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`Retinal Physician — Pre—filled Syringe Delivery of lntra—vitreal Anti—VEGF Medications
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`Prefilled Syringe Delivery of Intravitreal Anti-VEGF
`Medications
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`Advantages for patients and physicians.
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`By MICHAEL COLUCCIELLO, MD
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`March 1, 2019
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`9
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`Related
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`Analysis of Intraocular Inflammation Following Intravitreal Injection of Eylea
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`Ocular Inflammation After Intravitreal Injections
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`The most common exudative retinal diseases — neovascular age-related macular degeneration (nAMD), diabetic
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`retinopathy-associated macular edema (DME), and macular edema associated with retinal venous occlusive
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`disease — are usually treated with serial intravitreal injection of soluble anti-vascular endothelial growth factor
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`(anti-VEGF) pharmacologic agents. Since their inception in 2005, the number of anti-VEGF injections in the United
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`States has increased 10% to 20% annually.1 Currently, we often rely on filling syringes in the office via vials; in the
`near future, we will have prefilled syringes available for delivery of these important agents to our patients — and
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`many benefits will be realized.
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`Michael Colucciello, MD, is a medical/surgical retina specialist and partner at Vantage EyeCare, South
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`Jersey Eye Physicians division, and a clinical associate at the University of Pennsylvania School of
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`Medicine. Dr. Colucciello reports no relevant financial disclosures. Reach him at michael@macula.us.
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`Editor’s note: This article is featured in a journal club episode of Straight From the Cutter’s Mouth: A Retina
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`Podcast. Listen to the episode at www.retinapodcast.com I.
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`RATIONALE FOR FREQUENT, SERIAL, CHRONIC INTRAVITREAL INJECTIONS
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`Patients with these diseases benefit by having available a critical level of anti-VEGF agent in the vitreous during a
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`period of active disease; at this time, we are limited to frequent serial repeated delivery of the anti-VEGF agent via
`intravitreal injection. Therefore, an important consideration is the intravitreal half-life of the various anti-VEGF
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`agents. Positron emission tomography—computed tomography (PET/CT) imaging of I-124-Iabeled bevacizumab
`(Avastin; Genentech), ranibizumab (Lucentis; Genentech), and aflibercept (Eylea; Regeneron) in a nonhuman
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`primate (owl monkey) model disclosed intravitreal half-lives of 3.60 days for l-124 bevacizumab, 2.73 days for l-
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`124 ranibizumab, and 2.44 days for l-124 aflibercept.2 In a rabbit model, the vitreous half-life of bevacizumab is
`6.99 days, aflibercept is 3.92 days, and ranibizumab is 2.51 days.3 The liquefied nature of the vitreous found in
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`Retinal Physician — Pre—filled Syringe Delivery of lntra—vitreal Anti-VEGF Medications
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`adult owl monkey eyes yields shorter half—life time periods in the primate model; similarly, significantly faster
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`clearances are found in postvitrectomized eyes in a rabbit model using similar PET methodology. In the primate
`model, clearance patterns for each agent fit a 2-phase curve: an initial rapid distribution phase until day 4 was
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`followed by a slower elimination phase from day 8 onward. Bevacizumab was detected in the vitreous cavity until
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`day 30; aflibercept and ranibizumab were detectable until day 21.2
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`Consistent with the current limitations of anti—VEGF levels after intravitreal injection and the need for critical
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`therapeutic levels to treat active disease, it has been shown that more frequent injections (to maintain vitreous
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`anti-VEGF levels) provide better results than less frequent treatment. For instance, in the treatment of nAMD, the
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`PIER study protocol of monthly ranibizumab intravitreal injections for 3 months followed by quarterly dosing and
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`SAILOR study protocol (3 monthly loading doses followed by PRN dosing based on a quarterly monitoring
`schedule) both yielded inferior visual acuity results compared to consistent monthly closing in the ANCHOR and
`MARINA studies.“7
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`Regarding diabetic retinopathy, in the Ranibizumab for Edema of the mAcuIa in Diabetes follow-up study (READ-
`2), more frequent ranibizumab injections resulted in a significant gain of best—corrected visual acuity (BCVA) of 3.1
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`letters and a reduction in foveal thickness of 70 pm. The authors concluded that more aggressive therapy (monthly
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`injections) may be necessary in many patients to optimally control edema and maximize vision.8 Regarding the
`treatment of macular edema associated with retinal venous occlusive disease, in both the CRUISE and BRAVO
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`studies, monthly ranibizumab dosing versus sham for 6 months showed clear improvement with ranibizumab over
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`sham. Then, during the second 6 months, sham group patient vision improved because they were able to receive
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`ranibizumab, but at month 12 their vision was not as good as that in patients in the ranibizumab groups, because
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`they had received far fewer doses by month 1219,10
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`IMPLICATIONS FOR CHRONIC INTRAVITREAL ADMINISTRATION AND ADVANTAGES OF PREFILLED
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`SYRINGE DELIVERY
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`The need for chronic, serial dosing in these common retinal diseases has made the intravitreal injection procedure
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`the most common procedure performed in ophthalmology. It is estimated that more than 6 million injections were
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`performed in the United States in 2016 alone.11
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`Chronic, serial intravitreal injections are most efficiently performed with prefilled syringes. The anti-VEGF agents
`bevacizumab and ranibizumab (Figure 1) are currently available in prefilled syringes. It is anticipated that the other
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`major VEGF blocker, aflibercept, will soon be available in a prefilled syringe. Prefilled syringes are a boon to
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`patients requiring this treatment (generally our largest patient group) and retinal physicians because of the
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`decreased endophthalmitis risk, dose accuracy, and improved clinic efficiency they can provide.
