Effectiveness and safety of ziv aibercept in myopic choroidal neovascularisation patients

Background: Myopic choroidal neovascularization (CNV) is the most common sight threatening complication in high myopia. The present study evaluates the ecacy and safety of intravitreal injection of ziv-aibercept in patients with myopic CNV. Methods: This is a prospective interventional study that was conducted on 20 eyes of 20 patients with active myopic CNV. Twelve patients were 40 years old or more. The study was performed in Ophthalmology department, Tanta University Eye Hospital ,Tanta University, Egypt. Complete ophthalmic evaluation was performed including best corrected visual acuity (BCVA), fundus examination and anterior segment examination. OCT was done for all patients at baseline and monthly after injection during the 6 months follow up period of the study. Statistical calculations were performed using the computer program SPSS (S tatistical Package for the Social Science) . Results: The younger age group received lower number of injections than the older age group, the best corrected visual acuity ( BCVA) and the central macular thickness (CMT) improved signicantly in both groups with more improvement in the younger age group as regarding the BCVA. No signicant correlation was found between the nal BCVA and both the spherical equivalent and the central macular thickness after 6 months.No signicant changes in IOP after intravitreal injection were detected in both groups .No complications were reported apart from mild sub conjunctival hemorrhage that occurred in three eyes after injection. Conclusion: Ziv-aibercept is a highly effective and safe drug in cases of active myopic CNV that can produce similar results to other anti VEGF agents with less cost. The study was retrospectively registered with clinical trial .gov ID (NCT04290195) in 26-2-2020.


Background
The prevalence of pathological myopia in adults is about 1-3%, myopic choroidal neovascularisation (CNV) is one of the most sight-threatening complications that occurs in approximately 5-11% of pathological myopia patients [1,2]. Several treatment approaches were proposed due to the poor understand of its pathological nature [2]. Photodynamic therapy (PDT) is one of the treatment options for myopic CNV that can reduce the risk of visual loss which was supported by several studies [3,4]. However, patients treated with PDT did not gain better mean visual acuity, and it did not prevent visual loss for longer than 2 years [5]. Recently anti-vascular endothelial growth factor (Anti-VEGF) agents such as bevacizumab, ranibizumab, and a ibercept were introduced for the treatment of many retinal diseases with high safety pro le. Bevacizumab is a recombinant humanized monoclonal antibody that binds all isoforms of VEGF-A [6], while ranibizumab is an antigen-binding fragment derived from bevacizumab [6].
A ibercept is a soluble receptor fusion protein that binds VEGF-A, VEGF-B, and placental growth factor [6,7]. According to phase 3 RADIANCE trial [8], ranibizumab was recently approved for the treatment of visual impairment due to myopic CNV, in addition MYRROR; a phase 3 study, con rmed the e cacy and safety of intravitreal a ibercept in the treatment of CNV in pathological myopia patients [9]. Ziv-a ibercept (Zaltrap; Regeneron, New York, USA) is a recombinant fusion protein which is nearly similar to a ibercept. It was approved by FDA in August 2012 for the treatment of resistant metastatic colorectal carcinoma. Recently, it was reported that off-label intravitreal ziv-a ibercept is an effective and safe treatment at 4 weeks interval without any ocular toxicity in patients with age-related macular degeneration [10].
The present study evaluates the e cacy and safety of ziv-a ibercept as a primary treatment in cases of myopic CNV.

