`v. 29, no. 10 (Nov-Dec 2009)
`General Collection
`W1 RE2498
`2009-11-16 11:42:51
`
`>
`
`>
`
`N
`
`~
`
`y
`
`2
`
`>
`
`NS
`
`a
`
`NN
`
`q
`
`~
`
`’
`
`\i
`
`COMPARISON OF TWO DOSES OF INTRAVITREAL BEVACIZUMAB
`AS PRIMARY TREATMENT FOR MACULAR EDEMA SECONDARY
`TO BRANCH RETINAL VEIN OCCLUSIONS: RESULTS OF THE
`PAN AMERICAN COLLABORATIVE RETINA STUDY GROUP
`Wu, Arevalo, Berrocal, Maia, Roca, Morales-Canton, Alezzandrini, Diaz-Llopis
`AT 24 MONTHS
`VASCULAR EVENTS IN PATIENTS WITH AGE-RELATED MACULAR
`DEGENERATION TREATED WITH INTRAOCULAR BEVACIZUMAB
`Sheybani, Kymes, Schlief, Apte
`A PROSPECTIVE STUDY OF BLOOD PRESSURE AND INTRAOCULAR
`PRESSURE CHANGESIN HYPERTENSIVE AND NONHYPERTENSIVE
`PATIENTS AFTER INTRAVITREAL BEVACIZUMAB INJECTION
`Lee, Yang, Lim, Lew
`INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION
`SECONDARY TO PRESUMED OCULAR HISTOPLASMOSIS SYNDROME
`Ehrlich, Ciulla, Maturt, Kheradiya, Hrisomalos, Shulman, Guess, Coyle, Harris
`“TREAT AND EXTEND” DOSING OF INTRAVITREAL ANTIVASCULAR
`ENDOTHELIAL GROWTH FACTOR THERAPY FOR TYPE 3
`NEOVASCULARIZATION/RETINAL ANGIOMATOUS PROLIFERATION
`Engelbert, Zweifel, Freund
`PHACOEMULSIFICATION WITH INTRAVITREAL BEVACIZUMAB
`INJECTION IN DIABETIC PATIENTS WITH MACULAR EDEMA
`AND CATARACT
`Akinci. Batman, Ozkilic, Altinsoy
`THE COURSE OF RESPONSE TO FOCAL/GRID PHOTOCOAGULATION
`FOR DIABETIC MACULAR EDEMA
`The Diabetic RetinopathyClinical Research Network
`.
`A 1-YEAR RETROSPECTIVE REVIEW OF RANIBIZUMAB FOR NAIVE
`NONSUBFOVEAL CHOROIDAL NEOVASCULARIZATION SECONDARY
`TO AGE-RELATED MACULAR DEGENERATION
`Arias, Ruiz-Moreno, Gomez-l Illa, Fernandez, Montero
`PHOTODYNAMIC EFFECTS ON RETINAL OXYGEN SATURATION, BLOOD
`FLOW, AND ELECTROPHYSIOLOGICAL FUNCTION IN PATIENTS
`WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION
`Tsuchihashi, Mori, Peyman, Shimada, Yoneya
`INTRAOPERATIVE USE OF HANDHELD SPECTRAL DOMAIN OPTICAL
`COHERENCE TOMOGRAPHY IMAGING IN MACULAR SURGERY
`Dayani, Maldonado, Farsiu, Toth
`ENHANCED DEPTH IMAGING OPTICAL COHERENCE TOMOGRAPHY OF
`THE CHOROID IN CENTRAL SEROUS CHORIORETINOPATHY
`{mamura, Fujiwara, Margolis, Spaide
`Mudvari, Ravage, Rezaei
`RETINAL DETACHMENT AFTER PRIMA"™ Poke
`NATIONAL
`€|
`LIBRARY OF
`SSC]
`BDnwewa!—MEDICINE
`
`
`
`PROPERTY OF THE
`
`Sublecr WS Convrieht Laws
`
`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`_
`7
`Page 1
`Joining Petitioner: Apotex
`
`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`Joining Petitioner: Apotex
`
`
`
`
`
` TIN
`
`
`
`
`
`CHARLES P. WILKINSON
`Baltimore, MD
`GEORGE A. WILLIAMS
`Royal Oak, Mi
`
`Diagnostic and Therapeutic Editor
`H. RICHARD McDONALD
`San Francisco, CA
`
`III
`
`THE JOURNAL OF RETINAL AND VITREOUS DISEASES
`EDITOR-IN-CHIEF
`ALEXANDER J. BRUCKER
`Philadelphia, PA
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`*1928-2005
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`Baltimore, MD
