|Year : 2016 | Volume
| Issue : 3 | Page : 180-185
Safety and efficacy of Razumab – The new biosimilar in India: Our experience
VV Sameera, AG Apoorva, Shrinivas Joshi, AS Guruprasad
Department of Vitreo - Retina, M. M. Joshi Eye Institute, Hubli, Karnataka, India
|Date of Web Publication||2-May-2017|
Dr. V V Sameera
M. M. Joshi Eye Institute, Hubli - 580 021, Karnataka
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study was to evaluate the safety and efficacy of biosimilar intravitreal ranibizumab (Razumab) for the treatment of chorioretinal vascular diseases such as diabetic macular edema (DME), neovascular age-related macular degeneration (nAMD), and macular edema secondary to retinal vein occlusions (RVOs).
Methods: A prospective analysis was performed on consented patients with DME (Group 1), nAMD (Group 2), and macular edema secondary to RVO (Group 3). All patients received Razumab at baseline. Snellen visual acuity assessment, anterior segment and fundus evaluation, fundus photo, and optical coherence tomography imaging were done at days 0, 1, 7, and 30, respectively. The International Society for Clinical Electrophysiology of Vision standard electroretinography (ERG) was performed at baseline and day 30 (23 eyes who could afford the investigation). Primary and secondary outcome measures were safety parameters that included signs of clinical and ERG toxicity and changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT), respectively.
Results: One hundred and twenty-three eyes of 95 patients received biosimilar intravitreal ranibizumab injection between November 2015 and April 2016. No serious drug-related ocular or systemic adverse events were identified. Mean pretreatment BCVA was 0.67 ± 0.41 logMAR with CMT 345.90 ± 128.84 μm and postinjection BCVA at day 30 was 0.57 ± 0.37 logMAR with CMT reducing to 287.66 ± 90.28 μm, indicating statistical significance (P = 0.001 and P< 0.0001, respectively) for all groups.
Conclusion: The biosimilar intravitreal ranibizumab for DME, nAMD, and macular edema secondary to RVO was tolerated over a month with improvements in BCVA and CMT without detectable ocular and systemic toxicity. While the long-term safety and efficacy remain unknown, these short-term results suggest that biosimilar ranibizumab could become a safe, low-cost therapy for macular diseases.
Keywords: Age-related macular degeneration, diabetic macular edema, Razumab, retinal vein occlusion
|How to cite this article:|
Sameera V V, Apoorva A G, Joshi S, Guruprasad A S. Safety and efficacy of Razumab – The new biosimilar in India: Our experience. Kerala J Ophthalmol 2016;28:180-5
|How to cite this URL:|
Sameera V V, Apoorva A G, Joshi S, Guruprasad A S. Safety and efficacy of Razumab – The new biosimilar in India: Our experience. Kerala J Ophthalmol [serial online] 2016 [cited 2019 Jan 16];28:180-5. Available from: http://www.kjophthal.com/text.asp?2016/28/3/180/205421
| Introduction|| |
The most frequently occurring ocular diseases that cause certified visual loss are associated with pathological retinal neovascularization and edema. Of these diseases, diabetic retinopathy (DR) (proliferative DR and diabetic macular edema [DME]), neovascular age-related macular degeneration (nAMD), and retinal vein occlusion (RVO) are of particular epidemiological importance as leading causes of blindness.
Drugs that inhibit the actions of vascular endothelial growth factor (VEGF) have become the standard-of-care for several chorioretinal vascular conditions including nAMD, DME, and macular edema due to RVOs.,, The US Food and Drug Administration (FDA) has approved three anti-VEGF drugs (pegaptanib [Macugen; Eyetech, New York, USA], ranibizumab [Lucentis; Genentech, South San Francisco, CA, USA/Roche, Basel, Switzerland], and aflibercept [Eylea; Regeneron, Tarrytown, NY, USA]) for many of these conditions,,,, but a less expensive alternative (off-label bevacizumab [Avastin; Genentech/Roche]) is the most commonly used anti-VEGF drug worldwide. Several factors influence the surgeons' choice of drugs, but low cost is important in many cases. Intravitreal ranibizumab has emerged as an effective alternative for the primary treatment of retinal vascular diseases as “salvage” therapy for eyes that inadequately respond to bevacizumab. Unfortunately, ranibizumab is quite expensive and is not affordable to all patients in many countries such as India.
