Dr.Aniket Ginodia, Dr.Preeyam Biswas,Dr.Sneha Batra,Dr.Partha Biswas
Abstract
Aim:
To study the safety and efficacy of biosimilar ranibizumab for treatment naïve DME patients.
Methods:
A retrospective cross sectional study done in 34 naïve DME patients, followed for 6 months after last injection of biosimilar ranibizumab.Primary and secondary outcomes were improvement in BCVA and decrease in CMT from last injection.
Results:
Data analyzed using two-tailed paired t-test.
Mean±SE BCVA and CMT improved from baseline after injection indicate statistically significant (P= 0.0217 at 1 month and P= 0.0045 at 3 months) for BCVA and (P<0.0001 at 1 month and P= 0.0002 at 3 months) for CMT.No adverse event noted.
Conclusion:
Biosimilar ranibizumab effectively improved the visual acuity and macular edema in treatment naïve patients of DME without any ocular and systemic toxicity at an affordable cost.
Introduction
The total number diabetic population has increased from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014 [1].
Diabetic retinopathy and diabetic macular edema (DME) are the most common and frequent cause of visual loss in diabetic patients and is an important public health problem. Its early detection and the control of diabetes associated metabolic abnormalities (i.e., hyperglycemia, hyperlipidemia, and hypertension) is critical in preventing visual loss. A large epidemiological study indicated that 26% of patients with diabetic retinopathy presented with DME [2]
Several clinical trials have shown anti-vascular endothelial growth factor (VEGF) therapy improved visual acuity and macular edema , and currently it has become the initial first line treatment of DME.
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 diabetic retinopathy (DR) (proliferative DR and diabetic macular edema [DME]), neovascular age-related macular degeneration (nAMD), and retinal vein occlusion (RVO)[3-6].
Several clinical studies including the READ [7], RESOLVE [8], RESTORE [9], RETAIN [10], RISE and RIDE [11], RELIGHT [12], and TREX studies [13] have confirmed the safety and efficacy of ranibizumab in the treatment of DME.
These anti-VEGF are quite expensive and is not affordable to all patients in many countries such as India. So to reduce the cost burden to these patients, an Indian pharmaceutical company developed the biosimilar of ranibizumab, which is the first ophthalmic biosimilar developed in India and is also approved by the Drug Controller General of India.
A Biosimilar also known as follow-on biologic or subsequent entry biologic- “A Biologic that is highly similar to the reference product with no clinically meaningful differences in terms of safety, purity & potency”[14]
Method
Study design & Population
This was a retrospective cross sectional study done in tertiary care eye hospital, Kolkata from december,2016 to november,2017 in thirty four eyes of thirty four treatment naïve DME patients. All patients received intravitreal biosimilar ranibizumab at baseline. The follow up schedule were 1, 3 and 6 months from last injection of intravitreal Biosimilar Ranibizumab. The comprehensive ocular examinations were performed in all the seleced patients like best corrected visual acuity (BCVA), intra ocular pressure (IOP), slit lamp examination, dilated fundus evaluation with indirect ophthalmoscope, fundus photograph, SD-OCT, DFA.
- Inclusion Criteria :
- Treatment naïve DME patients
- Age > 18 yrs [ Both male and female ]
- BCVA worse than 20/40 (6/9) but better than 20/400 (3/60)
- SD – OCT central foveal thickness >300 μ
- Exclusion Criteria :
- CME-RVO,CNVM
- PDR with DME, Ischemic DME
- Laser therapy
- Any previous intravitreal injection
- Vitreous hemorrhage , TRD,VMT
- Cataract , Glaucoma, Vitrectomy surgery
- signs of ocular infection, Uveitis
All patients were given a detail explanation of the treatment & its potential risks & benefits.
Intravitreal injection
Intravitreal biosimilar ranibizumab comes in a single‑use glass vial with a concentration of 10 mg/ml in 0.05 ml. It was performed with 29‑gauge needles(1 ml tuberculin syringes) inserted through the inferotemporal pars plana (4 mm posterior to the limbus in phakic eyes & 3.5 mm in pseudophakic eyes). All patients received topical gatifloxacin 0.3% four times a day for 1 week after the injection.
Outcome measures
The primary outcome was improvement in best corrected visual acuity (BCVA) and the secondary outcome was decrease in central macular thickness (CMT) from last injection.
Statistical analysis
Best corrected visual acuity and central macular thickness data were analyzed using two-tailed paired t-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
The mean age of patients was 53.76 ± 12.368 years; 27 males and 7 female patients were treated for DME indication.
Table 1. Patients baseline characteristics.
| Treatment naïve DME patient [n=34]
(Baseline) |
Values |
| Age [Years, Mean ± SD] | 53.76 ± 12.368 |
| Gender – Male
Female |
27
7 |
| BCVA Score [LogMAR; Mean ± SD] | 0.95 ± 0.665 |
| Central Macular Thickness [µm; Mean ± SD] | 478.412 ± 248.182 |
Repeat injections were given in 5/34 patients [3 patient receive 2 injections and 2 patients receive 3 injections], these patients had fluctuating blood parameters (HbA1C > 8.5). Other 29 patients had HbA1C level between 6-8.