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`irvine, CA
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`RONALD G. MICHELS*
`Baltimore, MD
`*1943-1991
`DAVID C. MUSCH
`Ann Arbor, MI
`DAVID H. ORTH
`Chicago, IL
`ARNALL PATZ
`Baltimore, MD
`GHOLAM A. PEYMAN
`Tucson, AZ
`INGRID SCOTT
`Miami, FL
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`Philadelphia, PA
`LAWRENCE J. SINGERMAN
`Cleveland, OH
`JASON §. SLARTER
`New York, N¥
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`Nashville, TN
`YASUO TANO*
`Osaka, Japan
`*1948-2009
`JOHN T. THOMPSON
`Baltimore, MD
`CYNTHIA A. TOTH
`Durham, NC
`LAWRENCE A, YANNUZZI
`New York, NY
`MANAGING EDITOR: TERRY ROTHSTEIN BRUCKER
`ASSOCIATE MANAGING EDITOR: GENE SEABOLT
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`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`Joining Petitioner: Apotex
`
`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`Joining Petitioner: Apotex
`
`
`
`“TREAT AND EXTEND” DOSING OF
`INTRAVITREAL ANTIVASCULAR
`ENDOTHELIAL GROWTH FACTOR
`THERAPY FOR TYPE 3
`NEOVASCULARIZATION/RETINAL
`ANGIOMATOUS PROLIFERATION
`
`MICHAEL ENGELBERT, MD, PHD,*† SANDRINE A. ZWEIFEL, MD,*†‡
`K. BAILEY FREUND, MD*†
`
`Purpose: The purpose of this study was to analyze long-term outcomes for the treat-
`ment of type 3 neovascularization/retinal angiomatous proliferation using a “Treat and
`Extend” dosing regimen for antivascular endothelial growth factor therapy.
`Methods: This was a retrospective analysis of visual acuity and optical coherence
`tomography data of 11 eyes of 10 consecutive patients with newly diagnosed type 3
`neovascularization/retinal angiomatous proliferation treated with intravitreal bevacizumab
`and/or ranibizumab with at least a 12-month follow-up. Three monthly injections were
`followed by continued treatment at intervals increasing by 2 weeks per visit, to a maximum
`of 10 weeks, unless clinical or optical coherence tomography evidence of persistent or
`recurrent fluid was present, in which case, the interval was shortened.
`Results: Mean baseline Snellen visual acuity was 20/80, improved to 20/40 at 1 month,
`and was maintained throughout the 36-month period (n ⫽ 11 at 12 months, n ⫽ 10 at 24
`months, and n ⫽ 8 at 36 months) (P ⬍ 0.04, paired t-test). The mean center point optical
`coherence tomography thickness decreased from 320 m to 180 –230 m, and was
`maintained during the study period (P ⬍ 0.02). The mean number of injections was seven
`in the first year, six in the second year, and seven in the third year.
`Conclusion: “Treat and Extend” antivascular endothelial growth factor dosing in type 3
`neovascularization/retinal angiomatous proliferation delivers promising outcomes at a
`reduced burden for the patient and health care system compared with monthly and optical
`coherence tomography-guided dosing regimens.
