International Journal of Ophthalmology & Eye Science (IJOES) IJOES-2332-290X-06-401

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

(Major) Sharma S1*, RE-ENACT Study Investigators Group2, Khan MA3, Chaturvedi A3

1 Medical Lead - Ophthalmology, Medical Services, Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.
2 RE-ENACT Study Investigators Group.
3 Medical Services, Intas Pharmaceuticals Ltd., Ahmedabad, Gujarat, India.

*Corresponding Author

Dr. (Major) Shashikant Sharma, MD,
Medical Lead, Ophthalmology, Medical Services,
Intas Pharmaceuticals Ltd. Ahmedabad, Gujarat, 380054, India.
E-mail: shashikant_sharma@intaspharma.com

Received: May 17, 2018; Accepted: June 12, 2018; Published: June 13, 2018

Citation: (Major) Sharma S, RE-ENACT Study Investigators Group, Khan MA, Chaturvedi A. 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 Ophthalmol Eye Res. 2018;6(4):377-383. doi: dx.doi.org/10.19070/2332-290X-1800076

Copyright: (Major) Sharma S© 2018. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.

Abstract

Purpose: To evaluate the effectiveness of Razumab® (world’s first biosimilar ranibizumab; Intas Pharmaceuticals Ltd., India) in Indian patients with wet age-related macular degeneration (wet AMD), diabetic macular edema (DME) and retinal vein occlusion (RVO).

Methods: RE-ENACT, a retrospective, multicenter study, analyzed pooled data of patients with wet AMD, DME, and RVO. Patients who had received ≥3 injections of Razumab® between January and August 2016, were included. Endpoints were: improvement in best corrected visual acuity (BCVA, measured by logMAR/Snellen’s chart), decrease in central macular thickness (CMT, measured by Spectral Domain Optical Coherence Tomography), and proportion of patients with intraretinal fluid (IRF) and subretinal fluid (SRF) at Weeks 4, 8 and 12.

Results: Of 561 patients included, 348 (62.04%) were men. Mean ± SE BCVA improved from baseline (0.75 ± 0.01) to Week 4 (0.72 ± 0.01, p = 0.0318), attained significance at Week 8 (0.59 ± 0.01, p < 0.0001), which was maintained at Week 12 (0.49 ± 0.01, p < 0.0001). Mean ± SE CMT significantly (p < 0.0001) decreased from baseline (418.47 ± 4.78μm) to Weeks 4 (407.35 ± 4.65μm), 8 (342.10 ± 3.66μm), and 12 (301.17 ± 2.82μm). Proportion of patients with IRF and SRF significantly (p < 0.0001) decreased from baseline to Weeks 4, 8 and 12 (67.02% vs. 48.48%, 42.60%, and 34.22%, respectively for IRF; and 72.37% vs. 48.48%, 37.97%, 31.37%, respectively for SRF). No new safety concerns with biosimilar ranibizumab were observed.

Conclusions: Razumab® is effective in reducing macular thickness and improving visual acuity in patients with wet agerelated macular degeneration, diabetic macular edema, and retinal vein occlusion in routine clinical practice. Razumab® demonstrated considerable effectiveness with no new safety concerns.

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1.Keywords
2.Introduction
3.Methods
    3.1 Study Design and Population
    3.2 Statistical Analysis
4.Results
    4.1 Patients Disposition and Demographics
5.Discussion
6.Limitations
7.Acknowledgments
8.Competing Interests
9.Funding
10.RE-ENACT Study Investigators Group
11.References

Keywords

Razumab; Wet Age-Related Macular Degeneration; Diabetic Macular Edema; Retinal Vein Occlusion; Wet AMD; DME; RVO.

Introduction

Ranibizumab is a recombinant, humanized fragment of a murine monoclonal antibody that binds to the vascular endothelial growth factor (VEGF)-A and subsequently improves the visual acuity (VA). It has become the preferred treatment for various retinal disorders, including wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) [1-3].

