The NEW ENGLAND JOURNAL of MEDICINE
`
`l~l _________ o_R_ 1G_ 1_N_A_ L_A_R_ T_1_c_L_E _________ ~II
`
`Pegaptanib for N eovascular Age-Related
`Macular Degeneration
`
`Evangelos S. Gragoudas, M.D., Anthony P. Adamis, M.D.,
`Emmett T. Cunningham,Jr., M.D., Ph.D., M.P.H., Matthew Fein sod, M.D.,
`and David R. Guyer, M.D., for the VEG F Inhibition Study
`in Ocular Neovascularization Clinical Trial Group
`
`ABSTRACT
`
`BACKGROUND
`Pegaptanib, an anti-vascular endothelial growth factor therapy, was evaluated in the
`treatment of neovascular age-related macular degeneration.
`
`METHODS
`We conducted two concurrent, prospective, randomized, double-blind, multicenter,
`dose-ranging, controlled clinical trials using broad entry criteria. Intravitreous injec(cid:173)
`tion into one eye per patient of pegaptanib (at a dose of0.3 mg, 1.0 mg, or 3.0 mg) or
`sham injections were administered every 6 weeks over a period of 48 weeks. The pri(cid:173)
`mary end point was the proportion of patients who had lost fewer than 15 letters of
`visual acuity at 54 weeks.
`
`RESULTS
`In the combined analysis of the primary end point (for a total of 1186 patients), efficacy
`was demonstrated, without a dose-response relationship, for all three doses of pegap(cid:173)
`tanib (P<0.001 for the comparison of0.3 mg with sham injection; P<0.001 for the com(cid:173)
`parison ofl.0 mg with sham injection; and P=0.03 for the comparison of3.0 mg with
`sham injection). In the group given pegaptanib at 0.3 mg, 70 percent of patients lost
`fewer than 15 letters of visual acuity, as compared with 55 percent among the controls
`(P<0.001). The risk of severe loss of visual acuity (loss of 30 letters or more) was re(cid:173)
`duced from 22 percent in the sham-injection group to 10 percent in the group receiving
`0.3 mgofpegaptanib (P<0.001). More patients receivingpegaptanib (0.3 mg), as com(cid:173)
`pared with sham injection, maintained their visual acuity or gained acuity (33 percent vs.
`23 percent; P=0.003). As early as six weeks after beginning therapy with the study drug,
`and a tall subsequent points, the mean visual acuity among patients receiving 0.3 mg of
`pegaptanib was better than in those receiving sham injections (P<0.002). Among the
`adverse events that occurred, endophthalmitis (in 1.3 percent of patients), traumatic
`injury to the lens (in 0. 7 percent), and retinal detachment (in 0.6 percent) were the
`most serious and required vigilance. These events were associated with a severe loss of
`visual acuity in 0.1 percent of patients.
`
`CONCLUSIONS
`Pegaptanib appears to be an effective therapy for neovascular age-related macular de(cid:173)
`generation. Its long-term safety is not known.
`
`From the Massachusetts Eye and Ear lnf1r(cid:173)
`mary, Boston (E.S.G.); and Eyetech Phar(cid:173)
`maceuticals, New York (A.PA, E.T.C., M.F.,
`D.R.G.). Address reprint requests to Dr.
`Gragoudas at the Retina Service, Massa(cid:173)
`chusetts Eye and Ear lnf1rmary and Harvard
`Medical School, 243 Charles St., Boston,
`MA 02114, or at evangelos_gragoudas@
`meei.harvard.edu.
`
`N EnglJ Med 2004;351:2805-16.
`Copyright© 2004 Massachusetts Medical Society.
