PCV is an abnormality in choroidal vasculature which results in recurrent serous exudation and hemorrhages . Furthermore, increased levels of VEGF are observed in the affected eyes of patients with PCV. Thus, anti-VEGF agents are a valuable treatment option for PCV. Anti-VEGF agents can reduce the IRF and the SRF and aid in the restoration of macular morphology and visual function. Although PDT has shown excellent results in PCV, its availability is quite challenging. Moreover, it is associated with a few disadvantages, such as the risk of choroidal ischemia and atrophy, RPE rips, hemorrhages (subretinal, vitreous, suprachoroidal), its unsuitability for the treatment of multiple, widely distributed lesions, and its poor results for patients with substantial PED or submacular hemorrhage.
The efficacy of the innovator ranibizumab molecule in PCV patients has been well established by the EVEREST and the LAPTOP [7, 8] studies. However, the role of the biosimilar agent Razumab in the management of PCV remains unexplored. Our study demonstrated the equivalence in efficacy between the BRm and IRm when administered for treatment of PCV, which has never been evaluated before. Both the two ranibizumab molecules showed no significant difference in visual acuity and residual fluid (IRF/SRF) at week 52 in our real-world study.
In our real-world study, the patients were treated on a PRN basis after the initial three loading doses of injection in both arms. Even though both medications displayed comparable efficacy in terms of vision after the loading dosage, the BRm eyes had more residual IRF than the IRm eyes. This could be attributable to a greater proportion of eyes with IRF at baseline in this group. The higher number of previously treated PCV eyes could explain this finding in the BRm arm at baseline. These eyes most likely had persistent IRF, and because the patented ranibizumab is expensive, patients may have chosen the more economical option, Razumab. This difference in residual IRF, on the other hand, was not found at weeks 24, and 52, respectively. This observation indicates that the BRm is effective at resolving the fluid, however, the response may be delayed. The presence of resistant PCV could also have influenced this observation as this group included significantly more eyes with previous anti-VEGF treatment in comparison to predominantly treatment naïve eyes in the IRm group. Further long-term prospective studies with this novel biosimilar (Razumab) in the management of treatment-naïve PCV will throw further insights into its efficacy on fluid resolution.
Neither of the ranibizumab molecules demonstrated any significant difference in visual acuity between them at all visits until week 52. Improvement in BCVA from the baseline until week 52 was noted in both the groups, although it did not attain statistical significance in the BRm eyes. The presence of a greater number of previously treated eyes and/or more eyes having IRF at baseline in the BRm group can account for the lack of significant visual improvement in these eyes. Indeed, the presence of IRF has a greater bearing on the final visual outcomes as demonstrated by multiple studies. Even though data on comparison of biosimilar ranibizumab with innovator ranibizumab in PCV do not exist; a comparison of both these agents in neovascular AMD has been reported. While one study involving the same biosimilar used in this study found similar efficacy with the reference ranibizumab at 8 weeks , the other comparative phase 3 study involving another biosimilar (SB11, Samsung Bioepis Co. Ltd, South Korea) demonstrated equivalence in safety and efficacy at 8 weeks in eyes with neovascular AMD . At 12 months, the present comparative study has the longest follow-up evaluation.
PCV belongs to the pachychoroid disease spectrum characterized by increased CT and/or presence of underlying pachyvessels. An anti-VEGF agent with the ability to alter the choroidal morphometry can conceivably modify the underlying disease. In our study, the SFCT was reduced significantly at week 52 after treating with the biosimilar agent but not with the innovator molecule. These results are encouraging and further studies evaluating the changes in choroidal biomarkers on multimodal imaging after treating with the BRm are warranted to validate our findings.
While using anti-VEGF medicines, ocular and systemic safety remains a concern. Endophthalmitis caused by IRm and aflibercept has been estimated to be 0.35%. Simultaneously, the use of BRm has been fraught with difficulties due to the occurrence of sporadic episodes of sterile endophthalmitis. In our real-world study, the presence of mild intraocular inflammation (IOI) was seen in one eye (5.26%) after BRm injection which resolved with topical steroids. This is a concern with biosimilars where impurities such as endotoxin levels often influence these reactions. Though this problem is now less relevant due to the stringent quality processes, a distant concern remains. Monitoring these patients in the post-injection period is essential. No additional safety concerns, either ocular or systemic, were noted with the BRm- and IRm-treated patients.
The mean number of injections in the IRm arm was significantly greater than in the BRm eyes. Since the patients were advised PRN regimen after the initial loading doses, the likelihood of dropout is greater as compared to other regimens such as the treat-and-extend. Also, patients in the BRm arm had received a significantly greater number of injections prior to switching to the biosimilar agent. The chronicity of the condition in these BRm group eyes, as well as the related cumulative expense of treatment, meant that these patients were more likely to discontinue the therapy. In developing countries such as India, the expense of an anti-VEGF treatment regimen can be a major determinant of long-term compliance. The per-dose cost of the FDA-approved agents, including Lucentis ($320), Eylea ($760), and Beovu ($380), is quite high in India considering the low per-capita GDP ($1900). Although bevacizumab is more economical ($40 per dose), its compounding and labeling issues limit its broader acceptance. Approved biosimilars such as Razumab, which are cost-effective ($125) and packaged as a single-use vial, make them an attractive anti-VEGF agent in the retinal physician’s armamentarium. Biosimilar products can add to cost savings in health care systems and facilitate patients' access to therapy . Therefore, a safe and effective biosimilar may decrease the cost of therapy and allow patients to have a greater chance of receiving a full-fledged standardized protocol of treatment with better compliance and therefore effective treatment regimen. Razumab seems to be well placed in this regard. In India, more than 200,000 Razumab injections had been administered as of December 2021. Since PCV is more prevalent in the Asian population, treatment options which are as effective and more economical than the previously practiced options are essential. We would like to recommend larger RCT’s to be conducted for further evaluating the efficacy and safety of biosimilar Razumab in PCV.
The generalizability of the outcomes from this study is upheld by its consistency with those of past studies of ranibizumab like EVEREST, LAPTOP, and PLANET study [7, 8, 11] in terms of mean changes in visual as well as anatomical outcomes. Although the randomized controlled trials provide a good platform for developing management regimens for vitreoretinal disorders, their broad use is limited because they may not fully reflect real-world delivery settings and population diversity. In PCV, proof from the real-world practice settings shows that patients might be undertreated and receive fewer anti-VEGF injections than recommended, irrespective of the treatment regimen. This results in lower efficacy than observed in clinical trial settings, as observed from our results.
The limitations of the current study include the retrospective design and limited sample size. Also, the details of the patients who had received previous treatments before the timeline was not captured. Furthermore, because the biosimilar arm has fewer treatment-naive patients than the innovator arm, the biosimilar arm may have had suboptimal outcomes. Despite these limitations, this study is the first to compare the safety and efficacy of the two licensed ranibizumab molecules in patients with PCV. The longer follow-up period of 1 year is a major strength of the study. Long-term prospective studies are proposed to further examine the function of BRm in the management of PCV, both treatment-naïve and resistant cases, in comparison to other anti-VEGF agents, namely IRm, Eylea, and Beovu.