|Year : 2020 | Volume
| Issue : 3 | Page : 154-158
Clinical effectiveness and safety of razumab (a biosimilar of ranibizumab)
Sriram Gopal1, Supraja Kasturirangan1, Nivean Madhivanan2, Henderson Henry2, Pratheeba Devi Nivean2, Sangeetha Shekharan2
1 Athreya Retinal Centre, Dr. VAS Hospital, Tiruchirapalli, Tamil Nadu, India
2 M.N. Eye Hospital, Chennai, Tamil Nadu, India
|Date of Submission||19-Apr-2020|
|Date of Decision||06-May-2020|
|Date of Acceptance||20-Jul-2020|
|Date of Web Publication||14-Sep-2020|
Dr. Henderson Henry
781, Thiruvottiyur High Road, Opposite Tondiarpet Police Station, Tondiarpet, Chennai - 600 021, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Context: This study was done to evaluate the effectiveness and safety of biosimilar Razumab for the treatment of diabetic macular edema (DME), neovascular age related macular degeneration (ARMD), and cystoid macular edema (CME) due to retinal vein occlusions (RVOs) and to assess the central foveal thickness (CFT) and LogMAR best corrected visual acuity(BCVA) post Intravitreal Anti- VEGF Razumab at the end of 1 month from the baseline values. Aims: The purpose of this study was to evaluate the safety and efficacy of intravitreal biosimilar Razumab© in the treatment of wet ARMD, DME, and RVOs. Settings and Design: This was a retrospective, observational study which was conducted in a tertiary eye care institute in Tamil Nadu. Subjects and Methods: Three hundred and nine patients having active or previously treated retinal vascular conditions including neovascular ARMD, DME, and CME due to RVO were subjected to best-corrected visual acuity (BCVA) using LogMAR charts, Goldmann applanation tonometry to measure intraocular pressures, slit-lamp biomicroscopy, indirect ophthalmoscopy, color fundus photography, and spectral-domain optical coherence tomography at baseline and 1 month postintravitreal injection Razumab©, respectively. Statistical Analysis Used: Microsoft Excel was used to enter the data of the findings, and the analysis was done using SPSS 22 version software (IBM, SPSS Inc.,Chicago,IL). Frequencies and proportions were used to enter the categorical data. Chi-square was used as a test of significance. Continuous data were represented as mean and standard deviation. BCVA and CFT data were analyzed using two-tailed paired t-test. Paired t-test is the test of significance for paired data such as before and after injection. P < 0.05 was considered statistically significant. Results: There was a significant improvement in visual acuity and a marked reduction in CFT at the end of 1 month from the baseline values collectively and in each disease pathology. Conclusions: Our study revealed the short-term result of the efficacy of Razumab©, the biosimilar of ranibizumab, as an effective treatment alternative in the management of wet ARMD, DME, and RVO by reducing CFT and improving visual acuity. However, long-term follow-up and repeat injections are required to determine its long-term safety and efficacy.
Keywords: Antivascular endothelial growth factor, biosimilar, diabetic macular edema, ranibizumab, razumab, retinal vein occlusions, wet ARMD
|How to cite this article:|
Gopal S, Kasturirangan S, Madhivanan N, Henry H, Nivean PD, Shekharan S. Clinical effectiveness and safety of razumab (a biosimilar of ranibizumab). TNOA J Ophthalmic Sci Res 2020;58:154-8
|How to cite this URL:|
Gopal S, Kasturirangan S, Madhivanan N, Henry H, Nivean PD, Shekharan S. Clinical effectiveness and safety of razumab (a biosimilar of ranibizumab). TNOA J Ophthalmic Sci Res [serial online] 2020 [cited 2020 Sep 20];58:154-8. Available from: http://www.tnoajosr.com/text.asp?2020/58/3/154/294992
| Introduction|| |
Retinal ischemia inducing neovascularization of the retina and macular edema amounts to certified loss of visual acuity in the working and nonworking populations all over the world. Wet ARMD associated with choroidal neovascularization (CNV), diabetic retinopathy associated with diabetic macular edema (DME), and retinal vein occlusions (RVOs) are some of the leading causes of blindness owing to the above mentioned ocular pathology.