`
`N ENGL J MED 351;27 WWW.NEJM.0RG DECEMBER 30, 2004
`
`2805
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
`
`Regeneron Exhibit 1063.001
`
`

`

`The NEW ENGLAND JOURNAL oJMEDICINE
`
`T HE USE OF A SPECIFIC ANTAGONIST OF
`
`an angiogenic factor as a strategy to treat
`disease was proposed in the Journal more
`than 30 years ago. 1 Since that time, extensive evi(cid:173)
`dence has suggested a causal role of vascular endo(cid:173)
`thelial growth factor (VEGF) in several diseases of
`the human eye in which neovascularization and in(cid:173)
`creased vascular permeability occur. 1
`12 In humans,
`•
`ocular VEGF levels have been shown to rise synchro(cid:173)
`nously with and in proportion to the growth and
`leakage of new vessels. 2•4 Animal models of corne(cid:173)
`al, 5 iridic, 6 retinal, 7 and choroidal8 neovasculariza(cid:173)
`tion have shown that neovascularization is depen(cid:173)
`dent on the presence ofVEGF. In a complementary
`fashion, the introduction ofVEGF into normal an(cid:173)
`imal eyes resulted in a recapitulation of the patho(cid:173)
`logic neovascularization that occurs in these tissues
`12 Taken together, these data pro(cid:173)
`during disease. 9 •
`vided a strong rationale for the targeting ofVEGF
`in human disorders that manifest as ocular neovas(cid:173)
`cularization and increased vascular permeability.
`Age-related macular degeneration is the leading
`cause ofirreversible, severe loss of vision in people
`55 years of age and older in the developed world,
`and it remains an area ofunmet medical need. 13 The
`neovascular form of the disease represents approx(cid:173)
`imately 10 percent of the overall disease prevalence,
`but it is responsible for 90 percent of the severe vi(cid:173)
`sion loss. 14 It is expected to develop in almost 1 mil(cid:173)
`lion people over the age of 55 years in the United
`States within the next five years, making it a major
`public health issue in an increasing population of
`older persons. 15
`N eovascular age-related macular degeneration is
`characterized by choroidal neovascularization that
`invades the subretinal space, often leading to exu(cid:173)
`dation and hemorrhage. If the condition is left un(cid:173)
`treated, damage to photoreceptors and loss of cen(cid:173)
`tral vision usually result, and after several months to
`years, the vessels are largely replaced by a fibrovas(cid:173)
`cular scar. 16
`18 Patients in whom a central scotoma
`-
`develops have difficulty performing critical tasks
`that are typically associated with central vision, such
`as reading, driving, walking, and recognizing faces,
`and the difficulty has a major effect on their quality
`oflife. 19
`With greater understanding of the pathogenesis
`of neovascular age-related macular degeneration,
`drug therapies targeted at the causal molecular
`mechanisms have been advanced. Pegaptanib (Ma(cid:173)
`cugen), a 28-base ribonucleic acid aptamer (from
`the Latin aptus, to fit; and the Greek meros, part or
`
`region) covalently linked to two branched 20-kD
`polyethylene glycol moieties, was developed to bind
`and block the activity of extracellular VEGF, specif(cid:173)
`ically the 165-amino-acid isoform (VEGF165). Ap(cid:173)
`tamers characteristically bind with high specificity
`and affinity to target molecules, including proteins.
`The binding relies on the specific three-dimensional
`conformation of the properly folded aptamer. To
`prolong activity at the site of action, the sugar back(cid:173)
`bone of pegaptanib was modified to prevent degra(cid:173)
`dation by endogenous endonucleases and exonu(cid:173)
`cleases, and the polyethylene glycol moieties were
`added to increase the half-life of the drug in the vit(cid:173)
`reous. 20
`We hypothesized that the targeting ofVEGF165
`would affect the underlying conditions common to
`all forms of choroidal neovascularization, including
`the three angiographic subtypes of neovascular
`age-related macular degeneration. We conducted
`two concurrent clinical trials to test the short-term
`safety and effectiveness of pegaptanib in patients
`with a broad spectrum of visual acuities, lesion sizes,
`and angiographic subtypes oflesions at baseline.