Neovascular or wet AMD is one of the major causes of vision impairment worldwide [4]. Intravitreal anti-VEGF drugs including ranibizumab, are the current gold standard for wet AMD management [5]. Several studies have shown the efficacy and safety of ranibizumab in the treatment of wet AMD including pivotal long-term Phase III MARINA [2] and ANCHOR [1] studies. Diabetic macular edema is the most common complication of diabetic retinopathy [6] and is a major cause of vision loss in the working population [7]. The treatment of DME has evolved with anti-VEGF agents; amongst which ranibizumab is the first approved agent for DME treatment [6]. Several short- and long term clinical studies including the READ [8], RESOLVE [9], RESTORE [10], RETAIN [11], RISE and RIDE [12], RELIGHT [13], and TREX studies [14] have confirmed the efficacy and safety of ranibizumab in the treatment of DME. Retinal vein occlusion (RVO) is a common cause of unilateral, sudden and painless loss of vision. Increase in the VEGF levels are observed in the ocular fluid of RVO (BRVO or CRVO) patients, which is proportional to the severity of macular edema [15]. The approval of ranibizumab for the treatment of macular edema secondary to RVO was based on the results of the Phase III BRAVO [16] and CRUISE [17] studies.

Ranibizumab is approved for the treatment of several choroidal vascular complications i.e., wet AMD, DME, RVO, and mCNV. The innovator ranibizumab is quite an expensive treatment option [18]; hence, the world’s first biosimilar of ranibizumab - Razumab ® was developed by Intas Pharmaceuticals Ltd., India, as a cost-effective alternative, and is approved by the Drug Controller General of India.

Razumab® has been approved for the treatment of wet age-related macular degeneration (wet AMD), diabetic macular edema (DME), macular edema following retinal vein occlusion (RVO), and visual impairment due to choroidal neovascularization (CNV) secondary to pathological myopia. The efficacy and tolerability of Razumab® has been documented in the treatment of wet AMD, RVO, and DME in Indian patients in a prospective study [18]. However, these data may not completely reflect the conditions found in routine clinical settings due to their restrictive design and strict inclusion and exclusion criteria. Hence, the effectiveness of Razumab® in Indian patients was evaluated in the RE-ENACT study. This was a retrospective, multicenter, observational study in patients with wet AMD, DME and RVO. The subgroup analyses from the RE-ENACT study for wet AMD and RVO populations have been published elsewhere [19, 20]. This report presents the effectiveness of Razumab® in Indian patients from the pooled data of patients with wet AMD, DME, and RVO.

Methods

Study Design and Population

The complete methodology of this study has been published earlier with the results of the subgroup analyses [19, 20] and briefly described here. This observational, organized study analyzed the data of patients who had received treatment with Razumab® for the treatment of wet AMD, DME or RVO at different centers across India between January and August 2016. Adult patients who received at least three injections (4-weekly) of Razumab® were included in the study. Endpoints included the mean change in the best corrected visual acuity (BCVA) and central macular thickness (CMT), and proportion of patients with no intraretinal fluid (IRF) and subretinal fluid (SRF) from baseline to Weeks 4, 8 and 12.

The BCVA is defined as the measurement of clarity of central vision which was measured by Snellen’s chart and converted to logarithm of the minimal angle of resolution (logMAR) scale for statistical analysis. The CMT is the distance between the inner limiting membrane (ILM) and the inner boundary of retinal pigment epithelium (RPE), which was measured using spectral domain optical coherence tomography. Subretinal fluid corresponds to the accumulation of clear or lipid-rich exudates (serous fluid) in the subretinal space, i.e., between the neurosensory retina (NSR) and the underlying retinal pigment epithelium (RPE), in the absence of retinal breaks, tears, or traction. Intraretinal fluid consists of contiguous fluid-filled spaces containing columns of retinal tissue.

Statistical Analysis

Best corrected visual acuity and central macular thickness data were analyzed using two-tailed paired t-test. Intraretinal fluid and subretinal fluid data were analyzed using χ2 test. Mean % change in BCVA and CMT was calculated as an average value of % change from baseline to a particular visit. All statistical analyses were done using SAS 9.3 or higher.