BCVA
Mean pre-treatment best corrected visual acuity (BCVA) was 0.95 ± 0.665 logMAR for DME indication.
After the first biosimilar ranibizumab injection, the mean BCVA observed at 1 month was 0.73 ± 0.524 logMAR, indicating statistically significant (P= 0.0217) improvement in visual acuity.
Mean BCVA observed at 3 months was 0.69 ± 0.411 logMAR, indicating significant (P= 0.0045) improvement in visual acuity.
However, the mean BCVA observed at 6 months was 0.83 ± 0.585 logMAR, indicating non significant (P= 0.0612) improvement in visual acuity.
A statistically significant and clinically meaningful increase in Visual Acuity was observed up to 3 months follow up.
Table 2. Mean ± SE BCVA (logMAR) at baseline and month 1, 3 and 6 after biosimilar ranibizumab administration.
| BCVA [LogMar] | BASELINE | 1 MONTH | 3 MONTHS | 6 MONTHS |
| DME | 0.95 | 0.73 | 0.69 | 0.83 |
| P value | —— | 0.0217* | 0.0045* | 0.0612 |
* Statistically significant p-value [i.e. p < 0.05]
Figure 1. Mean ± SE BCVA (logMAR) at baseline and month 1, 3 and 6 after biosimilar ranibizumab administration.
CMT
Mean pre-treatment central macular thickness (CMT) was 478.412 ± 248.182 μm for DME indication.
After the first biosimilar ranibizumab injection, the mean CMT observed at 1 month was 350.353 ± 187.596 μm, indicating significant (P<.0001) improvement in the macular edema.
Mean CMT observed at 3 months was 330.059 ±178.335 μm, indicating significant (P=0.0002) improvement in the macular edema.
Mean CMT observed at 6 months was 342.324±173.714 μm, indicating significant (P=0.0006) improvement in the macular edema.
A statistically significant and clinically meaningful reduction in CMT was observed up to 6 months follow up
TabLE 3. Mean ± SE CMT (μm) at baseline and month 1, 3 and 6 after biosimilar ranibizumab administration.
| CMT (µm) | BASELINE | 1 MONTH | 3 MONTHS | 6 MONTHS |
| DME | 478.41 | 350.35 | 330.06 | 342.32 |
| P value | —— | <0.0001* | 0.0002* | 0.0006* |
* Statistically significant p-value [i.e. p < 0.05]
Figure 2. Mean ± SE CMT (μm) at baseline and month 1, 3 and 6 after biosimilar ranibizumab administration.
Safety Assessment
No adverse events especially intra-ocular inflammation was observed during 6 months follow up period.
| Complication | No. of eyes |
| Endophthalmitis | 0 |
| Retinal detachment | 0 |
| Cataract | 0 |
| Sub Conjunctival Haemorrhage | 2 |
| Raise Intra Ocular Pressure(IOP) | 0 |
Discussion
Francois et al study showed head to head comparison of ranibizumab and biosimilar ranibizumab using a panel of analytical techniques, and found no differences using size-exclusion chromatography, capillary electrophoresis-sodium dodecyl sulfate and potency assays, different acidic
peaks were identified with cation ion exchange chromatography and capillary zone electrophoresis. There were no differences in VEGF binding, nor in inhibition of VEGF-induced proliferation were found between two.[15]
Sameera et al did prospective study on 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) on one hundred and twenty-three eyes of 95 patients which were followed up for 1 month and found that intravitreal biosimilar ranibizumab was tolerated over a month with improvements in BCVA and CMT without detectable ocular and systemic toxicity.[16]
Sharma et al did a retrospective, multicenter study on 561 patients with wet age-related macular degeneration (wet AMD), diabetic macular edema (DME) and retinal vein occlusion (RVO) who were given ≥ 3 intravitreal biosimilar ranibizumab who were followed up for 3 months and found that biosimilar ranibizumab is effective in reducing macular thickness and improving visual acuity in patients with wet ARMD, DME and RVO in routine clinical practice.[17]
Our study which followed up over a period of 6 months showed improvement in visual acuity and macular edema which were statistically significant upto 3 months without any ocular and systemic toxicity.
Limitations
- Retrospective in nature
- Small sample size
- Only treatment naïve DME patients included in study
- Short term follow up period (6 months)
Conclusion
Biosimilar ranibizumab effectively improved visual acuity and macular edema in treatment naïve patients of DME without any ocular and systemic toxicity at an affordable cost. This injection can be used as an alternative to the existing expensive generic molecule to serve greater number of DME population.
References
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[14] Biologics Price Competition and Innovation Act, US,2009
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