`
`METHODS
`
`STUDY DESIGN
`We conducted two concurrent, prospective, ran(cid:173)
`domized, double-blind, multicenter, dose-ranging,
`controlled clinical trials at 117 sites in the United
`States, Canada, Europe, Israel, Australia, and South
`America in our study. Patients were eligible for in(cid:173)
`clusion iftheywere 50 years of age or older and had
`subfoveal sites of choroidal neovascularization sec(cid:173)
`ondary to age-related macular degeneration and a
`range of best corrected visual acuity of 20/40 to
`20/320 in the study eye and of 20/800 or better in
`the other eye.
`The angiographic subtype of a patient's lesion
`was defined in relation to the visualization of cho(cid:173)
`roidal new vessels (classic) in the fluorescein an(cid:173)
`giogram. The total area of a predominantly classic
`lesion includes more than 50 percent classic cho(cid:173)
`roidal neovascularization, the total area of a mini(cid:173)
`mally classic lesion includes less than 50 percent
`classic choroidal neovascularization, and the total
`area of an occult lesion includes no classic choroi(cid:173)
`dal neovascularization. The total size of a lesion,
`choroidal neovascularization, or leakage was mea(cid:173)
`sured on a frame on the fluorescein angiogram
`with the optic-disk area as the unit of measure; it is
`equal to 2.54 mm2 • The size of a lesion, choroidal
`
`2806
`
`N ENGL J MED 351;27 WWW.NEJM.0RG DECEMBER 30, 2004
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
`
`Regeneron Exhibit 1063.002
`
`

`

`PEGAPTAN IB FOR AGE-RELATED MACULAR DEGENERATION
`
`neovascularization, or leakage is expressed as mul(cid:173)
`tiples of this standard optic-disk area.
`Patients with all angiographic subtypes of le(cid:173)
`sions were enrolled, and lesions with a total size
`up to and including 12 optic-disk areas (including
`blood, scar or atrophy, and neovascularization)
`were permitted. Details of the method are provided
`in the Supplementary Appendix, available with the
`full text of this article atwww.nejm.org.
`
`TREATMENT AND OUTCOMES
`Patients were randomly assigned to receive either
`sham injection or intravitreous injection of pegap(cid:173)
`tanib (Macugen, Eyetech Pharmaceuticals) into one
`eye every 6 weeks over a period of 48 weeks, for a
`total of nine treatments. To maintain masking of
`the patients, the patients receiving sham injections
`and those receiving the study medication were
`treated identically, with the exception of scleral pen(cid:173)
`etration. All patients (including those receiving
`sham injection) underwent an ocular antisepsis
`procedure and received injected subconjunctival
`anesthetic. The patients receiving sham injections
`had an identical syringe - but without a needle -
`pressed against the eye wall to mimic the active
`doses that were injected through the pars plana into
`the vitreous cavity. The injection technique preclud(cid:173)
`ed the patient from seeing the syringe. To maintain
`masking of the investigators, the study ophthalmol(cid:173)
`ogist responsible for patient care and for the as(cid:173)
`sessments did not administer the injection. In all
`cases, a separate, certified visual-acuity examiner
`masked to the treatment assignment and to previ(cid:173)
`ous measurements of visual acuity assessed distance
`visual acuity.
`Owing to ethical considerations, the use of pho(cid:173)
`todynamic therapy with verteporfin was permitted
`only in the treatment of patients with predominant(cid:173)
`ly classic lesions, as defined in the product label ap(cid:173)
`proved by the Food and Drug Administration, and
`at the discretion of the ophthalmologist, who was
`masked as to the treatment assignment. The pre(cid:173)
`specified primary end point for efficacy was the pro(cid:173)
`portion of patients who lost fewer than 15 letters of
`visual acuity (defined as three lines on the study eye
`chart) between baseline and week 54.