Results

Patients Disposition and Demographics

Data of 561 patients (348 [62.04%] men and 213 [37.96%] women) was analyzed. The spectrum of indications included wet AMD in 194 (34.59%) patients, DME in 207 (36.89%) and RVO in 160 (28.52%) patients. The majority (335, 59.71%) of the patients were treatment naïve and 217 (38.68%) patients were previously treated with other anti-VEGF/steroids/laser treatment. A total of 66.84% (375/561) of the patients had diabetes and 56.32% (316/561) had hypertension; history of smoking was present in 10.16% (57/561) patients. At baseline, IRF was present in: left eye, 40.1% (225/561) patients and right eye, 31.01% (174/561) patients; SRF in: left eye, 41.17% (231/561) patients and right eye, 35.82% (201/561) patients. The baseline characteristics of the patients are summarized in Table 1.

Table 1. Patients Disposition and Baseline Characteristics.

An improvement in the mean ± SE logMar BCVA scores indicating improved visual acuity was observed from baseline (0.75 ± 0.01) to Week 4 (0.72 ± 0.01; p = 0.0318), which attained significance at Week 8 (0.59 ± 0.01) and maintained till Week 12 (0.49 ± 0.01; p < 0.0001 for both time points). Biosimilar ranibizumab led to a rapid and continuous improvement in visual acuity, with benefits observed as early as Week 4 (Figure 1). From baseline, the mean % change in the BCVA was 0.36% at Week 4, 16.75% at Week 8, and 28.42% at Week 12 (Figure 2).

Figure 1. Mean ± SE BCVA (logMAR) at baseline and Weeks 4, 8 and 12 after biosimilar ranibizumab administration.

Figure 2. Mean % change in BCVA from baseline to Weeks 4, 8 and 12 after biosimilar ranibizumab administration.

Similarly, significant improvement in disease condition as measured by a decrease in mean ± SE CMT scores was observed from baseline (418.47 ± 4.78μm) to Weeks 4 (407.35 ± 4.65μm), 8 (342.10 ± 3.66μm) and 12 (301.17 ± 2.82μm); P < 0.0001 for all time points (Figure 3). From baseline, the mean % change in CMT was 2.02% at Week 4, 16.06% at Week 8 and 25.23% at Week 12 (Figure 4).

Figure 3. Mean ± SE CMT (μm) at baseline and Weeks 4, 8 and 12 after biosimilar ranibizumab administration.

Figure 4. Mean % change in CMT from baseline to Weeks 4, 8 and 12 after biosimilar ranibizumab administration.

A significant reduction in the proportion of patients having IRF or SRF from baseline to all the time points (Weeks 4, 8 and 12) were observed, indicating improved disease condition. The percentage of patients having IRF at baseline vs. Weeks 4, 8 and 12 were 67.02% vs. 48.48%, 42.60%, and 34.22%, respectively (P < 0.0001 for all). The percentage of patients having SRF at baseline vs. Weeks 4, 8 and 12 were 72.37% vs. 48.48%, 37.97%, 31.37% respectively (P < 0.0001 for all) (Figure 5).

Figure 5.Proportion of patients with IRF and SRF at baseline and Weeks 4, 8 and 12 after biosimilar ranibizumab administration.

Discussion

Anti-VEGF agents have dramatically changed the treatment of retinal diseases which may progress to blindness. These agents provide a great treatment option for patients to preserve their sight as they are known to improve vision along with the prevention of vision loss leading to significantly improved prognosis and outcomes, and eventually improved quality of life [21-25].

The efficacy and tolerability of ranibizumab have been demonstrated in several multi-center, randomized, prospective studies, and it has become the first-choice treatment for various retinal disorders including wet AMD, DME, and RVO. Differences in the treatment outcomes have been observed with innovator ranibizumab in real-world clinical practice than those seen in its controlled clinical trials [26, 27]. Hence, it was necessary to have the real-world clinical data with ranibizumab. RE-ENACT, a retrospective data collection study sought to investigate the ‘real-world’ clinical effectiveness of Razumab® in the treatment of patients with wet AMD, DME, and RVO with the results pooled from all the 3 indications. Pooled data are scarce in the public domain and this is one of the few studies to provide pooled analysis of the data to understand the effectiveness of ranibizumab. The pooled results showed that BCVA improved from baseline indicating improvement in the visual acuity as early as after the 1st injection and attained significance after the 2nd injection and maintained after the 3rd injection of biosimilar ranibizumab. The CMT values decreased showing significant improvement in the disease condition after the 1st biosimilar ranibizumab injection (Week 4), that was maintained till Weeks 8 and 12. Furthermore, improvements in the subretinal fluid (SRF) and intraretinal fluid (IRF) were also seen at all time points. The results for reduction in macular thickness and improvement in visual acuity for pooled data are in consistence with the subgroups analyses of the RE-ENACT study on wet AMD [19] and RVO [20] populations published earlier. Similarly, in a study conducted in 100 Indian patients with wet AMD, DME, and RVO, ranibizumab treatment showed a significant improvement in the visual acuity (measured by Snellen’s chart) in the majority of the patients [22]. Furthermore, a recent study conducted in Indian patients (n=95) with wet AMD, DME, and RVO demonstrated that biosimilar ranibizumab treatment improved the visual acuity and disease outcomes (measured by BCVA and CMT). The treatment was well tolerated over a month and there was no ocular and systemic toxicity detected [18].