`RETINA 29:1424 –1431, 2009
`
`Type 3 neovascularization (otherwise known as reti-
`
`nal angiomatous proliferation [RAP])1,2 is a subtype
`of neovascular age-related macular degeneration (AMD)
`with distinct angiographic and optical coherence tomog-
`raphy (OCT) features related to intraretinal proliferation
`of the abnormal vessels with associated retinal–retinal
`and retinal–choroidal anastomosis. Its natural course is
`
`From the *LuEsther T. Mertz Retinal Research Center, Manhat-
`tan Eye, Ear and Throat Hospital; †Vitreous-Retina-Macula Con-
`sultants of New York, New York, New York; and ‡University
`Hospital Zurich, Department of Ophthalmology, Frauenklin-
`ikstrasse 24, 8032 Zurich, Switzerland.
`Supported by The Macula Foundation Inc.
`Reprint requests: K. Bailey Freund, MD, 460 Park Avenue, 5th
`Floor, NY 10022; e-mail: kbfny@aol.com
`
`typically worse than other more frequent lesion types
`such as subretinal pigment epithelium neovascularization
`(type 1)/occult choroidal neovascularization or subneu-
`rosensory neovascularization (type 2)/well-defined (clas-
`sic) choroidal neovascularization.3–5 Many different
`such as photocoagulation,3,4,7
`treatment
`strategies6
`transpupillary thermotherapy,3,8 photodynamic therapy
`(PDT),9 –13 intravitreal antivascular endothelial growth
`factor (anti-VEGF) agents,6,14,15 intravitreal triamcino-
`lone acetonide, surgical excision,16,17 and many combi-
`nations of the above18 –21 have been tried in small case
`series with limited follow-up.
`Monthly injections of antiangiogenic agents have be-
`come the standard of care for the treatment of neovas-
`
`1424
`
`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`Joining Petitioner: Apotex
`
`
`
`“TREAT AND EXTEND” DOSING FOR TYPE 3/RAP ● ENGELBERT ET AL
`
`1425
`
`cular AMD22,23 but are expensive and difficult to sustain
`in this elderly patient population. However, the less frequent
`dosing in the PIER trial,24 in which patients received quar-
`terly injections after an initial series of three monthly injec-
`tions, could not reproduce the excellent results obtained in
`trials using monthly dosing. The PrONTO Study25,26 at-
`tempted to tailor the dosing to the individual needs of the
`patient based on acuity decline, clinical findings, or OCT
`evidence of disease activity and was able to demonstrate
`good visual results after a ⬎24-month period.
`Although PrONTO-style dosing has become widely
`adopted in the retinal community and seems to yield
`favorable results, this strategy does require monthly vis-
`its, clinical examinations, and OCTs with patients uncer-
`tain if or when they will need treatment. Because eyes
`with type 3 neovascularization/RAP typically manifest
`retinal–choroidal anastomosis, recurrent exudation may
`occur earlier and more frequently than with other neo-
`vascular lesion types. In our experience, some patients
`managed with this strategy will return for assessments
`having already developed macular hemorrhages in the
`injection-free interval with irreversible vision loss.27–29
`In theory, a dosing regimen that does not maintain the
`macula in a “dry” state could deny some patients the
`opportunity for further visual recovery.
`The “Treat and Extend” dosing regimen is a strategy
`intended to resolve macular exudation and maintain the
`macula in this “dry” state indefinitely with, when possi-
`ble, fewer patient visits and treatments than monthly
`dosing.30,31 The strategy consists of an initial induction
`or “loading” sequence of at least three monthly injec-
`tions. If stable visual acuity, an absence of macular
`hemorrhage, and a dry OCT have been achieved at this
`point, patients continue to receive regular maintenance
`injections at increasing intervals. At 6 weeks after the last
`of the three monthly injections, visual acuity, clinical
`findings, and OCT changes are recorded again, and pa-
`tients receive an injection regardless of the presence or
`absence of disease activity. However, the interval to the
`next visit (and scheduled injection) is based on an observed
`change in the above parameters. If there are no changes, the
`next visit is scheduled for 8 weeks later. If there is a change,
`the patient comes for another scheduled injection and ex-
`amination after 4 weeks. The observation and scheduled
`treatment interval is extended (hence the term “Treat and
`Extend”) to a maximum of 10 weeks. We report on 11 eyes
`of 10 patients with type 3 neovascularization/RAP managed
`with the “Treat and Extend” dosing regimen and with
`follow-up of between 12 and 36 months.