Methods
Study design: A prospective interventional case study that was conducted on 20 eyes of 20 patients with active myopic CNV who attended the outpatient clinic of Tanta University Eye Hospital from March 2019 till September 2019 after approval of the Ethical Committee of the Faculty of Medicine, Tanta University, Egypt (approval code 32970/02/19). Twelve patients were ≥ 40 years old and the remaining 8 patients were < 40 years old which is quite similar to Yoshida T et al [27] to detect the in uence of age on the visual prognosis. All procedures were carried out under the tenets of the Helsinki Declaration. Written consent was provided by all participants after discussing the procedure, alternative treatment plans, follow-up schedules, and possible bene ts and risks. The study was retrospectively registered with clinical trial .gov ID (NCT04290195) in 26-2-2020.
Participants: The study included treatment naive patients with recently diagnosed active myopic subfoveal or juxtafoveal CNV of less than two months duration con rmed by fundus uorescein angiography (FFA) and optical coherence tomography (OCT). Pathological myopia patients with spherical equivalent more than 6 Diopters and axial length more than 26 mm were enrolled in the study.
Patients with history of previous intraocular surgery, coincident retinal pathology as diabetic retinopathy, retinal vein occlusion(RVO), CNV due to other causes like age related macular degeneration, angioid streaks, trauma, choroiditis and extrafoveal myopic CNV were excluded from the study. In addition patients who received other lines of treatment for CNV like photodynamic therapy, laser photocoagulation or intravitreal injection of triamcinolone or other anti VEGF agents, and those known to be glaucomatous or have IOP more than 20 mmHg were also excluded.
Furthermore, patients with other retinal pathology as prior ocular in ammation, retinal degeneration, dense media opacity including nuclear sclerosis and those who did not complete 6 months of follow up were not enrolled in the study.
Thorough ophthalmic evaluation was performed for all patients including BCVA using Snellen chart that was converted to logMAR for statistical analysis, IOPmeasurement using applanation tonometry, anterior segment examination using slit lamp, posterior segment examination by slit lamp bimicroscopy using +78 D lens and indirect ophthalmoscopy. Spectral domain OCT (Topcon 3D Optical Coherence Tomography) was performed for all patients at baseline and at the postoperative rst month visit then monthly for 6 months.
Surgical procedure : Preoperative preparation:Patients were prepared by applying topical uoroquinolone eye drops (Moxi oxacin hydrochloride 0.5% Vigamox ,Alcon, USA) 4 times daily for three days before injection.
Procedure:The intravitreal injection was carried out in the operating room under complete aseptic technique with an operating microscope. After applying topical anaesthetic drops (Benoxinate hydrochloride 0.4%, Benox, Epico, Egypt) to the ocular surface followed by topical application of 10% povidone iodine (Betadine) for periocular area,lids and eye lashes and 5% povidone iodine inside the conjunctival sac for three minutes before the intravitreal injection. Injection of 0.05 ml of 1.25 mg of Ziva ibercept (Zaltrap) was done into the vitreous cavity in the inferotemporal quadrant of the globe using 30 gauge needle 4 mm fom the limbus.
Postoperative care:After the injection, topical antibiotic drops were applied (Moxi oxacin hydrochloride 0.5% Vigamox, Alcon, USA) and the eye was patched for several hours. Patients were instructed to administer antibiotic drops four times daily for 3 days. Patients were examined the next day and the third day after injection to exclude any complication like elevation of the IOP, endophthalmitis, retinal break , retinal detachment and vitreous haemorrhage. All patients were followed up at 4 weeks interval after the rst injection. At each visit, thorough ophthalmic examination and SD OCT were performed. Pro re nata (PRN regimen) was followed in this study in which additional intravitreal injection of Zaltrap was given after one month if persistent intraretinal or subretinal uid was detected in SD OCT and/or haemorrhge was detected on clinical examination.
Statistical data were expressed as percentages or means ± SD when appropriate. Chi X2 was used to compare the ndings. P-values < 0.05 were considered signi cant. All statistical calculations were performed using the computer program SPSS (Statistical Package for the Social Science; SPSS, Chicago, IL, USA) version 23 for Microsoft Windows, USA.

Results
The study was performed from March 2019 till September 2019.Twenty eyes of active myopic CNV were included in the study, the baseline demographic data of all patients including; age, gender, spherical equivalent and number of injections were recorded. Patients with myopic CNV less than 40 years old needed lower number of injections (2.00±0.76) than patients 40 years old or more (2.50±1.00), this is shown in table (1).The BCVA improved signi cantly after 6 months of injection in both age groups with more improvement in the younger age group, (p=0.001) in patients <40 years and (p=0.028) in patients ≥40 years old. Furthermore, the central macular thickness (CMT) decreased signi cantly in both groups after 6 months follow up (p=0.001) as shown in table (2).
No signi cant changes in IOP after intravitreal injection were detected in both groups after 6 months (p=0.140) as illustrated in table (3).
Also, there was no signi cant correlation between the nal BCVA and both the spherical equivalent and the nal CMT after 6 months ( gure 1, gure 2). During injection, subconjunctival haemorrhage occurred in 3 eyes, no cases of reaction, endophthalmitis, retinal breaks, retinal detachment or vitreous haemorrhage were reported. No systemic complications like myocardial infarction, stroke or death were reported during the study. For example; in a 55 years old female patient with active myopic CNV with retinal haemorrhages as documented by uorescein angiography ( gure3), the BCVA improved by 3 consecutive injections from1 to 0.52 by logMAR, also the CMT declined from 283 um ( gure4) to 226 um, 213 um ,184 um after 3 monthly injections ( gure 5 a, b, c).The CNV remained inactive till the last follow up visit.