These ophthalmological indications are generally chronic, requiring long-term administration of anti-VEGF treatment, with few studies evaluating the effects up to 5-years [28]. Ranibizumab has shown to be effective for improvement in visual functions, and the reduction of intraretinal and subretinal fluids [23]. The current study, which was only for a duration of 3 months, demonstrated marked improvements in BCVA, CMT, SRF and IRF as early as 4 weeks of biosimilar ranibizumab administration with lasting benefits till 12 weeks follow-up.

Ranibizumab has shown to be effective for not only preventing vision loss, but also for significant gains in visual activity, and has been considered as the standard of care [1, 2, 29]. In clinical studies (including ANCHOR, MARINA, RESTORE, BRAVO, and CRUISE), patients with wet AMD, DME, and RVO treated with ranibizumab had a marked improvement in their visual acuity scores. In the current study, the visual acuity improved (as measured by BCVA) in patients with wet AMD, DME, and RVO at each time point. The results are consistent with the findings from earlier studies in wet AMD patients in which improvement in the visual acuity was observed as early as after the first dose, which was maintained at 3 months [30]. Similar results have been demonstrated by other studies in real-world settings including retrospective [31], and a multi-centre, prospective, observational post-marketing surveillance study [32].

Similar to our study, previous reports in DME patients have also demonstrated improvement in the BCVA scores starting at 1 month of ranibizumab, which was maintained till 3 months [33-35]. For patients with RVO, studies have demonstrated a significant improvement in BCVA, sustaining over 12 months with ranibizumab treatment [15, 16, 36]. Another prospective randomized study (RABAMES) showed improvements in the logMAR BCVA at Weeks 4, 8 and 12 after ranibizumab treatment in 30 patients with BRVO [37]. Ranibizumab was associated with improved BCVA till 6 months in macular edema after BRVO. The short-term effects of ranibizumab were positively correlated with long-term improvements [38].

The visual acuity is worsened with very thin or thick retinas, thick subretinal tissue, atrophy, and scar [39]. A greater central macular thickness is indicative of ganglion cell damage due to traction in the ganglion, and a pharmacological treatment is expected to decrease the CMT with an accompanying increase in the visual acuity [39, 40]. In our study, a significant decrease in the CMT values were seen with biosimilar ranibizumab treatment, which are consistent with the findings from earlier studies in patients with wet AMD [41, 42], DME [43] and RVO [44].

The presence of IRF and SRF is a predictor of a worse visual acuity [45, 46]. Biosimilar ranibizumab has shown a consistent decrease in both the IRF and SRF values from baseline to Weeks 4, 8 and 12 endpoints in the current analysis. Previously reported studies with innovator ranibizumab have also demonstrated a decrease in IRF and SRF after ranibizumab administration in wet AMD [45], DME [47], and RVO patients [48]. There was a reduction in the proportion of patients having IRF or SRF after biosimilar ranibizumab treatment, similar to that seen in other prospective studies with innovator ranibizumab [45].

Limitations

Details pertaining to the bilaterality, previous treatments, ischemia and severity of the disease were not captured in the medical records and therefore could not be included in this study due to its retrospective nature. Another limitation is the short duration of the study at 3 months but still, the study results provide a clear picture about the effectiveness of the biosimilar ranibizumab in the real-world setting. Furthermore, in this study, visual acuity measurement was done by logMAR BCVA/Snellen’s values, which is considered inferior to ETDRS [49].