`
`Materials and Methods
`
`A waiver of authorization for use of protected
`health information for the above-referenced research
`
`and a waiver of consent for this retrospective chart
`review were obtained from the Institutional Review
`Board committee of the Manhattan Eye Ear and
`Throat Hospital, New York, NY.
`The diagnosis of type 3 neovascularization/RAP was
`made by the treating physician (K.B.F.) based on the
`characteristic clinical, OCT, and angiographic features
`including intraretinal hemorrhage, cystoid macular edema,
`intraretinal vascular anastomosis, retinal–choroidal anasto-
`mosis, and in some cases, the presence of pigment epithelial
`detachment (PED) on OCT. Patients treated previously with
`thermal laser, PDT, or intravitreal pegaptanib (Macugen,
`Pfizer Inc., New York, NY), or who presented with subfo-
`veal fibrosis or atrophy, a history of vitrectomy, aphakia or
`absence of posterior capsule, history of idiopathic or auto-
`immune associated uveitis in either eye, or diabetic retinop-
`athy more severe than mild nonproliferative stage, were
`excluded from this study. Patients with preexisting cardiac
`or cerebrovascular conditions were not excluded from the
`study.
`The treatment consisted of intravitreal injection of
`1.25 mg of bevacizumab (Avastin, Genentech Inc.,
`South San Francisco, CA) or 0.5 mg ranibizumab
`(Lucentis, Genentech Inc.) suspended in 0.05 mL. For
`the purpose of this analysis, no distinction between
`either antiangiogenic drug was made. Before intra-
`vitreal injection, topical anesthesia and surface disin-
`fection with 5% povidone–iodine was performed. In-
`travitreal injections were administered at the time of
`diagnosis and subsequently followed a protocol we
`termed “Treat and Extend.” Patients all received at
`least 3 monthly injections followed by continued treat-
`ment at intervals increasing by 2 weeks per visit once
`visual acuity was stable, OCT showed an absence of
`intra- and subretinal fluid, and all hemorrhage had
`resolved. Resolution of PED was not required before
`treatment intervals were lengthened. The treatment interval
`was extended to a maximum of 10-week “maintenance”
`unless clinical examination or OCTdetected new hemor-
`rhage or persistent/recurrent fluid. In those cases, the inter-
`val was shortened by 2 weeks and maintained at that dura-
`tion, provided this resolved the fluid.
`The main outcome measure in this study was visual
`acuity after treatment. Decrease in retinal thickness,
`number of injections needed, and change in funduscopic
`or tomographic appearance were assessed as well.
