrapolated to the management of eyes that were treated with anti-VEGF medications in the past and to a specific type of MNV. The ideal way of immunogenicity testing is to assess the anti-drug antibodies (ADA). Prospective studies with a larger sample size and long-term follow-up might help in understanding the differences.