`Medications
`Advantages for patients and physicians.
`
`By MICHAEL COLUCCIELLO, MD March 1, 2019
`
`17
`
`Related
`
`SUBSPECIALTY NEWS: Lucentis effective for RVO, endophthalmitis after anti-VEGF injection,
`perfluorocarbon toxicity in vitreoretinal surgery, and more
`
`Analysis of lntraocular Inflammation Following lntravitreal Injection of Eylea
`
`Ocular Inflammation After lntravitreal Injections
`
`The most common exudative retinal diseases - neovascular age-related macular degeneration (nAMD), diabetic
`retinopathy-associated macular edema (DME), and macular edema associated with retinal venous occlusive
`disease - are usually treated with serial intravitreal injection of soluble anti-vascular endothelial growth factor
`(anti-VEGF) pharmacologic agents. Since their inception in 2005, the number of anti-VEGF injections in the United
`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
`many benefits will be realized.
`
`Michael Colucciello, MD, is a medical/surgical retina specialist and partner at Vantage EyeCare, South
`Jersey Eye Physicians division, and a clinical associate at the University of Pennsylvania School of
`Medicine. Dr. Colucciello reports no relevant financial disclosures. Reach him at michael@macula.us.
`Editor's note: This article is featured in a journal club episode of Straight From the Cutter's Mouth: A Retina
`Podcast. Listen to the episode at www.retinapodcast.com ~-
`
`RATIONALE FOR FREQUENT, SERIAL, CHRONIC INTRAVITREAL INJECTIONS
`
`Patients with these diseases benefit by having available a critical level of anti-VEGF agent in the vitreous during a
`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
`agents. Positron emission tomography-computed tomography (PET/CT) imaging of I-124-labeled bevacizumab
`(Avastin; Genentech), ranibizumab {Lucentis; Genentech), and aflibercept (Eylea; Regeneron) in a nonhuman
`primate (owl monkey) model disclosed intravitreal half-lives of 3.60 days for 1-124 bevacizumab, 2.73 days for 1-
`124 ranibizumab, and 2.44 days for 1-124 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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`Novartis Exhibit 2271.001
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`adult owl monkey eyes yields shorter half-life time periods in the primate model; similarly, significantly faster
`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
`followed by a slower elimination phase from day 8 onward. Bevacizumab was detected in the vitreous cavity until
`day 30; aflibercept and ranibizumab were detectable until day 21.2
`
`Consistent with the current limitations of anti-VEGF levels after intravitreal injection and the need for critical
`therapeutic levels to treat active disease, it has been shown that more frequent injections (to maintain vitreous
`anti-VEGF levels) provide better results than less frequent treatment. For instance, in the treatment of nAMD, the
`PIER study protocol of monthly ranibizumab intravitreal injections for 3 months followed by quarterly dosing and
`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 dosing in the ANCHOR and
`MARINA studies.4-7
`
`Regarding diabetic retinopathy, in the Ranibizumab for Edema of the mAcula 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
`letters and a reduction in foveal thickness of 70 µm. The authors concluded that more aggressive therapy (monthly
`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
`studies, monthly ranibizumab dosing versus sham for 6 months showed clear improvement with ranibizumab over
`sham. Then, during the second 6 months, sham group patient vision improved because they were able to receive
`ranibizumab, but at month 12 their vision was not as good as that in patients in the ranibizumab groups, because
`they had received far fewer doses by month 12.9,10
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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
`the most common procedure performed in ophthalmology. It is estimated that more than 6 million injections were
`performed in the United States in 2016 alone. 11
`
`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
`major VEGF blocker, aflibercept, will soon be available in a prefilled syringe. Prefilled syringes are a boon to
`patients requiring this treatment (generally our largest patient group) and retinal physicians because of the
`decreased endophthalmitis risk, dose accuracy, and improved clinic efficiency they can provide.
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`Novartis Exhibit 2271.002
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`Figure 1. Prefilled syringe loaded with anti-VEGF agent.
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`ENDOPHTHALMITIS RISK
`
`Repetitive administration of these agents can be challenging for patients, not only from a frequency perspective,
`but also because of the risk involved for endophthalmitis with repeated injections. Postinjection endophthalmitis is
`one of the most serious complications that can occur. If prefilled syringes are not utilized, transfer from vials to
`syringes and filtered-injection needle exchanges increase chances of contamination and subsequently patient risk
`for endophthalmitis. The risk of endophthalmitis with an intravitreal injection has been studied extensively. Large
`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
`
`Recently, a retrospective cohort study was done to determine whether sterile preloading of anti-VEGF agents
`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),
`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
`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
`study, 1 case of endophthalmitis occurred every 2,857 injections, this translates into the potential of avoidance of 1
`out of every 3 cases of endophthalmitis - a highly significant result.