`The trials were designed by the steering com(cid:173)
`mittee of the VEGF [Vascular Endothelial Growth
`Factor] Inhibition Study in Ocular N eovasculariza(cid:173)
`tion Clinical Trial Group. The data were held and
`analyzed by the data management and statistics
`group. The manuscript was prepared by the writing
`
`committee. Dr. Gragoudas chaired the writing com(cid:173)
`mittee, served as the outside academic investigator
`vouching for the veracity and completeness of the
`data analyses, had access to the full data set, and was
`responsible for the decision to submit the manu(cid:173)
`script for publication.
`
`RESULTS
`
`One trial included 586 patients at 58 sites in the
`United States and Canada and was conducted from
`August 2001 through July 2002; the other trial in(cid:173)
`cluded 622 patients at 59 other sites worldwide and
`was conducted from October 2001 through August
`2002. Of the 1208 patients randomly assigned to
`treatment in the two studies (297 patients assigned
`to receive 0.3 mg of pegaptanib; 305 patients,
`1.0 mg of pegaptanib; 302 patients, 3.0 mg of pe(cid:173)
`gaptanib; and 304 patients, sham injections), 1190
`received at least one study treatment (295 patients
`received 0.3 mg of pegaptanib; 301 patients, 1.0 mg
`of pegaptanib; 296 patients, 3.0 mg of pegaptanib;
`and 298 patients, sham injections). The demo(cid:173)
`graphic and ocular characteristics of the patients at
`baseline were similar among the treatment groups
`(Table 1).
`Four patients were not included in the efficacy
`analyses, because a sufficiently standardized assess(cid:173)
`ment of visual acuity was not completed at base(cid:173)
`line. Therefore, a total of1186 patients received at
`least one study treatment, had visual acuity assess(cid:173)
`ments at baseline, and were included in efficacy
`analyses (294 patients who received 0.3 mg of pe(cid:173)
`gaptanib; 300 patients, 1.0 mg of pegaptanib; 296
`patients, 3.0 mg of pegaptanib; and 296 patients,
`sham injections). A total of7545 intravitreous in(cid:173)
`jections of pegaptanib and 2557 sham injections
`were administered. Approximately 90 percent of the
`patients in each treatment group completed the
`study. In all the treatment groups, an average of
`8.5 injections were administered per patient out of
`a possible total of9 injections.
`The general health status of the patients enter(cid:173)
`ing the trial, calculated for all patients receiving pe(cid:173)
`gaptanib as compared with those receiving sham in(cid:173)
`jection, was as follows: hypertension (55 percent in
`the pegaptanib groups vs. 48 percent in the sham(cid:173)
`injection group), hypercholesterolemia (21 per(cid:173)
`centvs. 18 percent), diabetes mellitus (10 percent
`vs. 7 percent), cardiac disorders (35 percent vs. 34
`percent), cerebrovascular disease (3 percent vs.
`1 percent), peripheral arterial disease (3 percent vs.
`
`N ENGL J MED 351;27 WWW.NEJM.0RG DECEMBER 30, 2004
`
`2807
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
`
`Regeneron Exhibit 1063.003
`
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`The NEW ENGLAND JOURNAL oJMEDICINE
`
`Table 1. Demographic and Ocular Characteristics of Patients at Baseline.'~
`
`Characteristic
`
`Sex- no.(%)
`
`Male
`
`Female
`
`Race -
`
`no. (%)t
`
`White
`
`Other
`
`Age- no.(%)
`
`50--64 yr
`