`Snellen visual acuity was measured by a certified
`ophthalmic technician. Snellen acuity was converted
`into logarithm of the minimum angle of resolution
`(logMAR) for statistical analysis at baseline and at 1,
`3, 12, 24, and 36 months after injection of an antiangio-
`genic agent. Changes in logMAR-converted acuities
`were tested with a paired Student’s t-test and accepted as
`significant if P ⬍ 0.05. Also, the proportions of patients
`
`Mylan Exhibit 1026
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`Joining Petitioner: Apotex
`
`
`
`1426 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2009 ● VOLUME 29 ● NUMBER 10
`
`
`—
`P
`P
`P
`L
`L
`
`
`
`
`
`————
`—
`
`6
`7
`—
`
`10
`
`
`—
`—
`
`
`
`
`
`6765
`7
`
`163
`181
`
`—
`
`136
`
`197
`218
`225
`199
`134
`
`—
`—
`
`20/40
`20/80
`
`—
`
`20/40
`
`20/50
`20/40
`20/30
`20/30
`20/20
`
`—
`—
`
`10
`
`85
`
`—
`
`
`
`
`
`8566
`7
`
`5
`5
`
`
`
`174
`108
`117
`177
`174
`
`175
`224
`224
`196
`174
`
`—
`
`20/25
`20/30
`20/25
`20/40
`20/200
`
`20/60
`20/40
`20/25
`20/30
`20/20
`
`—
`
`7
`7
`
`
`
`
`
`
`8666
`8
`
`5
`
`
`69
`
`10
`
`166
`315
`216
`254
`121
`232
`166
`118
`186
`150
`174
`
`20/50
`20/40
`20/40
`20/50
`20/25
`20/100
`20/20
`20/25
`20/25
`20/60
`20/100
`
`246
`206
`224
`374
`133
`174
`199
`289
`192
`183
`299
`
`20/40
`20/70
`20/40
`20/30
`20/25
`20/70
`20/30
`20/40
`20/25
`20/50
`20/160
`
`336
`388
`200
`548
`182
`410
`282
`433
`246
`241
`257
`
`91
`20/70
`82
`20/200
`92
`20/30
`76
`20/50
`71
`20/20
`92
`20/200
`83
`20/80
`—20/200
`20/25
`84
`20/50
`85
`20/400
`89
`
`FellowEye
`
`RAPin
`
`NoInj
`Year
`Third
`
`OCT(m)
`Month36
`
`36VA
`Month
`
`Second
`
`NoInj
`Year
`
`OCT(m)
`Month24
`
`24VA
`Month
`
`Month12
`
`NoInj
`
`OCT(m)
`Month12
`
`12VA
`Month
`
`1OCT(m)
`
`Month
`
`1VA
`Month
`
`Baseline
`
`(m)
`OCT
`
`Baseline
`
`VA
`
`(Years)
`
`Age
`
`PatientGender
`
`Table1.SummaryofPatientData
`
`approximately halving (ⱖ0.3 logMAR, but ⬍0.6 log-
`MAR-converted Snellen visual acuity improvement) or
`approximately quartering their visual angle (ⱖ0.6 log-
`MAR-converted Snellen visual acuity improvement), as
`well as those that remained stable (⬍0.3 logMAR-con-
`verted visual acuity improvement) or lost lines on the
`Snellen chart compared with baseline, were reported.
`The quantitative assessments of center point retinal
`thickness were made using Stratus OCT (Carl Zeiss
`Meditec, Dublin, CA) and Topcon OCT (Topcon 3D
`OCT-1000, Topcon Medical Systems, Paramus, NJ).
`The center point retinal thickness was defined as the
`distance between the internal limiting membrane and
`the retinal pigment epithelium under the fovea and did
`not include any fluid under the retinal pigment epithe-
`lium. For Topcon OCT images, the calipers provided
`by the Topcon image analysis software were used.
`The Stratus OCT measurements were made manually
`on the IMAGEnet software on a single horizontal line
`scan through the fovea (Topcon Medical Systems),
`and the calculated data in pixels were multiplied with
`a conversion factor of 8 m/pixel. This conversion
`factor had been derived from previous comparisons of
`controls on the different imaging platforms (based on
`20 normal eyes measured on the 2 platforms, Howard
`F. Fine, personal communication).
`The qualitative assessment included identification
`of intraretinal cysts, neovascular complex within the
`retinal layers, and PED. Additional funduscopic and
`tomographic changes and their development over time
`were recorded as well. Specifically, the presence of
`intraretinal hemorrhage or development of a pigment
`epithelial rip on funduscopy and the presence of intra-
`or subretinal fluid or PED on high-resolution B-scans
`were determined. Because staging of type 3 neovas-
`cularization/RAP is difficult and of controversial sig-
`nificance, this was not performed.
`
`Results
`
`Eleven eyes of 10 patients were included in this
`study. Eleven eyes completed the 12-month follow-
`up, 10 eyes completed the 24-month follow-up, and 8
`eyes completed the 36-month follow-up.