`
`DOSE ACCURACY
`
`Therapeutic doses of intravitreal anti-VEGF drugs (1.25 mg bevacizumab, 0.5 or 0.3 mg ranibizumab, and 2.0 mg
`aflibercept) are achieved by injecting a volume of 0.05 ml (50 ml) into the vitreous cavity. Studies have shown
`that the accuracy and reproducibility achieved with the typical syringes used for intravitreal injections can be highly
`variable. 16-19
`
`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.
`Overdelivery was more common than underdelivery (16.3%), but overall precision was enhanced with the use of
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`https://www.retinalphysician.com/issues/2019/march-2019/prefilled-syringe-delivery-of-intravitreal-anti-ve
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`Novartis Exhibit 2271.003
`Regeneron v. Novartis, IPR2021-00816
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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
`efficiency.21·22 Improved efficiency allows for an improved patient experience and allows the physician to treat
`more patients per session.
`
`FUTURE CONSIDERATIONS: NO NEED FOR INTRAVITREAL INJECTION?
`
`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
`reservoir delivery of medication has shown promise in early trials. The ranibizumab port delivery system (PDS;
`Genentech), in particular, has shown promise. Once implanted, the reservoir may be refilled periodically. In the
`phase II LADDER study, the top-line results showed that 80% of patients could go 6 months before requiring a
`refill of the PDS implant. The phase 2 LADDER study included 220 patients randomized to either 1 of 3
`concentrations of ranibizumab (10 mg/ml, 40 mg/ml, or 100 mg/ml) in a reservoir surgically implanted in the
`vitreous cavity or a monthly injection of ranibizumab (,5 mg). Outcomes included the time until a patient needed a
`refill of the implanted ranibizumab delivery system and the effectiveness of each concentration compared to
`monthly injections. Patients treated with the highest ranibizumab concentration were able to go a median of 15
`months before needing a refill of the reservoir in the office. Investigators found that the port delivery treatment was
`also as effective as monthly injections. Currently, a phase 3 study (ARCHWAY) is under way.23
`
`Also, gene therapy delivery brings the hope of allowing for very long-term therapeutic levels of medication through
`cellular nucleus incorporation of the genetic material that may lead to the manufacture of anti-VEGF medication for
`the patient. Adverum Biotechnologies product ADVM-022 uses a proprietary adeno-associated virus vector that
`carries an atlibercept coding sequence. A primate study using one intravitreal injection showed that a single
`injection of ADVM-022 administered intravitreally can generate stable levels of atlibercept found to be within the
`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
`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.
`
`CONCLUSION
`
`At least for the near term, frequent intravitreal injections of anti-VEGF agents will be important for managing
`several of the most common retinal diseases. Using syringes prefilled with the soluble anti-VEGF agents will
`protect patients from the disastrous consequences of endophthalmitis, assure the most efficient manner of precise
`dosing, and assist with patient flow in growing, busy clinics. RP
`
`REFERENCES
`
`1. Campbell RJ , Bronskill SE, Bell CM , Paterson JM, Whitehead M, Gill SS. Rapid expansion of intravitreal drug
`injection procedures, 2000 to 2008: a population-based analysis. Arch Ophthalmol. 2010;128(3):359-362.
`
`2. Christoforidis JB, Hinkle GH, Wang J, et al. Pharmacokinetic properties of intravitreally placed 1-124
`radiolabeled bevacizumab and ranibizumab after vitrectomy and lensectomy in a rabbit model. Retina.
`2013;33(5):946-952.
`
`3. Park SJ , Choi Y, Na YM , et al. lntraocular pharmacokinetics of intravitreal aflibercept (Eylea) in a rabbit model.
`Invest Ophthalmol Vis Sci. 2016;57(6):2612-2617.
`
`https:/ /www. retinal physician. com/issues/2019/ma rch-2019/prefi lled-syri nge-delivery--0f-intravitreal-a nti-ve
`
`Novartis Exhibit 2271.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`https://www.retinalphysician.com/issues/2019/march-2019/prefilled-syringe-delivery-of-intravitreal-anti-ve
`
`Novartis Exhibit 2271.005
`Regeneron v. Novartis, IPR2021-00816
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`
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`23. Awh CC. LADDER trial of the Port Delivery System for ranibizumab: preliminary study results. Late-breaking
`abstract presented at: the 36th Annual Meeting of the American Society of Retina Specialists; July 25, 2018;
`Vancouver, British Columbia, Canada.
`
`24. Adverum Biotechnologies. Long-term aflibercept expression levels in non-human primates following intravitreal
`administration of ADVM-022, a potential gene therapy for wet age-related macular degeneration. Poster
`#P223 presented at the European Society of Gene and Cell Therapy; October 17, 2018; Oxford, UK.
`
`25. Liu Y, Fortmann SD, Shen J, et al. AAV8-antiVEGFfab ocular gene transfer for neovascular age-related
`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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