`
`PUBLISHED 15 OCTOBER 2006
`
`Anita Prasad, MD, Rajendra S. Apte, MD, PhD
`The DRCR Network Aids DR Treatment
`The government-sponsored network allows clinical researchers to communicate more
`effectively.
`
`The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative effort sponsored by the National Eye Institute
`of the National Institutes of Health (U.S. Department of Health and Human Services) for facilitating clinical research into diabetic
`retinopathy, macular edema, and their associated retinal conditions. The Network was formed in 2002 and currently includes
`more than 150 sites (See Figure 1) and 500 physicians. Its main goal is to support the identification, design and implementation
`of multicenter clinical trial research as well as epidemiology studies regarding diabetic eye disease. The Network is joining forces
`of numerous community and university-based clinical centers in order to best determine optimal treatment options for diabetic
`eye disease.
`
`New Options Call for Better Communication
`
`Diabetic eye disease is a leading cause of blindness among adults. Among diabetics over the age of 40 years, the estimated
`prevalence of diabetic retinopathy is approximately 40 percent, with 8 percent of subjects developing vision-threatening retinal
`complications.2
`
`The standard treatment for diabetic macular edema (DME) is focal photocoagulation, the efficacy of which was determined in the
`Early Treatment Diabetic Retinopathy Study (ETDRS).3 However, attempts to treat refractory and persistent edema have led to
`new treatment options under evaluation. Intravitreous and peribulbar corticosteroid injections have been used in recent years to
`reduce macular edema, but large scale prospective studies have yet to be published regarding safety and efficacy. An
`exploratory, Phase II, randomized, controlled trial with the anti-VEGF aptamer Macugen suggested that inhibiting VEGF may be
`beneficial in the management of DME,4 but long-term studies of safety and efficacy of anti-VEGF agents in the treatment of DME
`are lacking.
`
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`Figure 1. Participating sites of the Diabetic Retinopathy Clinical Research Network.
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 1
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`Some of the ongoing studies of the DRCR.net are described below. Each one aims to elucidate some aspect in the treatment of
`diabetic retinopathy, which is becoming more complex as treatment options increase.
`
`Currently Recruiting Studies
`
` • Evaluation of Vitrectomy for Diabetic Macular Edema Study. This is a prospective, non-randomized treatment study, the
`goal of which is to identify subgroups of subjects with DME for whom vitrectomy may or may not be beneficial. The outcomes to
`be evaluated are change in best-corrected visual acuity, change in retinal thickening on OCT, resolution of traction, if present,
`and surgical complications (See Figures 2 and 4). Eligible subjects should have at least one eye in which vitrectomy is being
`used to treat DME as seen on clinical examination. Best corrected visual acuity (BCVA) should be a Snellen equivalent of
`approximately 20/800 or better (ETDRS ≥3 letters); however the acuity in the primary analysis cohort was a Snellen equivalent of
`20/63 to 20/400.
`
`Up to 400 subjects will be enrolled, of which approximately 100 subjects will have macular traction, baseline visual acuity
`between an approximate Snellen equivalent of 20/63 to 20/400, retinal thickness ≥300 µm, and cataract surgery not combined
`with vitrectomy. Subjects will be treated with vitrectomy per the investigator's "usual routine." Data first will be analyzed at six
`months, but the final data collection will occur after three years of follow-up. At this time point, long-term visual outcomes and
`complications such as cataract formation will be analyzed.
`
` • An Observational Study of the Development of Diabetic Macular Edema Following Scatter Laser Photocoagulation.
`This prospective, multi-center nonrandomized treatment study will determine the incidence and extent of macular edema
`following scatter panretinal photocoagulation using ocular coherence tomography measurements. The study will also determine
`if the development of edema varies according to the number of sittings used for the treatment. One-hundred and fifty eyes will be
`included in the study, and eligible eyes should not have macular edema prior to PRP. The study eye must have a central retinal
`thickness ≤299 µm on OCT, and early proliferative or severe nonproliferative diabetic retinopathy that indicates performing
`scatter PRP in one or four sessions.
`
`Figure 2. Pre-vitrectomy OCT image of DME with associated vitreomacular traction. Vision was 20/200.
`
`Treatment will be given as 1,200 to 1,600 burns during one sitting, or four sittings separated by four weeks with a total of 1,200 to
`1,600 burns. Subjects whose treatment is divided into four sessions will receive 300 burns in each of the first two sittings. The
`treatment groups will not be randomized. Study participants will be followed for 34 weeks for the development of retinal
`thickening and change in visual acuity.
`
` • Subclinical Diabetic Macular Edema Study. This is a prospective, multicenter observational study. Its primary objective is to
`
`determine the progression of subclinical DME, which is defined as no edema involving the center of the fovea on biomicroscopy,
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`but with a center point thickness on OCT at least two standard deviations beyond a mean value between 225 and 299 µm.