`Patient demographics, baseline, and follow-up vi-
`sual acuity, center point retinal thickness data, and
`number of injections in the first, second, and third year
`are presented in Table 1. Median patient age was 85
`years (range, 71–92 years). Seven of 10 patients were
`women. Two contralateral eyes had evidence of anteced-
`ent type 3 neovascularization/RAP lesions, and 2 pa-
`tients developed disease in the contralateral eye during
`the study period. Only one of these two latter eyes was
`treated with a “Treat and Extend” protocol and included
`
`Inj,injections;P,atpresentation;L,later.
`
`10OS
`9OS
`8OD
`7OS
`6OS
`5OS
`4OS
`3OS—
`3OD
`2OS
`1OD
`
`
`
`FFF
`
`
`
`
`
`
`
`MF MF
`
`
`
`MF
`F
`
`
`
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`“TREAT AND EXTEND” DOSING FOR TYPE 3/RAP ● ENGELBERT ET AL
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`1427
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`Table 2. Optical Coherence Tomography Center Point
`Retinal Thickness of Eyes With Type 3
`Neovascularization/RAP Treated With the “Treat and
`Extend” Dosing Regimen (n at baseline and 1, 3, and 12
`Months ⫽ 11, n at 24 Months ⫽ 10, and n at 36
`Months ⫽ 8)
`
`Baseline
`
`Month
`1
`
`Month
`3
`
`Month
`12
`
`Month
`24
`
`Month
`36
`
`Mean
`Median
`
`320
`282
`
`229
`206
`
`183
`174
`
`191
`174
`
`181
`175
`
`182
`189
`
`This difference was statistically significant at all time points
`(paired 2-tailed Student’s t-test, P ⬍ 0.02).
`
`in the study. The mean number of injections was seven in
`the first year, six in the second year, and seven in the
`third year.
`Mean Snellen visual acuity at presentation was
`20/80 at baseline (n ⫽ 11), improved to 20/40 at 1
`month and 20/30 at 3 months, and was maintained at
`a level of 20/40 during the rest of the 36-month study
`period (n ⫽ 11 at 1, 3, and 12 months, n ⫽ 10 at 24
`months, and n ⫽ 8 at 36 months; Tables 1 and 2;
`Figures 1 and 2). The difference in logMAR-con-
`verted visual acuity was statistically significant at all
`time points (paired 2-tailed t-test, P ⬍ 0.04).
`The center point retinal thickness measurements
`improved in all patients (Table 2) and more rapidly
`
`Fig. 1. Scatter plot of logMAR-converted visual acuity change of
`eyes with type 3 neovascularization/RAP treated with the “Treat and
`Extend” dosing regimen (n at 24 months ⫽ 10). Mean Snellen visual
`acuity at presentation was 20/80 at baseline (n ⫽ 11), improved to
`20/40 at 1 month and 20/30 at 3 months, and was maintained
`thereafter at a level of 20/40. The difference in logMAR-converted
`visual acuity was statistically significant at all time points (paired
`2-tailed t-test, P ⬍ 0.04).
`
`Fig. 2. Scatter plot of logMAR-converted visual acuity change of eyes
`with type 3 neovascularization/RAP treated with the “Treat and Ex-
`tend” dosing regimen (n at 36 months ⫽ 8). The difference in logMAR-
`converted visual acuity was statistically significant at all time points
`(paired 2-tailed t-test, P ⬍ 0.04).
`
`than visual acuity, even in those patients who experi-
`enced initial worsening in visual acuity. Mean center
`point retinal thickness at the time of diagnosis was
`⬃320 m and rapidly decreased to ⬃230 m 1 month
`after the first injection. After the first 3 monthly in-
`jections, center point retinal thickness had decreased
`to ⬃180 m and remained stable at that level during
`the 36-month observation period. This difference was
`statistically significant (paired 2-tailed Student’s
`t-test, P ⬍ 0.02 at all time points).
`The majority of eyes (9 of 11) had PEDs in the area
`of type 3 neovascularization/RAP. During the treat-
`ment period of 36 months, the size of the PED dimin-
`ished in seven of eight eyes and resolved completely
`in four out of eight eyes.