Since this study is retrospective in nature, the complete information on adverse events was not captured in the medical records and hence, not used in the analysis. However, there were no new safety concerns compared to what is known for the innovator product as per published information or no AEs were reported that were severe in nature.

Overrall, the intravitreal injection of Razumab® improved the visual acuity and decreased the macular thickness without new safety concerns in patients with wet age-related macular degeneration, diabetic macular edema, and retinal vein occlusion in the real-world setting.

Acknowledgments

The authors thank Mr. Shreekant Sharma (Lambda Therapeutic Research Ltd.) for providing writing assistance and Dr. Venugopal Madhusudhana (Lambda Therapeutic Research Ltd.) for additional editorial assistance for the development of this manuscript. The authors also thank the clinical data management and biostatistics department of Lambda Therapeutic Research Ltd. for their contribution in the preparation of statistical analysis report in this retrospective data collation and analysis.The authors are thankful to Dr. Ramandeep Sharma (Intas Pharmaceuticals Ltd.) for the conceptualization of the RE-ENACT study. The authors also thank Mr Tanishq Sharma (Shree Krishna Hospital and Pramukhswami Medical College, Karamsad, Anand, Gujarat, India) for conceptualization of the RE-ENACT study and also providing support for data collection and analysis.

Competing Interests

Drs. Shashikant Sharma, Mujtaba Khan, and Alok Chaturvedi are employees of Intas Pharmaceuticals Ltd, Ahmedabad.

Funding

RE-ENACT Study Investigator Group received an honorarium from Intas Pharmaceuticals Ltd. for their patient data contribution.

RE-ENACT Study Investigators Group

1. Dr. Manjunath Bhaskar Anandkumar, MS; Ganesh Netralaya, Sirsi, Karnataka, India, 581401. Email:manj009@gmail.com
2. Dr. Naresh Yadav, FRCS; Narayana Nethralaya Bengaluru, Karnataka, India, 560010. Email: vasudha.naresh@gmail.com
3. Dr. Vaibhav Shrivastava, MS; Shradha Eye Care, Kolkata, West Bengal, India, 700038. Email: vaibhav.shrivastava.28@gmail.com
4. Dr. Pasupathy Elankumaran, MD; Navasakthi Netralaya Bengaluru, Karnataka, India, 560043. Email: drelankumaran@gmail.com
5. Dr. Shrinivas Joshi, MS; MM Joshi Eye Institute Hubli, Karnataka, India, 580031. Email: shrinivasmjoshi@gmail.com
6. Dr. Subijay Sinha, MD; Susrut Eye Hospital Kolkata, West Bengal, India, 700106. Email: subijay.sinha@gmail.com
7. Dr. Ananyabrata Das, DOMS; Spectra Eye Hospital Kolkata, West Bengal, India, 700136. Email: drananyabrata@yahoo.com
8. Dr. Naveenam Srinivasa Muralidhar, MS; Retina Institute of Karnataka, Bengaluru, Karnataka, India, 560018. Email: retina. nsm@gmail.com
9. Dr. Sangita Jain, MS; Dev Bhumi Superspeciality Hospital, Dehradun, Uttarakhand, India, 248001. Email: sangitavrs@yahoo.co.uk
10. Dr. Prosenjit Mondal, MS; Susrut Eye Hospital Kolkata, West Bengal, India, 700106. Email: drprosenjit2007@gmail.com
11. Dr. Hemanth Murthy, MS; Retina Institute of Karnataka Bengaluru, Karnataka, India, 560018. Email: hemanthmurthy@yahoo.com
12. Dr. Alay Banker, MS; Bankers Retina Clinic Ahmedabad, Gujarat, India, 380014. Email: alay.banker@gmail.com
13. Dr. Nishikant Borse, MS;Insight Eye Clinic Mumbai, Maharashtra, India, 400014. Email: nishikantborse@yahoo.com
14. Dr. Girish Rao, MS; Sri Ganpati Netralaya, Jalna; Maharashtra, India, 431203. Email:drgr1968@gmail.com
15. Dr. Rajender Pal Singh, MD; Visitech Eye Centre Delhi, India, 110025. Email: rp@visitech.org
16. 16. Dr.Gunjan Prakash, MD; SPG Medicare & Diagnostics Agra, Uttar Pradesh, India, 282005. Email:gunjanprakash@gmail.com

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