An upregulation of retinal ischemia and hypoxia leads to a surge in vascular endothelial growth factor (VEGF) release and a number of other stimuli. The VEGF concentration in the ocular fluid is increased, which correlates with the severity of macular edema., VEGF is also known to disrupt the blood–retinal barrier, stimulates vascular endothelial growth, and enhancing permeability of these new vessels. Several anti-VEGF agents have been widely used for treating macular edema secondary to DME, RVO, including ranibizumab. Ranibizumab binds to and inhibits VEGF, a key instigator of neovascularization and macular edema. Anti-VEGFs which are now recognized as the primary standard of care involving macular edema due to diabetic retinopathy, retinal vein occlusions and wet ARMD.
Intravitreal ranibizumab has emerged as the primary treatment option for the treatment of retinal vascular diseases. Unfortunately, due to financial constraints, affordability to all patients becomes a factor in many developing countries including India.
The biosimilar ranibizumab (Razumab©: Intas Pharmaceuticals) was thus developed as a cost-effective alternative for this very reason. It is the first ophthalmic biosimilar developed in India, which has been approved by the Drug Controller General of India.
A biosimilar is a biological drug that is prepared to be similar to an existing biological drug (the “reference drug”). The active product of a biosimilar and its reference drug are more or less the same component, although there would slight alterations due to its manufacturing process.
This is where the biosimilar Razumab© mimics its biologic reference drug (Lucentis; Genentech) which also is a recombinant humanized monoclonal murine IgG1 antibody fragment which binds to all isoforms of VEGF thereby used for the treatment of wet ARMD, RVO, DME, and myopic CNV.
Similar to the reference drug, the biosimilar will have few alterations in its basic structure and function but will have an overall similar efficacy and safety.
The purpose of this study was to evaluate the safety and efficacy of intravitreal biosimilar Razumab© in wet ARMD, DME, and RVOs.
This was achieved by observing baseline post anti-VEGF intravitreal injection central foveal thickness (CFT) and visual acuity values, and the same was repeated at the end of 1 month.
A thorough literature search revealed that there has been no prior study involving a large sample of patients with varying pathologies injected with an intravitreal biosimilar evaluating the efficacy of Razumab©.
| Subjects and Methods|| |
Three hundred and nine patients who were included in the study should have had active or previously treated retinal vascular conditions including ARMD as a result of neovascularization, DME, and macular edema due to RVO. Exclusion criteria included any signs of ocular infectious pathology, dense cataracts where the assessment by means of spectral-domain optical coherence tomography (SD-OCT) was not possible, eyes which were vitrectomized, and a previous history of transient ischemic attack (TIA) or myocardial infarction.
Masked ophthalmologists would then carry out a complete comprehensive ocular examination best-corrected visual acuity (BCVA) using standardized LogMAR charts, Goldmann applanation tonometry to measure intraocular pressures, slit-lamp biomicroscopy, and indirect ophthalmoscopy at baseline and 1 month postintravitreal injection Razumab©, respectively.
All patients underwent color fundus photography (Carl Zeiss, Dublin, CA, USA) and SD-OCT (Optovue) at baseline and 1 month after the intravitreal injection.
Patients were thoroughly evaluated for any signs of systemic adverse events such as thromboembolic phenomenon at baseline and 1 month postinjection and a detailed medical history of any medications they might be on. Patients' blood sugar, blood urea, and creatinine were closely monitored as well.
The primary outcome measures included the changes in the changes in BCVA and CFT for all the three pathologies collectively as a whole and each one of them separately as well. They were measured at the baseline prior to intravitreal Razumab© and 1 month postinjection as well.
| Results|| |
Three hundred and nine eyes of 297 patients with retinal pathologies such as wet ARMD, DME, and macular edema secondary to RVOs were enrolled in this study. Two hundred and thirteen patients were male (69.93%) and 96 patients were female (30.07). The mean age of the patients was 61.66 ± 11.702 years for females and 61.80 ± 11.53 years for males [Figure 1]. Two hundred and nine eyes were treatment naïve and 100 had been previously treated with anti-VEGF agents or intravitreal steroids in the past 6 months. There was no significant medical history of any thromboembolic disease or myocardial infarctions. There were no adverse effects (AEs) to any patients on intravitreal injection of biosimilar Razumab©.
