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.
References
US Food and Drug Administration. Drugs@FDA:FDA-approved drugs: Lucentis. 2006. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125156. Accessed 24 Mar 2021.
European Medicines Agency. Lucentis. 2007. https://www.ema.europa.eu/en/medicines/human/EPAR/lucentis#authorisationdetails-section. Accessed 24 Mar 2021.
Central Drugs Standard Control Organization, Directorate General of Health Services, Ministry of Health & Family Welfare, Government of India. Permission to manufacture and market ranibizumab solution for injection (r-DNA origin) (permission no: MF-35/2015; BULK-36/2015). Manufacturer Intas Pharmaceuticals Limited, Ahmedabad, Gujarat, India. 2013. https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/download_file_division.jsp?num_id=NTUzNg==. Accessed 24 Mar 2021.
Sharma S, Khan MA, Chaturvedi A, RE-ENACT 2 Study Investigators Group. A multicenter, retrospective study (RE-ENACT 2) on the use of RazumabTM (World’s First Biosimilar Ranibizumab) in Wet AMD, DME, RVO and Myopic CNV. J Clin Exp Ophthalmol. 2019;10:2.
Sharma S, Khan M, Chaturvedi A. A multicenter, retrospective study (RE-ENACT 2) on the use of RazumabTM (world’s first biosimilar ranibizumab) in wet age-related macular degeneration. Ophthalmol Ther. 2020;9:103–14.
Sharma S, Khan M, Chaturvedi A. A Multicenter, retrospective study (RE-ENACT 2) on RazumabTM (world’s first biosimilar ranibizumab) in retinal vein occlusion. Ophthalmol Ther. 2020;9:625–39.
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. Ophthalmologica. 2019;241:24–31.
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: a subgroup analysis of pooled retrospective RE-ENACT study. Int J Oph thalmol Eye Res. 2018;6:368–73.
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;6:377–83.
Woo SJ, Veith M, Hamouz J, Ernest J, Zalewski D, Studnicka J, et al. Efficacy and safety of a proposed ranibizumab biosimilar product vs a reference ranibizumab product for patients with neovascular age-related macular degeneration: a randomized clinical trial. JAMA Ophthalmol. 2021;139:68–76.
Sharma A, Kumar N, Parachuri N. Biosimilar ranibizumab (SB11) vs reference ranibizumab—diving deeper for safety and efficacy. JAMA Ophthalmol. 2021;139:677–9.
Sharma A, Reddy P, Kuppermann BD, Bandello F, Lowenstein A. Biosimilars in ophthalmology: “Is there a big change on the horizon?”. Clin Ophthalmol. 2018;12:2137–43.
Sharma A, Hafeez Faridi M, Kumar N, Parachuri N, Sharma R, Kuppermann BD, et al. Immunogenicity and efficacy after switching from original Ranibizumab to a Ranibizumab biosimilar: real-world data. Eye. 2020;34:1008–9.
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;104:2–7.
Sharma A, Kumar N, Parachuri N, Bandello F, Kuppermann BD, Loewenstein A. Biosimilars for retinal diseases: an update. Am J Ophthalmol. 2020;224:36–42.
Sharma A, Kumar N, Bandello F, Loewenstein A, Kuppermann BD. Need of education on biosimilars amongst ophthalmologists: combating the nocebo effect. Eye. 2020;34:1006–7.
Sharma A, Kumar N, Kuppermann BD, Francesco B, Lowenstein A. Ophthalmic biosimilars: lessons from India. Indian J Ophthalmol. 2019;67:1384–5.
Author information
Authors and Affiliations
Contributions
AS was responsible for conception, design, analysis, and the final approval of the study. NP and NK were responsible for data collection and drafting. FB, BDK, and AL were responsible for review of design protocol, result interpretation, integrity check.
Corresponding author
Ethics declarations
Competing interests
AS: CONSULTANT: for Novartis, Allergan, Bayer and Intas. FB: CONSULTANT: Allergan, Bayer, Boehringer- Ingelheim, Fidia Sooft, Hofmann La Roche, Novartis, NTC Pharma, Sifi, Thrombogenics, Zeiss. BDK: CLINICAL RESEARCH: Alcon, Alimera, Allegro, Allergan, Apellis, Clearside, Genentech, GSK, Ionis, jCyte, Novartis, Regeneron, ThromboGenics; CONSULTANT: Alimera, Allegro, Allergan, Cell Care, Dose, Eyedaptic, Galimedix, Genentech, Glaukos, Interface Biologics, jCyte, Novartis, Ophthotech, Regeneron, Revana, Theravance Biopharma. AL reports other from Allergan, other from Novartis, other from Roche, other from Notal Vision, other from Forsightslabs, other from Beyeonics, other from Bayer Health Care. NK: None. NP: None
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Sharma, A., Kumar, N., Parachuri, N. et al. Ranibizumab Biosimilar (Razumab) vs Innovator Ranibizumab (Lucentis) in neovascular age-related macular degeneration (n-AMD)- efficacy and safety (BIRA study). Eye 36, 1106–1107 (2022). https://doi.org/10.1038/s41433-021-01616-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41433-021-01616-9
This article is cited by
-
Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration
Journal of Translational Medicine (2023)
-
Innovator Versus Biosimilar Ranibizumab in Polypoidal Choroidal Vasculopathy: Real-World Evidence
Ophthalmology and Therapy (2022)
-
Comparison Between Ranibizumab Biosimilar, Innovator Ranibizumab and Bevacizumab in a Real-World Situation
Ophthalmology and Therapy (2022)