`In the 10 patients we followed for at least 24 months,
`16 recurrences of fluid occurred, 12 during the first year.
`After establishment of a defined treatment interval, 6
`recurrences occurred in 10 patients (Figure 3) during the
`first 24 months of observation. During the cumulative
`observation period of 336 months, a total of 21 recur-
`rences of fluid occurred. Because fluid would not always
`quickly regress within 1 month, a “wet” macula after the
`initial 3 monthly injections was encountered for a total of
`35 of 240 cumulative months of observation in the group
`of 10 patients we followed for 24 months.
`Despite the presence of a presumably vascularized
`PED at presentation in most patients and frequent injec-
`tions (mean of 20 injections after 36 months), we did not
`observe any tears of the pigment epithelium during the
`
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`1428 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2009 ● VOLUME 29 ● NUMBER 10
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`Fig. 3. Color fundus photograph (A) at baseline of an 85-year-old woman showing intraretinal hemorrhages and retinal edema at the inferior edge of the
`fovea characteristic of type 3 neovascularization/RAP. Early- (B) and late-phase (C) fluorescein angiograms at baseline show poorly defined intraretinal
`leakage. Early- (D) and late-phase (E) indocyanine angiograms show a focal area of increasing hyperfluorescence (“hot spot”) consistent with type
`3 neovascularization/RAP. Color fundus photograph (F) at month 39 shows increased pigment hyperplasia and no evidence of exudative changes.
`
`study period. There were no injection-related complica-
`tions such as endophthalmitis or retinal detachment.
`Figure 3 illustrates the case of an 85-year-old
`woman with type 3 neovascularization/RAP treated
`with the “Treat and Extend” dosing strategy. Color
`fundus photograph (A) at baseline demonstrates in-
`traretinal hemorrhages and retinal edema at the infe-
`rior edge of the fovea, characteristic of type 3 neovas-
`cularization/RAP. Early-
`(B) and late-phase (C)
`fluorescein angiograms at baseline show poorly de-
`fined intraretinal late leakage. Early- (D) and late-
`phase (E) indocyanine angiograms show a focal area
`of increasing hyperfluorescence (“hot spot”), consis-
`tent with type 3 neovascularization/RAP. A color fun-
`dus photograph (F) at month 39 shows increased pig-
`ment hyperplasia and no evidence of exudative
`changes. Optical coherence tomography images of the
`same patient as shown in Figure 3 at baseline are
`shown in Figure 4A, and the response to treatment
`after 1, 12, 14, 15, 36, and 44 months is shown in
`Figure 4, B–G. Intra- and subretinal fluid present at
`baseline decreased after the first injection (B), with a
`corresponding visual acuity improvement from 20/200
`at baseline to 20/40. After 3 monthly injections, the
`patient received injections every 6 weeks to 7 weeks
`until, at month 14, a mild recurrence of intraretinal fluid
`was observed (C), with a decline in visual acuity from
`
`20/40 to 20/50. The injection interval was reduced to 5
`weeks. At month 15, the fluid was resolved, and visual
`acuity had returned to 20/40 and remained stable until the
`most recent follow-up visit at 44 months (G). The patient
`continues to receive injections at 5-week intervals.
`
`Discussion
`
`Although intravitreal anti-VEGF therapy has revo-
`lutionized the treatment of neovascular AMD, the
`optimal dosing regimen for these agents remains un-
`certain. Whether different neovascular lesion types
`warrant different dosing regimens is also unclear.
`Type 3 neovascularization/RAP is a subtype of neo-
`vascular AMD which has been difficult to treat21,32
`and usually involves the second eye within 3 years of
`onset in the first involved eye.33
`Preliminary short-term data on visual acuity outcomes
`for the treatment of type 3 neovascularization/RAP with
`bevacizumab have been promising but have not yet led
`to an established consistent dosing regimen.6,15,34 –36
`Although monthly dosing of anti-VEGF agents for
`neovascular AMD have produced results far superior
`to previous treatments such as thermal
`laser and
`PDT,22,23 cost, convenience, and safety concerns have
`prompted studies of less frequent dosing regimens.