The patients who fell into the inclusion criteria were broadly divided into three separate groups to evaluate the efficacy of biosimilar Razumab© for that specific disease pathology, and all the patients' data were collectively pooled to know the net reduction of central macular thickness (CMT) and best corrected visual acuity (BCVA).
The first group included all patients with wet ARMD, the second group had patients with DME, and the third group included all patients with RVO with macular edema.
The mean age of patients in the first group was 64.02; 79 males and 34 females were treated for wet ARMD indication. The mean pretreatment BCVA was 0.77 LogMAR [Figures 2 and 3]. After the first Razumab© injection, the mean BCVA observed after 1 month was 0.67 logMAR, indicating a statistically insignificant improvement in visual acuity [Figures 2 and 3]. The mean pretreatment CFT was 377.59 μm. After the first Razumab© injection, the CFT was reduced to 303.58 μm, indicating significant improvement in the disease condition, after 1 month [Figures 4 and 5].
|Figure 2: Visual acuity assessment – mean increase in best-corrected visual acuity (LogMAR): Indication wise|
Click here to view
|Figure 3: Visual Acuity Assessment-Mean increase in BCVA [LogMar]: Indication-Wise|
Click here to view
The mean age of patients in the second group was 59.78; 91 males and 29 females were treated for DME indication. The mean pretreatment (BCVA) was 0.59 logMAR. After the first Razumab© injection, the mean BCVA observed after 1 month was 0.47 logMAR, indicating significant improvement in visual acuity [Figures 2 and 3]. The mean pretreatment CFT was 393.49 μm. After the first Razumab© injection, the CFT was reduced to 321.70 μm, indicating significant improvement in the disease condition after 1 month [Figures 4 and 5].
The mean age of patients in the third group was 61.53 years; 43 males and 33 females were treated for RVO + ME indication. The mean pretreatment BCVA was 0.63 logMAR for RVO + ME indication. After the first Razumab© injection, the mean BCVA observed after 1 month was 0.39 logMAR, which shows significant improvement in visual acuity [Figures 2 and 3]. The mean pretreatment CFT was 443.80 μm for RVO + ME indication. After the first ranibizumab injection, the CFT was reduced to 325.83 μm, indicating significant improvement in the disease condition, after 1 month [Figures 4 and 5].
Finally, we considered the net mean age of the 309 patients, which was 61.76 years; 213 males and 96 females were treated for all the three indications (i.e., wet ARMD, DME, and RVO with ME). The mean pretreatment BCVA was 0.66 logMAR. After the first Razumab© injection, the mean BCVA observed at 1 month was 0.52 logMAR, indicating a statistically significant improvement in visual acuity [Figures 6 and 7].
|Figure 7: Central Foveal Thickness Assessment-Mean reduction in CFT [µm] showing Significant reduction in central foveal thickness was observed showing improvement with Intas Razumab|
Click here to view
The mean pretreatment CFT was 400.16 μm. One month post the first Razumab© injection, the CFT was significantly reduced to 315.98 μm, indicating significant improvement in all the disease conditions [Figures 8 and 9].
|Figure 8: Central Foveal Thickness Assessment - Mean reduction in CFT (µm): Indication-Wise|
Click here to view
|Figure 9: Central Macular Thickness Assessment – Mean reduction in CMT (µ): Indication wise|
Click here to view
Three hundred and nine patients who were included in the study were examined at 1 month postinjection. The patients did not complain of any ocular infection or blurring of vision in that time scale. On slit-lamp examination, there were no signs of any anterior or posterior segment inflammation, cataract, vitreous hemorrhage, retinal detachment, or endophthalmitis.