The biosimilar ranibizumab (Razumab; Intas Pharmaceuticals) is the first ophthalmic biosimilar developed in India which has been approved by the Drug Controller General of India. A biosimilar is a biological medicine that is developed to be similar to an existing biological medicine (the “reference medicine”). The active substance of a biosimilar and its reference medicine is essentially the same biological substance, though there may be minor differences due to their complex nature and production methods. The biosimilar ranibizumab like its biologic reference drug (Lucentis; Genentech) is a recombinant humanized IgG1 monoclonal antibody fragment designed for intraocular use. Like the reference medicine, the biosimilar has a degree of natural variability. When approved, its variability and any differences between it and its reference medicine will have been shown not to affect the safety or effectiveness.
To the best of our knowledge, there has been no analysis on the short-term safety and efficacy of this new biosimilar in patients with chorioretinal vascular diseases. We believe that intravitreal biosimilar ranibizumab may be safe and effective when used in human eyes with such conditions, and herein, we present a detailed safety evaluation using sequential clinical evaluations and electroretinographic (ERG) testing after single intravitreal injection of biosimilar ranibizumab (Razumab).
| Methods|| |
This prospective study was approved by the Institutional Review Board of M. M. Joshi Eye Institute. All study participants provided written informed consent before enrollment. Patients were recruited from November 2015 to April 2016 at M. M. Joshi Eye Institute, Hubli, Karnataka, India.
Eligible patients had active, treatment-naïve, or previously treated chorioretinal vascular conditions including choroidal neovascularization due to AMD, DME, and macular edema due to RVO.
Exclusion criteria included signs of ocular infection, previous vitrectomy, and a history of cerebrovascular accident or myocardial infarction. Comprehensive ocular examinations performed by masked investigators included measurement of best-corrected visual acuity (BCVA) using standardized Snellen visual acuity charts, applanation tonometry, slit-lamp biomicroscopy of the anterior and posterior segments, and indirect ophthalmoscopy at baseline and days 1, 7, and 30, respectively. All patients underwent fundus photography (Carl Zeiss, Dublin, CA, USA) and spectral-domain optical coherence tomography (OCT) (Optovue) at baseline and days 1, 7, and 30 after the intravitreal injection. Full-field ERG (Roland consult) studies were performed at baseline and 1 month (for the 23 affordable patients) according to the International Society for Clinical Electrophysiology of Vision guidelines.
Systemic evaluations at baseline and day 30 included a detailed medical history during which patients were asked about current medications and any systemic adverse events (AEs), thromboembolic or neurological issues, and measurement of arterial blood pressure.
Intravitreal biosimilar ranibizumab comes in a single-use glass vial like the reference product with a concentration of 10 mg/ml in 0.05 ml. Intravitreal injections were performed according to the physicians' standard protocol using a strict aseptic technique under topical anesthesia in an outpatient procedure room. Preinjection topical antibiotics were not administered, but all patients received topical gatifloxacin 0.3% four times a day for 1 week after the injection. Intravitreal injections were performed with 29-gauge needles (1 ml tuberculin syringes; DispoVan) inserted through the superotemporal pars plana, 4 mm posterior to the limbus in phakic eyes and 3.5 mm in pseudophakic eyes.
The primary outcome measures evaluated drug safety. These included any signs of toxicity noted on clinical examination such as anterior segment reaction, progression of cataract, vitritis, retinal hemorrhages, retinal vasculitis, retinal necrosis or detachment, or on ERG testing. ERG changes were considered significant if the 30-day a- and b-wave amplitudes or implicit times changed by more than 30% from the baseline values. Systemic evaluations included survey questions regarding systemic adverse effects. The secondary outcome measures included changes in BCVA and CMT.