Discussion
Various methods of treatment were attempted for myopic CNV before the era of anti-VEGF as laser photocoagulation, transpupillary thermotherapy (TTT), PDT (photodynamic therapy), submacular surgery and macular translocation. In spite of all these attempted treatment approaches, results were unsatisfactory with no evident clinical improvement. Damage of the adjacent photoreceptors and atrophic scar progression hindered the clinical improvement and decreased the BCVA in laser photocoagulation treated patients with subfoveal CNV due to age-related macular degeneration [11,12], with even poorer results in myopic extrafoveal CNV despite of the stoppage of activity [13][14][15][16].
This advocated the shift to PDT with vertepor n which resulted in more satisfactory results angiogra cally and clinicaly in myopic CNV patients. Many studies supported the use of vertepor n especially those reported by Photodynamic Therapy Study Group; that detected improvement of BCVA in PDT treated group in the rst 2 years that declined afterwards [4,17]. Another study that included 24 eyes of myopic CNV patients reported that PDT may result in good visual outcome in patients with extrafoveal CNV lesions with the laser spot adjusted to spare the fovea [18].
Regarding anti VEGF treatment for myopic CNV ; Baba et al [19] compared the e cacy of bevacizumab and PDT, intravitreal bevacizumab showed more improvement of BCVA than PDT in eyes with myopic CNV. Also; Arias et al [20] found that the mean visual acuity improved by 8.4 letters following an average of 1.5 intravitreal bevacizumab injections after 6 months follow-up. Another study conducted by Ikuno et a1 [21] reported improvement in the mean BCVA in a case series of 63 eyes of myopic CNV following one to six Bevacizumab injections during the 12 months of observation. As regard to ranibizumab; the REPAIR study [22,23] reported improvement of 13.8 letters following median of 3 ranibizumab injections based on PRN regimen after 12 months. RADIANCE study con rmed the results of REPAIR study [8]; it showed that around 40% of ranibizumab treated patients gained 15 or more letters of visual acuity at the third month compared with only 15% in PDT-treated patients. Whereas, after 1year, the BCVA improved by 13.8 letters in the rst group of ranibizumab (based on visual acuity stabilisation in the preceeding two follow up visits) and 14.4 letters in the second group of ranibizumab (based on disease activity criteria) compared with 9.3 letters improvement for PDT-treated patients, in addition some patients in PDT group switched to ranibizumab injection from the third month onwards (with a median number of 2.0 injections between 3 and 12 months).
Another case series conducted on ranibizumab in 16 patients with myopic CNV by Lai et al [24]; that reported improvement of the mean BCVA of 3 lines after 1 year in 75% of eyes with recurrence demonstrated by angiography in only 2 eyes after 3 months that required retreatment between the 3rd and 9th month. Signi cant reduction in the mean central foveal thickness was also reported by OCT .
In respect to a ibercept in myopic CNV, the MYRROR study in 2015 reported a mean change of +13.5 letters in BCVA in a ibercept-treated patients after a median of 2 injections within 12 weeks compared with +3.9 letters in patients received sham treatment that was maintained through 48 weeks. No further injections were needed till the end of the study. The visual gain correlated signi cantly with reduction of the central retinal thickness [9]. Other studies con rmed the e cacy of a ibercept in myopic CNV patients like Brue and coauthors that showed improvement of BCVA from 0.69 LogMAR to 0.15 LogMAR after 18 months [25].Moreover, Pece and Milani reported improvement of 10.6 letters after 1year follow-up [26].
The present study evaluated the e cacy and safety of ziv-a ibercept in myopic CNV patients and reported that a lower number of injections was needed in patients less than 40 years old, in addition the BCVA improvement was more signi cant in the younger age group, these results are similar to Yoshida et al [27] who also showed better clinical improvement in patients yonger than 40 years.The rational for less improvement in older patients can be related to several factors such as decreased integrity and function of the retinal pigment epithelium in myopic patients which might reduce the inhibition of angiogenesis that lead to the formation of larger and more active CNV, as well as a delay in the regression of CNV in these older patients. Moreover, myopic CNV in older patients has clinico-pathological correlation of both AMD and high myopia and tends to develop chorioretinal atrophic changes that markedly affect visual acuity [19].
Also, the improvement of BCVA and the reduction of the CMT after injection was achieved in both groups with statistical signi cance that re ects the e cacy of the new drug in myopic CNV patients with high safety pro le and lower cost, this was quite similar to recent studies performed on ziv-a ibercept on a larger number of patients [28,29] that discussed application of ziv-a ibercept in different retinal diseases and detected reasonable safety pro le for the drug comparable with other anti VEGF agents.
In contrast to a study performed by Chhablani et al (2017) on age related macular degeneration patients that suggested immediate IOP elevation after injection in 4 eyes that needed anterior chamber paracentesis [30], anterior chamber paracentesis was not performed in the present study as the IOP did not change signi cantly after injection of ziv-a ibercept either immediately or after a period of injection. This demonstrates the safety of ziv-a ibercept on IOP.
The costper dose of intravitreal bevacizumab and ziv-a ibercept is low [31,32], however that of a ibercept and ranibizumab is 20 to 30 times more [33]. This can be of great bene t to the low income countries with de cient insurance coverage.

Conclusions
Ziv a ibercept is a cheap and effective anti VEGF agent in patients with active myopic CNV with a high safety pro le.The authors recommend the use of this new anti VEGF agent in retinal diseases like myopic CNV. However, larger number of patients with longer period of follow up are needed in further studies to con rm these results. Data Availability: The datasets used during the current study are available from the corresponding author on reasonable request.

Competing interests:
The authors declare that they have no competing interests.

Funding:
The research was not supported by any funding agent.   Figure 1 linear correlation between the BCVA after 6 months and spherical equivalent in all eyes.

Figure 2
Correlation between the nal BCVA and the nal CMT after 6 months in all eyes. OCT of the same patient showing active subfoveal CNV, the CMT is 283 um.

Figure 5
A : OCT after the rst injection of ziv-a ibercept with reduced CMT to 226 um. B: OCT after the second injection of ziv-a ibercept with reduced CMT to 213um .C: OCT after the third injection of ziv-a ibercept, the CMT declined to 184 um.