No systemic or serious AEs were reported.
| Discussion|| |
The analysis reported the short-term result of the effectiveness of the Razumab© biosimilar in the treatment of patients with wet ARMD, DME, and RVO. The results showed that BCVA and CFT improved from baseline, indicating an improvement in both visual acuity and macular edema. Hence, an anatomical and physiological outcome was seen to be achieved, which was maintained at the end of 1 month [Figures 10 and 11].
|Figure 10: Wave frequency representation showing the reduction of cft indication wise|
Click here to view
|Figure 11: Wave frequency depicting visual acuity improvement in bcva logmar indication wise|
Click here to view
There was also a significant reduction in CFT [Figure 5]. The findings from the present study on the biosimilar Razumab© are consistent with those from several studies that demonstrate the effectiveness of ranibizumab in patients with these pathologies.
The efficacy and safety of Razumab© in the treatment of patients with DME, RVO, and wet ARMD by improving visual function, intraretinal fluid, and subretinal fluid have been established in several studies.,,, It had not only prevented the certain loss of visual acuity but also in fact improved visual acuity.
Our study noted no clinical evidence of toxicity following intravitreal injection of biosimilar Razumab©.
Owing to the high cost of biologics, it has become important to control health-care costs in such diseases by developing biosimilars which will have a similar efficacy and potency but with markedly lesser costs.
Biosimilars are highly similar to already approved reference biologics in terms of structure, efficacy, and safety.
| Conclusion|| |
The limitations of our study included its short period of recording outcomes owing to a large sample size. Our study revealed that Razumab©, the biosimilar of ranibizumab, was an effective treatment alternative in the management of several macular disorders such as wet ARMD, DME, and RVO by reducing CFT and improving visual acuity. A longer period of follow-up and repeat intravitreal injections could probably shed more insight into the longevity of the action of these drugs. It also revealed that similar efficacy and safety was achieved as compared to its reference biologic ranibizumab. It was also well accepted and tolerated by patients with no serious safety concerns. The short-term results indicate that biosimilar ranibizumab could go onto become a safe, low-cost therapy in developing countries. However, further investigations into its long-term safety and efficacy are warranted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Brand CS, Management of retinal vascular diseases: A patient-centric approach. Eye (Lond); 2012.
Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, Hartnett ME. Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 2008;27:331-71.
Keane PA, Sadda SR. Development of anti-VEGF therapies for intraocular use: A guide for clinicians. J Ophthalmol. 2012;2012:483034. doi:10.1155/2012/483034.
Kim R. Introduction, mechanism of action and rationale for antivascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol 2007;55:413-5. doi:10.4103/0301-4738.36473.
] [Full text]
Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Boyer D, et al
. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2011;118:1016. Eliot, Dean [corrected to Eliott, Dean]. Ophthalmology 2010;111:2146-2151. doi:10.1016/j.ophtha.2010.08.016.
Sameera VV, Apoorva AG, Joshi S, Guruprasad AS. Safety and efficacy of Razumab – The new biosimilar in India: Our experience. Kerala J Ophthalmol 2016;28:180-5. [Full text]
Campochiaro PA, Heier JS, Feiner L, Gray S, Saroj N, Rundle AC, et al
. Ranibizumab for macular edema following branch retinal vein occlusion: Six-month primary end point results of a phase III study. Ophthalmology 2010;117:1102-120.
Suñer IJ, Bressler NM, Varma R, Lee P, Dolan CM, Ward J, et al
. Reading speed improvements in retinal vein occlusion after ranibizumab treatment. JAMA Ophthalmol 2013;131:851-6.
Sharma S, Khan M, Chaturvedi A. RE-ENACT 2 Study Investigators Group. A Multicenter, Retrospective Study (RE-ENACT 2) on the Use of Razumab™ (World'sFirst Biosimilar Ranibizumab) in Wet Age-Related Macular Degeneration. Ophthalmol Ther. 2020;9:103-14. doi:10.1007/s40123-019-00228-7.
[Figure 1], [Figures 2 and 3], [Figures 2 and 3], [Figures 4 and 5], [Figures 4 and 5], [Figures 6 and 7], [Figures 6 and 7], [Figures 8 and 9], [Figures 8 and 9], [Figures 10 and 11], [Figures 10 and 11]