`65-74 yr
`
`75-84 yr
`
`2c8S yr
`
`Angiographic subtype of lesion -
`no. (%)t
`
`0.3 mg Pegaptanib
`(N=295)
`
`1.0 mg Pegaptanib
`(N=301)
`
`3.0 mg Pegaptanib Sham Injection
`(N=296)
`(N=298)
`
`133 (45)
`
`162 (55)
`
`283 (96)
`
`12 (4)
`
`19 (6)
`
`86 (29)
`
`155 (53)
`
`35 (12)
`
`136 (45)
`
`165 (55)
`
`291 (97)
`
`10 (3)
`
`21 (7)
`
`105 (35)
`
`147 (49)
`
`28 (9)
`
`105 (35)
`
`191 (65)
`
`286 (97)
`
`10 (3)
`
`18 (6)
`
`90 (30)
`
`153 (52)
`
`35 (12)
`
`120 (40)
`
`178 (60)
`
`284 (95)
`
`14 (5)
`
`21 (7)
`
`94 (32)
`
`160 (54)
`
`23 (8)
`
`80 (27)
`
`76 (26)
`
`Predominantly classic
`
`Minimally classic
`
`Occult with no classic
`
`Size of lesion§
`
`History of ocular surgery or laser
`treatment -
`no. (%)
`
`Visual acuity
`
`Study eye
`
`Mean
`
`72 (24)
`
`111 (38)
`
`112 (38)
`
`3.7±2.4
`
`123 (42)
`
`78 (26)
`
`108 (35)
`
`115 (38)
`
`4.0±2.4
`
`117 (39)
`
`105 (35)
`
`111 (38)
`
`3.7±2.5
`
`124 (42)
`
`102 (34)
`
`120 (40)
`
`4.2±2.8
`
`124 (42)
`
`52.8±12.6
`
`50.7±12.8
`
`51.1±12.9
`
`52.7±13.0
`
`Median (range)
`
`55 (11-75)
`
`52 (19-77)
`
`53 (14-76)
`
`53 (11-77)
`
`Other eye
`
`Mean
`
`Median (range)
`
`56.2±27.2
`
`68 (3-85)
`
`54.8±27.6
`
`67 (3-85)
`
`56±26.4
`
`65 (4-85)
`
`55.9±27.0
`
`67 (2-85)
`
`'' Plus-minus values are means ±SD.
`t Race was determined by the treating investigators.
`t In relation to the visualization of choroidal new vessels (classic) in the fluorescein angiogram, a predominantly classic
`lesion includes 50 percent or more classic choroidal neovascularization, a minimally classic lesion includes less than 50
`percent classic choroidal neovascularization, and an occult lesion includes no classic choroidal neovascularization.
`§ The size of lesions was measured as the number of optic-disk areas (including blood scar or atrophy and neovasculariza(cid:173)
`tion), each of which is 2.54 mm 2 .
`
`3 percent), and electrocardiographic abnormalities
`(53 percent vs. 48 percent).
`In the combined analysis, all three doses of pe(cid:173)
`gaptanib differed significantly from the sham injec(cid:173)
`tion in terms of the prespecified primary efficacy end
`point (Table 2). A loss of fewer than 15 letters of vi(cid:173)
`sual acuity was observed at week 54 in 206 (70 per(cid:173)
`cent) of294 patients assigned to receive 0.3 mg of
`pegaptanib (P<0.001), 213 (71 percent) of300 pa(cid:173)
`tients assigned to 1.0 mg of pegaptanib (P<0.001),
`and 193 (65 percent) of 296 patients assigned to
`3.0 mg of pegaptanib (P=0.03), as compared with
`
`164 (55 percent) of296 patients assigned to receive
`sham injection. Similar results were obtained when
`the analyses were restricted to the subgroup of pa(cid:173)
`tients who were evaluated both at baseline and at
`week 54 (accounting for 92 percent of those receiv(cid:173)
`ing0.3 mgofpegaptanib, 92 percent of those receiv(cid:173)
`ing 1.0 mg of the drug, 89 percent of those receiving
`3.0 mg of the drug, and 93 percent of those receiv(cid:173)
`ing sham injections); the similar findings indicate
`that missing data probably did not influence the re(cid:173)
`sults. In this population at week 54, a loss of fewer
`than 15 letters was observed in 192 (71 percent) of
`
`2808
`
`N ENGL J MED 351;27 WWW.NEJM.ORG DECEMBER 30, 2004
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