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`Retinal Physician — Pre—filled Syringe Delivery of lntra—vitreal Anti—VEGF Medications
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`Figure 1. Prefilled syringe loaded with anti-VEGF agent.
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`ENDOPHTHALMITIS RISK
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`Repetitive administration of these agents can be challenging for patients, not only from a frequency perspective,
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`but also because of the risk involved for endophthalmitis with repeated injections. Postinjection endophthalmitis is
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`one of the most serious complications that can occur. If prefilled syringes are not utilized, transfer from vials to
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`syringes and filtered-injection needle exchanges increase chances of contamination and subsequently patient risk
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`for endophthalmitis. The risk of endophthalmitis with an intravitreal injection has been studied extensively. Large
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`studies have reported postinjection rates of endophthalmitis at 0.02% to 0.05%.12'14 A meta-analysis found the
`rate of endophthalmitis following intravitreal injections in a clinical setting to be 0.049%.12
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`Recently, a retrospective cohort study was done to determine whether sterile preloading of anti-VEGF agents
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`reduces the risk of postintravitreal injection endophthalmitis.15 Using 2005-2016 medical claims data from a large,
`national US insurer, 706,725 bevacizumab (in a prefilled syringe), 210,849 ranibizumab (from vials until late 2016),
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`and 177,731 aflibercept (from vials) injections given to 130,327 patients were evaluated for endophthalmitis
`incidence. Based on the odds risk reduction of 1.29, the authors calculated that 1 case of endophthalmitis for
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`every 8,847 injections performed could be prevented using prefilled syringes (any changes in the calculus from
`prefilled syringes available for ranibizumab in late 2016 would favor prefilled syringes even more). Since, in their
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`study, 1 case of endophthalmitis occurred every 2,857 injections, this translates into the potential of avoidance of 1
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`out of every 3 cases of endophthalmitis — a highly significant result.
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`DOSE ACCURACY
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`Therapeutic doses of intravitreal anti-VEGF drugs (1.25 mg bevacizumab, 0.5 or 0.3 mg ranibizumab, and 2.0 mg
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`aflibercept) are achieved by injecting a volume of 0.05 mL (50 mL) into the vitreous cavity. Studies have shown
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`that the accuracy and reproducibility achieved with the typical syringes used for intravitreal injections can be highly
`variable.”"19
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`A recent “real-world” study evaluated the accuracy and precision of anti-VEGF volume delivery in the real-world
`setting demonstrated that the use of a prefilled syringe was associated with improved anti-VEGF dosing accuracy.
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`Overdelivery was more common than underdelivery (16.3%), but overall precision was enhanced with the use of
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`Retinal Physician — Pre—tilled Syringe Delivery of lntra—vitreal Anti-VEGF Medications
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`prefilled syringe delivery of medication.20
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`CLINIC FLOW
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`Prepackaged syringes have demonstrated a 40% reduction in office preparation time, offering clinical
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`efficiency?“22 Improved efficiency allows for an improved patient experience and allows the physician to treat
`more patients per session.
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`FUTURE CONSIDERATIONS: NO NEED FOR INTRAVITREAL INJECTION?