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 2
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`Progression of the edema is defined as an increase in the center point thickness of at least 50 µm to >300 µm and/or treatment
`for DME. Secondary objectives of the study are to evaluate predictive factors for the presence of subclinical DME and to
`determine the indicators of risk for progression.
`
`Eligible subjects must have a visual acuity of 20/32 or better in the study eye, normal macular thickness on examination not
`indicating treatment, and a center point thickness of 225 to 299 um. A total of 220 subjects will be followed for two years, with
`examinations performed at years one and two. At these time points, investigators will determine the presence of the main
`outcome, which is progression of macular edema as described above, or the development of DME that required treatment.
`
` • A Phase II Evaluation of Anti-VEGF for Diabetic Macular Edema. This study is a Phase II randomized, multicenter clinical
`trial involving 100 subjects. Its goal is to provide preliminary data on the dose and dose- interval-related effects of intravitreous
`bevacizumab (Avastin) on retinal thickness and visual acuity in subjects with DME. This study will also provide preliminary data
`on the safety of intravitreous bevacizumab, and will aid in planning a Phase III anti-VEGF trial.
`
`Figure 3. DME with evidence of exudative changes, macular microaneurysms, and retinal thickening.
`
`Studies in Follow-up Phase
`
` • A Pilot Study of Laser Photocoagulation for Diabetic Macular Edema. This is a randomized multi-center clinical trial
`aiming to compare the ETDRS "standard method" of laser to a "mild macular grid" treatment for DME (See Figure 3). The "mild
`macular grid" treatment is milder in intensity but more extensive in number of spots as compared to the ETDRS laser protocol.
`The study eyes have a visual acuity of 20/400 or better, with definite retinal thickening based on clinical examination at or within
`500 µm of the macular center that indicates laser treatment. OCT measurements show a retinal thickness of 250 µm or more in
`the central subfield, or a thickness of 300 µm or more in any one of four subfields adjacent to the central subfield.
`
`A total of 263 subjects with 323 eligible eyes were randomized to receive either modified ETDRS laser photocoagulation or "mild
`macular grid" photocoagulation. For those subjects with both eyes eligible for the study, one eye was randomized to one
`
`treatment technique, while the other eye received the other treatment technique. Subjects are to be followed for three years, with
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`the primary efficacy outcomes analyzed at one year being the change from baseline in visual acuity and in retinal thickening as
`measured on OCT.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 3
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` • A Randomized Trial Comparing Intravitreous Triamcinolone Acetonide and Laser Photocoagulation for Diabetic
`Macular Edema. This randomized, multicenter trial was designed to determine whether intravitreous triamcinolone acetonide
`(IVT) injections at doses of 1 mg or 4 mg produce greater benefit, with an acceptable safety profile, than macular laser
`photocoagulation in the treatment of diabetic macular edema. The study also aims to compare the safety and efficacy of the 1-
`mg and 4-mg doses of IVT. Subjects had a best-corrected visual acuity approximate Snellen equivalent of 20/40 to 20/320 in the
`study eye. The macular edema involves the central macula as seen on clinical examination and OCT, with a mean retinal
`thickness on two separate OCT measurements ≥250 µm in the central subfield. The fellow eye was either eligible for enrollment
`or had a visual acuity ≥20/400, with no history of previous IVT treatment.
`
`The treatment groups were randomly assigned among 813 eyes of 689 subjects. Subjects with one study eye were randomly
`assigned to one of three treatment groups: laser photocoagulation; 1-mg IVT; or 4-mg IVT. For subjects with two study eyes, the
`right eye was assigned to one of the three treatment groups, and the left eye received the alternative treatment, with the dose of
`IVT randomly assigned.
`
`The subjects will be followed for three years, with a preliminary outcome assessment at the end of one year. Both efficacy and
`safety outcomes will be evaluated. Efficacy is primarily defined as ≥15 letter improvement from baseline at three years, and
`secondarily as change in retinal thickening as measured on OCT. Safety outcomes that will be evaluated include increased
`intraocular pressure or glaucoma, cataract development or surgery, endophthalmitis (bacterial or inflammatory), and retinal
`detachment.
`
` • A Pilot Study of Peribulbar Triamcinolone Acetonide for Diabetic Macular Edema. This Phase II randomized, multicenter
`clinical trial has four objectives: 1) to estimate the incidence of improvement of DME following a posterior peribulbar injection of
`40 mg triamcinolone acetonide compared with laser; 2) to estimate the incidence of improvement of edema following an anterior
`peribulbar injection of 20 mg of triamcinolone acetonide compared with laser; 3) to estimate the incidence of elevated intraocular
`pressure with either type of injection; and 4) to compare the incidence of improvement of macular edema with peribulbar
`triamcinolone alone or followed by laser photocoagulation. Eligible eyes have a visual acuity ≥69 letters, retinal thickening due to
`DME based on clinical examination, and a retinal thickness of ≥250 µm or more in the central OCT subfield. Per the discretion of
`the investigator, the subject should not have already been treated with maximal laser, and should have potential for improvement
`in visual acuity with either peribulbar corticosteroids or laser.