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`PEGAPTAN IB FOR AGE-RELATED MACULAR DEGENERATION
`
`Table 2. Rate ofVisual-Acuity Loss, Measured as the Loss of Fewer Than 15 Letters, in 1186 Patients.'~
`
`Time
`
`0.3 mg Pegaptanib
`(N=294)
`
`1.0 mg Pegaptanib
`(N=300)
`
`3.0 mg Pegaptanib
`(N=296)
`
`P Value
`vs. Sham
`Injection
`
`0.01
`
`<0.001
`
`<0.001
`
`<0.001
`
`No.(%)
`
`259 (86)
`
`239 (80)
`
`229 (76)
`
`213 (71)
`
`P Value
`vs. Sham
`Injection
`
`0.04
`
`<0.001
`
`<0.001
`
`<0.001
`
`No.(%)
`
`251 (85)
`
`224 (76)
`
`222 (75)
`
`193 (65)
`
`P Value
`vs. Sham
`Injection
`
`0.13
`
`0.003
`
`<0.001
`
`0.03
`
`No.(%)
`
`256 (87)
`
`242 (82)
`
`220 (75)
`
`206 (70)
`
`Week 12
`
`Week 24
`
`Week 36
`
`Week 54
`
`Sham
`Injection
`(N=296)
`
`No.(%)
`
`237 (80)
`
`190 (64)
`
`175 (59)
`
`164 (55)
`
`'' The differences between the doses of pegaptanib were not significant.
`
`271 patients assigned to receive 0.3 mg ofpegap(cid:173)
`tanib (P<0.001), 198 (72 percent) of275 patients
`assigned to 1.0 mg of the study drug (P<0.001), and
`166 (63 percent) of264 patients assigned to 3.0 mg
`ofpegaptanib (P=0.14), as compared with 154 (56
`percent) of 275 patients assigned to sham injec(cid:173)
`tion. There was no evidence in any of the analyses
`that pegaptanib at 1.0 mg or 3.0 mg was more ef(cid:173)
`fective than at 0.3 mg. The results of the two trials
`were similar, with both reaching statistical signifi(cid:173)
`cance for the primary efficacy end point (0. 3 mg of
`pegaptanib, P = 0.03 and P=0.01).
`The outcomes for the secondary end points were
`consistent with those for the primary end point. A
`greater proportion of the patients treated with pe(cid:173)
`gaptanib maintained or gained visual acuity (that
`is, they had no change in the number ofletters or a
`gain of one or more letters). For the combined
`analysis, 33 percent of patients receiving 0.3 mg of
`pegaptanib (P=0.003), 37 percent of those receiv(cid:173)
`ing 1.0 mg (P<0.001), and 31 percent of those re(cid:173)
`ceiving 3.0 mg (P=0.02) maintained vision or
`gained vision as compared with 23 percent of those
`receiving sham injection. At week 54, larger pro(cid:173)
`portions of patients receiving pegaptanib, as com(cid:173)
`pared with those receiving sham injection, also
`gained 5, 10, or 15 letters of visual acuity (approxi(cid:173)
`mately equivalent to one, two, and three lines on the
`study eye chart, respectively) (Table 3).
`Patients in the sham-injection group were twice
`as likely to have a severe loss of vision (i.e., a loss of
`30 letters or more or six lines on the study eye chart)
`as patients receiving pegaptanib at 0.3 mg (22 per(cid:173)
`centvs. 10 percent, P<0.001) or 1.0 mg (22 percent
`vs. 8 percent, P<0.001). Among patients receiving
`a dose of3.0 mg, 14 percent had severe vision loss
`
`(P=0.01 for the comparison with the sham-injec(cid:173)
`tion group) (Table 3).
`A smaller percentage of patients receiving pe(cid:173)
`gaptanib had a Snellen equivalent visual acuity of
`20/200 or worse, or legal blindness, in the study eye
`at week 54 than of those in the sham-injection group
`(pegaptanib at 0.3 mg, 38 percent; 1.0 mg, 43 per(cid:173)
`cent; 3.0 mg, 44 percent; sham injection, 56 per(cid:173)
`cent; P<0.001 for the comparison between all
`treatment groups and the sham-injection group)
`(Table 3).