Data were entered into Microsoft Excel data sheet and was analyzed using SPSS 22 version software (IBM). Categorical data were represented in the form of frequencies and proportions. Chi-square was used as test of significance. Continuous data were represented as mean and standard deviation. Independent t-test was used as test of significance to identify the mean difference between two groups. Paired t-test is the test of significance for paired data such as before and after injection, and analysis of variance was the test of significance to identify the mean difference between more than two groups. P< 0.05 was considered statistically significant.
| Results|| |
One hundred and twenty-three eyes of 95 patients with retinal vascular diseases such as diabetic macular edema (DME), nAMD, and macular edema secondary to RVOs were enrolled in this study. The mean age of the patients was 59.99 ± 14.28 years. Seventy-seven patients were male and 46 were female; 75 eyes were phakic and 48 were pseudophakic. None of the patients had previously suffered from cerebrovascular events or myocardial infarctions. The mean intraocular pressure (IOP) was 13.64 ± 3.07 mmHg. Forty-two eyes were treatment-naive and the rest had been previously treated with anti-VEGF agents or intravitreal steroids. None had reacted adversely to previous anti-VEGF injections [Figure 1].
The consented patients receiving intravitreal biosimilar ranibizumab therapy were grouped into 3 according to the disease: DME (Group 1), nAMD (Group 2), and macular edema secondary to RVO (Group 3). Group 1 had 44 eyes, Group 2 with 46, and Group 3 with 33 eyes. All patients received biosimilar ranibizumab at baseline.
The mean BCVA of all the indications improved from baseline (logMAR 0.67 ± 0.41) to day 30 (logMAR 0.57 ± 0.37; P = 0.001). The mean BCVA of Group 1 improved from baseline (logMAR 0.6 ± 0.4) to day 30 (logMAR 0.5 ± 0.4; P = 0.19); of Group 2 improved from baseline (logMAR 0.8 ± 0.4) to day 30 (logMAR 0.6 ± 0.3; P = 0.11); and of Group 3 improved from baseline (logMAR 0.9 ± 0.5) to day 30 (logMAR 0.6 ± 0.4; P = 0.005) [Figure 1].
Of 42 treatment-naive patients, 18 eyes were of DME, 12 eyes were of choroidal neovascular membrane (CNVM), and 12 eyes were with macular edema secondary to RVO. In naive eyes, the mean BCVA improved from baseline (logMAR 0.7 ± 0.5) to day 30 (logMAR 0.6 ± 0.4; P = 0.206). While the mean BCVA of naive DME eyes showed no difference from baseline to day 30 (logMAR 0.7 ± 0.4), naive CNVM eyes improved from baseline (logMAR 0.9 ± 0.5) to day 30 (logMAR 0.6 ± 0.4; P = 0.20) and naive RVO eyes improved from baseline (logMAR 1.2 ± 0.7) to day 30 (logMAR 0.6 ± 0.5; P = 0.04).
All of the patients were examined at postinjection days 1, 7, and 30. None of the patients complained of blurred vision, ocular pain at any of the follow-up visits. None of the eyes developed inflammation in the anterior or posterior segments, and none had corneal edema, cataract, vitritis, vitreous hemorrhage, retinal detachment, or optic atrophy. None of the patients developed ocular serious adverse effects such as severe intraocular inflammation, endophthalmitis, or moderate or severe loss of vision (.0.3 logMAR). The mean day 30 IOP was 15.1 ± 2.0 mmHg. No systemic or serious AEs were reported.
Optical coherence tomography findings
Of 123 eyes, at baseline and day 30, the mean central macular thickness (CMT) improved from 345.9 ± 128.84 μm to 287.66 ± 90.28 μm (P < 0.001). In Group 1, the mean CMT improved from 366.8 ± 93.9 μm to 311.6 ± 83.2 μm (P < 0.001). In Group 2, the mean CMT improved from 291.4 ± 103.6 μm to 272.6 ± 77.1 μm (P = 0.685). In Group 3, the mean CMT improved from 430.1 ± 172.7 μm to 279.7 ± 109.6 μm (P < 0.001) [Figure 2].
Integrated Research Facility levels were completely resolved in 14 (out of 44 DME eyes), 35 (out of 46 CNVM eyes), and 18 (out of 33 RVO eyes) eyes (P < 0.001). Twenty-one cases (out of 46 CNVM eyes) had complete resolution of subretinal fluid (P = 0.015).