`The PIER study24 explored a regimen consisting of
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`“TREAT AND EXTEND” DOSING FOR TYPE 3/RAP ● ENGELBERT ET AL
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`1429
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`study explored three monthly injections followed by
`dosing on an as-needed or PRN basis guided by
`changes in visual acuity, clinical findings, and OCT
`evaluation.25,26 This open-label, prospective, nonran-
`domized study yielded results similar to those of the
`ANCHOR and MARINA studies22,23 with fewer in-
`jections but a similar number of patient visits.
`Although the PrONTO dosing regimen has gained
`popularity, it might not be ideal for patients with
`disease that follows a more relentless course, such as
`type 3 neovascularization/RAP. Furthermore, elderly
`patients with comorbidities often find it difficult or
`impossible to adhere to the monthly visits required
`when following a PrONTO-style dosing regimen.25,26
`Recurrent fluid or possibly a sudden macular hemor-
`rhage may put patients at risk for irreversible vision loss
`in this “wait and watch, treat if necessary” strategy. Also,
`noncompliant patients or patients forced to miss fol-
`low-up visits as a result of illness and/or hospitalization
`may not be suitable candidates for a PrONTO-style reg-
`imen. Finally, although the number of injections and cost
`are reduced with PrONTO-style dosing, patients still
`require monthly OCT evaluations.
`Type 3 neovascularization/RAP tends to follow a
`more aggressive course and has a higher risk of bilat-
`erality than other lesion types. These patients tend to
`be older than the average patient with neovascular
`AMD (median age ⫽ 85 years in this series). With the
`intention of reducing the risk of recurrent exudation or
`vision loss and the burden of monthly visits and the
`overall cost of treatment for these patients, we inves-
`tigated a dosing regimen that we call “Treat and
`Extend.” The “Treat and Extend” regimen consists of
`a minimum of three monthly injections followed by
`examination and treatment intervals which are gradu-
`ally extended provided there is stable visual acuity, no
`hemorrhage on clinical examination, and neither intra-
`nor subretinal fluid on OCT. The interval between
`examinations and treatment is extended in 2-week
`increments until a maintenance interval of ⱕ10 weeks
`is reached. If new hemorrhage or fluid is detected on
`any visit, the interval between evaluations and treat-
`ment is reduced until an interval is found that main-
`tains the macula in a “dry” state.
`The “Treat and Extend” dosing regimen is a tailored
`maintenance regimen which typically achieves reduc-
`tions in patient visits, decreased imaging studies, and
`fewer injections compared with other dosing regi-
`mens, in particular continuous monthly dosing. Al-
`though patients treated with a PrONTO-style regimen
`typically receive fewer injections than those receiving
`monthly dosing, these patients continue to undergo
`monthly examinations and OCT evaluations. In our
`series, patients following the “Treat and Extend” reg-
`
`Fig. 4. Optical coherence tomography images of the same patient as
`shown in Fig. 3 at baseline (A) and after 1, 12, 14, 15, 36, and 44 months
`(B–G). Intra- and subretinal fluid present at baseline decreased after the
`first injection (B), with a corresponding visual acuity improvement from
`20/200 at baseline to 20/40. After 3 monthly injections, the patient received
`injections every 6 weeks to 7 weeks until, at month 14, a mild recurrence
`of intraretinal fluid was observed (C), with loss of 1 line of visual acuity
`to 20/50. The injection interval was reduced to 5 weeks. At month 15, the
`fluid was resolved, and visual acuity had returned to 20/40 and remained
`stable until the most recent follow-up visit at 44 months (G). The patient
`continues to receive injections at 5-week intervals.
`
`three monthly injections followed by mandated quar-
`terly injections. However, this dosing regimen gave
`disappointing results, and this particular fixed-dosing
`strategy has largely been abandoned. The PrONTO
`
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`1430 RETINA, THE JOURNAL OF RETINAL AND VITREOU