Safety and efficacy of ranibizumab biosimilar (Razumab®) as a cost-effective alternative to the innovator molecule for macular disorders in real-world

Introduction

Biologics are biotechnology-based therapeutic proteins derived from living organisms.^[1] Recent advances in pharmacotherapy with biologics that inhibit the actions of vascular endothelial growth factor (anti‑VEGFs) have transformed the management of various chorioretinal disorders including neovascular age‑related macular degeneration (nAMD), diabetic macular edema (DME), and macular edema due to retinal vein occlusions (RVO).^[2] Currently, the anti‑VEGF drugs including ranibizumab (Lucentis^®; Genentech, S. San Francisco, CA/Roche, Basel, Switzerland), aflibercept (Eylea^®, Regeneron, Tarrytown, NY), and brolucizumab (Beovu^®; Novartis, Basel, Switzerland) are approved by the US Food and Drug Administration (FDA) and are widely used in various chorioretinal pathologies.^[3], ^[4], ^[5] At the same time, bevacizumab (Avastin^®; Genentech, S. San Francisco, CA/Roche, Basel, Switzerland) which is an economical anti-VEGF alternative is also routinely adopted by retinal physicians as an off-label drug.^[6] However, its use is limited due to a lack of regulatory approval and uncertainties related to the medicolegal and safety aspects.^[6]

Based on the literature, repeated intravitreal injection therapy over the long term is recommended for the optimal management of macular pathologies. However, because of the higher overall treatment costs, an anti-VEGF agent which is affordable, effective, safe, and broadly accessible is required to effectively treat these retinal conditions. Biosimilar drugs, which closely resemble the approved biological agents in structure and function, may offer a solution to this problem.^[7] Razumab®, the world's first regulated biosimilar of Ranibizumab, was developed by Intas Pharmaceuticals Ltd., Ahmedabad, India, and approved in 2015 by the highest Indian regulatory body, the Drug Controller General of India (DCGI).^[2]

The RE-ENACT studies have provided the initial phase 3 data related to the safety and efficacy of Razumab in nAMD and RVO.^[8], ^[9], ^[10], ^[11] However, the outcomes of these controlled trials may not truly reflect the outcomes in a real-world setting. Additionally, with changing global healthcare scenario in the backdrop of the COVID-19 pandemic, the impact of the preference for biosimilars over branded agents remains unexplored. To better understand this aspect, we present the real-world data of intravitreal Razumab (IVRz) therapy for various macular pathologies, in Indian patients who chose the biosimilar agent over the branded ranibizumab molecule.

Materials and Methods

This was a single‑center, prospective study of patients undergoing IVRz from the beginning of the COVID-19 pandemic in India (April 2020) till March 2021. The study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board. Written informed consent for treatment and data collection was obtained from each patient.

Results

Discussion

In this real-world study on the efficacy and safety of IVRz as an economical alternative to the branded agent Lucentis, significant improvement in visual acuity and tomographic biomarkers was seen as early as four weeks after the initial injection of IVRz and maintained upto 12 weeks. The effectiveness of IVRz was seen across a variety of chorioretinal diseases including DME, nAMD, RVO, and mCNVM. Additionally, no new safety concerns or systemic adverse events were noted.

The COVID-19 pandemic which began in 2019 has changed the face of healthcare delivery and health economics on a global scale. Virus containment measures including periodic lockdowns have been adopted universally by all governments. The global economic fallout has been catastrophic, resulting in widespread job losses.^[12] The situation was particularly grim in developing countries such as India and also in underdeveloped nations.^[13], ^[14] Health care has always been a challenge in a country like India, where the majority of the population lives in slums and rural areas and is below the poverty line.^[13], ^[14] A major health challenge in India is the high out-of-pocket expenditure (OOPE) on health, which accounts for 62.6% of total health expenditure.^[15] India has one of the highest OOPE on health in the world, nearly three times the global average of 20.5 percent.^[15]

Razumab was approved for intravitreal use in n-AMD and RVO by the DGCI in 2015. The approval was based on positive results from a 12-week phase 3 clinical trial (RE-ENACT), which demonstrated efficacy in 103 eyes with nAMD and 160 eyes with RVO.^[8], ^[9] Following that, at 48 weeks, the RE-ENACT-2 trial in nAMD demonstrated significant improvement in BCVA, CST, IRF, and SRF.^[10] Similarly, the comparable RE-ENACT-2 trial in RVO established Razumab to be an effective treatment option in RVO by demonstrating significant visual acuity gains and reduction in the CST at 48 weeks.^[11] We also similarly observed notable improvement in the visual parameters and SD-OCT, including a reduction in the CST, IRF, and SRF.