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`In the perhaps not too distant future, repeated intravitreal delivery of medication via needles on syringes will be
`less of a consideration, due to the possibilities of a port delivery (reservoir) system and gene therapy. Implanted
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`reservoir delivery of medication has shown promise in early trials. The ranibizumab port delivery system (PDS;
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`Genentech), in particular, has shown promise. Once implanted, the reservoir may be refilled periodically. In the
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`phase II LADDER study, the top-line results showed that 80% of patients could go 6 months before requiring a
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`refill of the PDS implant. The phase 2 LADDER study included 220 patients randomized to either 1 of 3
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`concentrations of ranibizumab (10 mg/mL, 40 mg/mL, or 100 mg/mL) in a reservoir surgically implanted in the
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`vitreous cavity or a monthly injection of ranibizumab (.5 mg). Outcomes included the time until a patient needed a
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`refill of the implanted ranibizumab delivery system and the effectiveness of each concentration compared to
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`monthly injections. Patients treated with the highest ranibizumab concentration were able to go a median of 15
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`months before needing a refill of the reservoir in the office. Investigators found that the port delivery treatment was
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`also as effective as monthly injections. Currently, a phase 3 study (ARCHWAY) is under way.23
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`Also, gene therapy delivery brings the hope of allowing for very long-term therapeutic levels of medication through
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`cellular nucleus incorporation of the genetic material that may lead to the manufacture of anti-VEGF medication for
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`the patient. Adverum Biotechnologies product ADVM-022 uses a proprietary adeno—associated virus vector that
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`carries an aflibercept coding sequence. A primate study using one intravitreal injection showed that a single
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`injection of ADVM-022 administered intravitreally can generate stable levels of aflibercept found to be within the
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`therapeutic window of the standard-of-care recombinant protein for 16 months.24 Another gene therapy product,
`RGX—314 (Regenxbio), utilizes a novel recombinant adeno-associated virus vector of an anti-VEGF gene delivered
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`in a subretinal fashion to allow for potential long-term host manufacture of the anti-VEGF therapy.25 This is
`currently undergoing a 24-week phase 1 trial.
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`CONCLUSION
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`At least for the near term, frequent intravitreal injections of anti—VEGF agents will be important for managing
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`several of the most common retinal diseases. Using syringes prefilled with the soluble anti—VEGF agents will
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`protect patients from the disastrous consequences of endophthalmitis, assure the most efficient manner of precise
`dosing, and assist with patientflow in growing, busy clinics. RP
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`REFERENCES
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`
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`3. Park SJ, Choi Y, Na YM, et al. Intraocular pharmacokinetics of intravitreal aflibercept (Eylea) in a rabbit model.
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`Retinal Physician — Pre—tilled Syringe Delivery of lntra—vitreal Anti-VEGF Medications
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`4. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, lanchulev T; ANCHOR Study Group. Ranibizumab vs
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`11. Williams GA. IVT injections: health policy implications. Rev Ophthalmol. 2014;21:62-64.
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`endophthalmitis. JAMA Ophthalmol. 2015;133(10):1159.
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`15. Bavinger JC, Yu Y, Vanderbeek BL. Comparative risk of endophthalmitis after intravitreal injection with
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`bevacizumab, aflibercept and ranibizumab. Retina. 2018. [Epub ahead of print]
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`16. Sampat KM, Wolfe JD, Shah MK, et al. Accuracy and reproducibility of seven brands of smallavolume syringes
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`17. Meyer CH, Liu Z, Brinkmann C, Rodrigues EB, Helb HM. Accuracy, precision and repeatability in preparing the
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`19. Moisseiev E, Rudell J, Tieu EV, Yiu G. Effect of syringe design on the accuracy and precision of intravitreal
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`[Epub ahead of print]
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`21. Souied E, Nghiem—Buffet S, Leteneux C, et al. Ranibizumab prefilled syringes: benefits of reduced syringe
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`preparation times and less complex preparation procedures. EurJ Ophthalmol. 2015;25(6):529—534.
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`22. Subhi Y, Kjer B, Munch IC. Prefilled syringes for intravitreal injection reduce preparation time. Dan Med J.
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`Retinal Physician — Pre—filled Syringe Delivery of lntra—vitreal Anti—VEGF Medications
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`23. Awh CC. LADDER trial of the Port Delivery System for ranibizumab: preliminary study results. Late-breaking
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`abstract presented at: the 36th Annual Meeting of the American Society of Retina Specialists; July 25, 2018;
`Vancouver, British Columbia, Canada.
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`24. Adverum Biotechnologies. Long-term aflibercept expression levels in non-human primates following intravitreal
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`administration of ADVM-022, a potential gene therapy for wet age-related macular degeneration. Poster
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`#P223 presented at the European Society of Gene and Cell TheraPY; October 17, 2018; Oxford, UK.
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`25. Liu Y, Fortmann SD, Sheri J, et al. AAV8-antiVEGFfab ocular gene transfer for neovascular age-related
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`macular degeneration. Mo/ Ther. 2018;26(2):542-549.
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`Retinal Physician, Volume: 16, Issue: March 2019, page(s): 50-52
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