Retrospective analysis of outcomes of biosimilar ranibizumab (BSR) in treating cystoid macular oedema (CME) in ischaemic central retinal venous occlusion (CRVO)

INTRODUCTION

Retinal vein thrombosis is strongly associated with age-related local and systemic factors. Central retinal venous occlusion (CRVO) is a retinal vascular condition that affects an estimated 16 million people worldwide.^[1] The second most common retinal vascular disease is retinal vein occlusion after diabetic retinopathy. CRVO is classified into ischaemic CRVO and non-ischaemic CRVO.^[2] Atherosclerotic changes of the central retinal artery cause occlusion of central retinal veins as the central retinal vein and artery possess a common sheath at crossing points, which are posterior to lamina cribrosa. The pathophysiology of CRVO involves ischemia through occlusion of the lumen of the central retinal vein, which triggers and upregulates expression of vascular endothelial growth factor (VEGF) on messenger Ribonucleic acid (mRNA), which, further tends to increased levels of VEGF in the vitreous along with other inflammatory mediators such as interleukin 6 and 8 and monokine.^[3-5] Elevated levels of VEGF play a key role in causing macular oedema and neovascularisation, which subsequently leads to vision loss. Therefore, inhibition of VEGF with anti-VEGF like ranibizumab is important in managing macular oedema secondary to CRVO.^[6] Ischaemic CRVO tends to cause ischaemic macular oedema and neovascular glaucoma, which are poor responders to treatment. Few studies are there that show the effectiveness of ranibizumab in ischaemic CRVO. Ranibizumab is a humanised monoclonal antibody that binds and inactivates VEGF-A and VEGF-B. The innovator ranibizumab molecule has a major obstacle for public use in terms of its high cost. Furthermore, the fact that CRVO is a disease which might require intravitreal ranibizumab injections at regular intervals further enhances the treatment cost. In India, an average innovator ranibizumab costs around 322 USD in contrast to biosimilar ranibizumab (BSR), will costs around 175 USD.^[7] BSR molecules are very similar to an innovator biological product in terms of clinical efficacy, immunogenicity and biosafety. This study is conducted to evaluate the efficacy of BSR in treating cystoid macular oedema (CME) in patients of ischaemic CRVO in developing countries like India, especially in government hospitals.

MATERIALS AND METHODS

A retrospective observational study was carried out among all the patients diagnosed with ischaemic CRVO over 6 months.

Diagnostic criteria for ischaemic CRVO include visual acuity (<6/60), >grade 2 relative afferent pupillary defect pupillary reaction, and multiple capillary non-perfusion areas (>10 Disc diameter) on fundus fluorescein angiography.^[2]

Inclusion criteria include patients aged ≥18 years with macular oedema who fulfil the diagnostic criteria of ischaemic CRVO and who have followed up for 6 months.

Patients having a history of recent myocardial infarction and stroke within the past 1 year, had a history of intravitreal injection in the past 3 months and with any other ocular comorbidities such as dense cataract, glaucoma and optic disc disorders were excluded from this study.

In our study, ten cases diagnosed with ischaemic CRVO having CME were treated with three doses of intravitreal BSR injection (Ranieyes^™ – Lupin Pharma-No Financial Disclosure) (0.05 mL) 1 month apart. The landing cost of BSR to the patient in our institute is 6000 rupees per injection. The patient was followed up after 1 month, 3 months and 6 months post 1^st dose injection. At all the visits, efficacy was evaluated in the form of the patient’s central foveal thickness (CFT) on spectral domain optical coherence tomography (OCT) and visual acuity.

Ocular side effects, such as periocular pain and any signs of inflammatory reactions like redness, were checked at each follow-up visit. Systemic adverse effects such as myocardial infarction and stroke were checked at every visit and the end of 6 months.

RESULTS

Table 1 shows significantly improved visual acuity at 3 and 6 months post-first injection (i.e., P < 0.05). After 1^st dose of BSR, there was no significant improvement in visual acuity (i.e., P = 0.07).

Table 2 shows a significant reduction in the mean CFT (i.e., P < 0.05) after 1, 3 and 6 months post 1^st dose of BSR.

The landing cost of BSR is 6000 rupees per injection and that of innovator ranibizumab is 20,000 per injection to the patients in our institute. In our study, three doses of ranibizumab were given, which cost around 18,000 rupees for three doses of BSR and 60,000 rupees for three doses of innovator ranibizumab which clearly shows that BSR is cheaper and a low-cost alternative as compared to innovator ranibizumab in a government hospital like our institute.

No ocular side effects such as periocular pain, any signs of inflammation such as redness were noted or no systemic adverse events such as thromboembolic events, stroke and myocardial infarction were noted during the study period.

DISCUSSION

Anti-VEGF agents have been found to be beneficial in patients with ischaemic CRVO in treating macular oedema and improving vision. It, further, prevents vision loss which results in better prognosis and outcomes. Ranibizumab, a humanised monoclonal antibody fragment, binds at the receptor site and, thus, prevents interaction of VEGF present on the endothelial surface, which will further decrease the proliferation of endothelial cells, vascular leakage and neovascularisation.^[8,9] Innovator ranibizumab is a high-cost molecule that has been a concern for use in healthcare. To overcome this, BSR, a molecule similar to the reference product, is derived, which has comparable pharmacokinetics, pharmacodynamics, immunogenicity, safety and efficacy to the biological reference product.^[10,11] In the present study, the mean CFT shows significant reduction (i.e., P < 0.05) after 1, 3 and 6 months post 1^st dose of BSR with significantly improved visual acuity after 3 and 6 months post 1^st dose of BSR (i.e., P < 0.05). After 1 month of BSR, there was no significant improvement in visual acuity (i.e., P = 0.07).

In the real life assessment of safety and effectiveness of razumab 2 (RE-ENACT 2) study, the visual acuity and CFT improvement, as measured by logarithm of the minimum angle of resolution (logMAR) best corrected visual acuity (BCVA) and OCT-domain, respectively, was significant with BSR starting at week 4 and throughout 48 weeks (i.e., 12 months), which was similar to our study conducted for over 6 months except for the statistical improvement which was not seen in BCVA after 1^st dose of BSR injection. ^[12-14]

A Phase 3, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection compared with sham in patients with macular edema secondary to CRVO. The CRUISE studies also demonstrated similar results with significant improvements in BCVA sustained over 12 months in patients with CRVO.^[15]

As in ischaemic CRVO, photoreceptor cells are damaged so in spite of a decrease in macular oedema; there would only be a qualitative visual improvement and not quantitative visual improvement. The standard cost of the innovator ranibizumab (three injections) to the patients is around 60,000 rupees as compared to BSR (three injections) which is around 18,000 rupees.^[16] Thus, BSR has shown to be a cost-effective alternative for economically poor people attending tertiary care centres and thus preventing ischaemic maculopathy and neovascular glaucoma, which is a complication of untreated ischaemic CRVO.

A retrospective study design with a small sample size and a short-term follow-up of 6 months was limitations of this study.

CONCLUSION

BSR is a low-cost alternative to conventional therapy in treating ischaemic CRVO to reduce CFT with moderate visual gain, especially in a tertiary care centre.