In India, the cost of the biosimilar Razumab ($125) is less than half of the branded agent (Branded Accentrix; $320). It is also very economical as compared to the other FDA-approved molecules, including Eylea ($760), and Beovu (Branded Pagenax; $350).^[2] Bevacizumab is also widely used as an economical anti-VEGF agent, although its use is off-label for chorioretinal pathologies.^[6] It is currently available in a 4-mL vial, from which multiple doses for ophthalmic use are aliquoted. Because multiple pricks may be performed during aliquoting, this technique carries an inherent risk of infection, as well as viability concerns due to the difficulty in maintaining the cold chain and storing the vial. Following a few cases of endophthalmitis caused by its use, the US-FDA issued a warning about its ocular use.^[6] Furthermore, due to safety concerns, the drug was temporarily banned in India.^[6] Regulatory approved biosimilar such as Razumab is available as a single-use vial and hence can be considered as a safer and economical anti-VEGF agent. A comparative survey conducted by the Vitreoretinal Society of India (VRSI) showed that a vast majority of Indian retinal physicians are well aware of biosimilars and there is an increasing trend toward prescribing a ranibizumab biosimilar.^[16] They were also largely satisfied with the biosimilar’s safety and efficacy.^[16] In our study, which included patients with a wide array of common chorioretinal pathologies such as DME, nAMD, RVO, and mCNVM, the safety and efficacy of IVRz were well established. In 100 eyes, significant improvement in visual and tomographic outcomes was noted after three loading doses of the ranibizumab biosimilar. Verma L et al retrospectively analyzed the clinical efficacy and safety of biosimilar Razumab in 153 eyes with AMD, DME, and RVO, and demonstrated significant clinical improvement with no ocular or systemic adverse events at three months.^[17] The authors however did not perform a detailed tomographic evaluation including IRF and SRF resolution that was conducted in the current study.

Systemic safety remains an ongoing challenge with anti-VEGF therapy. The use of these agents in the eyes has been linked to a small increase in the risk of systemic thromboembolic events, which can be serious in some cases. Additionally, biosimilars can also cause immunologic reactions when injected intraocularly. In 2015, 2017, and 2019, there were reports of sterile endophthalmitis following Razumab injections.^[18] In the first real-world data on the safety of 9406 IVRz, the rate of serious adverse events was 0.61%, which included one patient with infectious endophthalmitis, two with sterile vitritis, and 12 with non-fatal thromboembolic events.^[19] However, we found no cases of serious ocular or systemic adverse events following Razumab injection in our study.

The major limitations of the current study include a limited follow-up and lack of comparative group undergoing intravitreal therapy with the branded ranibizumab, Lucentis. Despite these limitations, the results reported here represent the first real-world data regarding the safety and efficacy of the ranibizumab biosimilar (Razumab) as an economical alternative to the innovator molecule (Lucentis) in the backdrop of the COVID-19 pandemic. With the biologics', including Lucentis and Eylea, patents on the verge of expiry and biosimilar acceptance growing, countries may shift away from branded drugs and toward biosimilars.

Conclusion

To conclude, IVRz therapy appears to be safe and effective in the treatment of a variety of macular pathologies, according to our real-world data. Management with this regulatory approved biosimilar agent can be considered for both treatment-naïve eyes and previously-treated ones as a cost-effective option to the other pricier anti-VEGF agents. This is especially true for patients who are financially strained due to the economic fallout of the COVID-19 pandemic. At the same time, further studies are warranted to evaluate the health economics of anti-VEGF therapy with biosimilar agents in comparison to branded agents. They may throw further insights into the benefit-cost analysis of these agents and help in the national healthcare policy formulations.

Source of Funding

None.

Conflict of Interest

None.