In treatment-naive patients, the mean CMT of all the indications improved from baseline (382.66 ± 153.4 μm) to day 30 (293.86 ± 91.7 μm; P< 0.001). The mean CMT of naive DME eyes improved from baseline (392 ± 114 μm) to day 30 (315 ± 103 μm; P = 0.023). The naive CNVM eyes showed improvement in the mean CMT from Day 0 (291 ± 103) to Day 30 (280 ± 85; P = 0.60). However, naive RVO eyes improved markedly from baseline (521 ± 179) to day 30 (264 ± 53; P = 0.01). [Figure 3],[Figure 4],[Figure 5] show the OCT scans of CMT reduction in three groups, respectively.
The mean (± standard deviation) ERG findings at baseline and day 30 are listed in [Table 1]. There were no significant differences in implicit times, “a-” and “b-”wave amplitudes, and b/a ratios at day 30 when compared to baseline.
|Table 1: Electroretinography analysis (International Society for Clinical Electrophysiology of Vision guidelines)|
Click here to view
| Discussion|| |
Our study failed to note any clinical or ERG evidence of toxicity following single intravitreal injections of biosimilar ranibizumab in 123 eyes with retinal vascular diseases.
Ranibizumab binds to and inhibits the biologic activity of human VEGF-A. It binds to the receptor binding site of active forms of VEGF-A, including the biologically active, cleaved form of this molecule, VEGF110. VEGF-A is thought to contribute to pathophysiology of nAMD, macular edema following RVO, DR, and DME. The binding of ranibizumab to VEGF-A prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2) on the surface of endothelial cells, reducing endothelial cell proliferation, vascular leakage, and new blood vessel formation.
The high cost of pharmaceuticals, especially biologics, has become an important issue in the battle to control health-care costs in such diseases. Biologicals are derived from living cells or organisms and consist of relatively large and often highly complex molecular entities that may be difficult to fully characterize. Biosimilars are highly similar to already approved innovator or “reference” biologics in terms of structure, efficacy, safety, and quality. By virtue of their lower price, biosimilars have the potential to reduce health-care costs relative to reference biologics, thereby increasing access to biologic drugs for patients who require them. The ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA/Roche, Basel, Switzerland) is an FDA-approved biologic for the treatment of retinal vascular disorders. The biosimilar ranibizumab (Razumab; Intas Pharmaceuticals) is the first ophthalmic biosimilar which has been developed in India based on a more extensive head-to-head comparison with the reference product (Lucentis), to ensure close resemblance in physicochemical and biologic characteristics, safety, and efficacy.
The safety of the biologic ranibizumab is already well known. The analysis in patients with AMD from the several AMD trials such as ANCHOR, MARINA, PIER, SAILOR, EXCITE, and EXTEND I N has revealed both safety and efficacy of intravitreal ranibizumab. Safety and efficacy of ranibizumab in DME (RESOLVE study*) which was a 12-month, randomized, controlled, double-masked, multicenter Phase II study concluded that the safety profile of ranibizumab appears to be similar to that reported for its registered use in nAMD. The safety outcomes in the BRAVO and CRUISE studies for RVOs showed that ranibizumab was generally well tolerated, with no new safety risks identified up to month 12. In parallel to all the above-mentioned studies, our study did not show any signs of both ocular and systemic adverse effects.
Nishimura et al. in 2012 reported that amplitudes and implicit times of each wave of the full-field cone ERGs were not significantly changed after intravitreal ranibizumab injections. Similarly, we found no ERG evidence of drug toxicity with our single dose of intravitreal biosimilar ranibizumab and it suggested that a single dose does not interfere with inner and outer retina function. The biosimilar can benefit the patients through access to alternative expensive drugs achieving better medical outcomes and lower prices.
The limitations of our study are short-term outcome of 1 month for enrolled patients. Another concern is the timing of the follow-up ERG (30 days) because any drug-induced toxicity may have recovered by 30 days. The promising short-term safety and efficacy data from this single-dose pilot, however, suggest that longer-term studies with repeat injections and larger sample sizes are reasonable.
| Conclusion|| |
We found the biosimilar intravitreal ranibizumab was matching with the reference product in both safety and efficacy with desirable quality attributes in India. The initial data show good clinical response though the study was only for a short period of 1 month. The pilot study in 123 eyes shows no evidence of acute adverse reaction and safety concerns. The drug was tolerated over a month with improvements in BCVA and CMT. Short-term results suggest that biosimilar ranibizumab (Razumab) could become a safe, low-cost therapy for macular diseases. Further investigations into its long-term safety and efficacy are warranted.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]