`
`Figure 4. Post-vitrectomy OCT image of the subject in Figure 2. The retinal edema has resolved, and vision has
`improved to 20/80.
`
`The treatment groups are comprised of a total of 113 subjects with 137 randomized eyes, at least 40 of which have not received
`prior treatment for diabetic macular edema. Subjects with one study eye were randomized into one of 5 treatment groups: 1)
`modified ETDRS focal laser photocoagulation; 2) posterior peribulbar injection of 40 mg triamcinolone; 3) anterior peribulbar
`injection of 20 mg triamcinolone; 4) the posterior triamcinolone injection followed in one month by laser; and 5) the anterior
`
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`triamcinolone injection followed in one month by laser. For subjects with both eyes enrolled in the study, one eye was randomly
`assigned to laser and the other eye was randomly assigned to one of the four triamcinolone groups. The subjects are to be
`followed for three years, with the primary efficacy and safety outcomes at eight months. The primary efficacy outcome is visual
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 4
`
`
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`acuity and secondary efficacy outcomes include retinal thickening on OCT, persisting or recurring edema indicating retreatment
`within the first eight months, and a change in the area of retinal thickening with involvement of the central macula based on color
`photos. Safety outcomes to be monitored include IOP elevation or glaucoma, cataract, ptosis, and complications of the injection
`procedure.
`
`Completed Studies
`
` • Temporal Variation in Optical Coherence Tomography Measurements of Retinal Thickening in Diabetic Macular
`Edema. This multicenter observational study involved 107 subjects and occurred on a single day from 7:30 a.m. to 4:30 p.m.
`Eligible subjects had at least one eye with definite retinal thickening due to DME in the central macula, with retinal thickening of
`the central subfield ≥225 µm on OCT. Its objective was to determine the proportion of eyes that demonstrate a meaningful
`change in central retinal thickening measured on OCT throughout the day and to establish a time course of change for eyes that
`experience diurnal change in central retinal thickening. It also evaluated intra-observer and inter-observer variability on OCT
`measurements.
`
`Studies Under Consideration
`
` • Intravitreous anti-VEGF or Steroid in Combination with Laser Photocoagulation for Diabetic Macular Edema. The
`objective of this study currently is planned to be to evaluate the safety and efficacy of intravitreous anti-VEGF treatment or
`intravitreous corticosteroids, alone or in combination with focal photocoagulation in eyes with center-involved diabetic macular
`edema.
`
`The subjects will be followed for three years. Both efficacy and safety outcomes will be evaluated.
`
` • Intravitreous anti-VEGF or Steroid as Adjunctive Treatment to Panretinal (Scatter) Photocoagulation. The objective of
`this study currently is to determine whether either an intravitreous injection of anti-VEGF or an intravitreous injection of
`corticosteroid can reduce the risk of visual acuity impairment that can occur following panretinal photocoagulation in eyes with
`evidence of center-involved macular edema that are undergoing PRP for proliferative diabetic retinopathy. Both efficacy and
`safety outcomes will be evaluated.
`
`All of the above studies require that study participants be ≥18 years old to be eligible for enrollment. Subjects or eye care
`providers or diabetic care providers who are interested in more information may access the network at the website
`http://public.drcr.net.
`
`The four central resource centers in the Network are as follows: Office of the Network Chair, Neil M. Bressler, MD (Wilmer Eye
`Institute at Johns Hopkins University, Baltimore); the Coordinating Center directed by Roy W. Beck MD, PhD (Jaeb Center for
`Health Research, Tampa, Fla.); the Fundus Photograph Reading Center directed by Ronald P. Danis, MD (University of
`Wisconsin-Madison, Madison, Wisc.); and the National Eye Institute under program director Paivi Miskala, PhD (Bethesda, Md.).
`The Barnes Retina Institute at Washington University in St. Louis is a participating site for a number of the protocols described in
`this article.
`
`Physicians interested in being involved with the DRCR.net may apply at the website http://public.drcr.net.
`
`Dr. Apte is an investigator within the DRCR Network but is writing on behalf of himself, not the Network. Contact him at
`Washington University School of Medicine, Dept. of Ophthalmology, 660 S. Euclid Ave., Box 8096, St. Louis, Mo. 63110. E-mail:
`apte@vision.wustl.edu. Dr. Prasad is a fellow at the same site.
`
`
`1. Diabetic Retinopathy Clinical Research Network. Retrieved June 30, 2006 from the National Eye Institute website:
`By using this site, you agree with our use of cookies.
`http://public.drcr.net.
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 5
`
`
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`2. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States.
`Arch Ophthalmol 2004;122:552-563.
`
`3. Early Treatment of Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early
`Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985;103:1796-1806.
`
`4. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-
`vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmol 2005;112:1747-57.
`
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`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2125 Page 6
`
`