`The effectiveness of pegaptanib was evident as
`early as the first study visit after the treatment was
`started (week 6), and it increased over time up to
`week 54, as measured by the mean loss of visual
`acuity from baseline to each study visit as compared
`with that in the sham-injection group (P<0.002
`at every point for a dose ofpegaptanib at 0.3 mg
`or 1.0 mg, and P<0.05 at every point for a dose of
`3.0 mg) (Fig. lA).
`There was no evidence that any angiographic
`subtype of the lesion, the size of the lesion, or the
`level of visual acuity at baseline precluded a treat(cid:173)
`ment benefit. For those receiving pegaptanib at
`0.3 mg, a treatment benefit was observed among all
`patients with all angiographic subtypes of lesions
`(P<0.03 for each subtype) (Fig. lB), baseline lev(cid:173)
`els of visual acuity ( <54 or ~54 letters, P<0.01 for
`each group) (Fig. lC), and lesion sizes at baseline
`( <4 or ~4 optic-disk areas, P<0.02 for each group)
`(Fig. lD). Numerically superior outcomes were ob(cid:173)
`served among patients with different subtypes ofle(cid:173)
`sions treated with pegaptanib at 1.0 mg and 3.0 mg
`as well (Fig. lB). The results of multiple logistic(cid:173)
`regression analyses revealed that no factor other
`than assignment to treatment with pegaptanib was
`
`N ENGL J MED 351;27 WWW.NEJM.ORG DECEMBER 30, 2004
`
`2809
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`The New England Journal of Medicine
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`The NEW ENGLAND JOURNAL oJMEDICINE
`
`Table 3. Maintenance, Gain, and Severe Loss ofVisual Acuity with Pegaptanib and Sham Injection.'~
`
`End Points
`
`Maintenance or gain 2c0 letters -
`
`no. (%)
`
`P value vs. sham injection
`
`Gain 2cS letters -
`
`no. (%)
`
`P value vs. sham injection
`
`Gain d0 letters -
`
`no. (%)
`
`P value vs. sham injection
`
`Gain dS letters -
`
`no. (%)
`
`P value vs. sham injection
`
`Loss 2c30 letters -
`
`no. (%)
`
`P value vs. sham injection
`
`Visual acuity in study eye eo20/200 (legal
`blindness) -
`no. (%)
`
`0.3 mg Pegaptanib 1.0 mg Pegaptanib 3.0 mg Pegaptanib Sham Injection
`(N=294)
`(N=300)
`(N=296)
`(N=296)
`
`98 (33)
`
`0.003
`
`64 (22)
`
`0.004
`
`33 (11)
`
`0.02
`
`18 (6)
`
`0.04
`
`28 (10)
`
`<0.001
`
`111 (38)
`
`110 (37)
`
`<0.001
`
`69 (23)
`
`0.002
`
`43 (14)
`
`0.001
`
`20 (7)
`
`0.02
`
`24 (8)
`
`<0.001
`
`128 (43)
`
`93 (31)
`
`0.02
`
`49 (17)
`
`0.12
`
`31 (10)
`
`0.03
`
`13 (4)
`
`0.16
`
`40 (14)
`
`0.01
`
`129 (44)
`
`67 (23)
`
`36 (12)
`
`17 (6)
`
`6 (2)
`
`65 (22)
`
`165 (56)
`
`P value vs. sham injection
`
`<0.001
`
`<0.001
`
`0.001
`
`'' Where data were missing, the last-observation-carried-forward method was used. P values were calculated with the use
`of the Cochran-Mantel-Haenszel test. Loss of 30 or more letters was defined as severe loss of visual acuity.
`
`significantly associated with this response (0. 3-mg
`dose, P<0.001).
`The majority (78 percent) of the study patients
`never received photodynamic therapy while in the
`study (at or after the baseline evaluation), and 75
`percent of the patients never received photodynam(cid:173)
`ic therapy at any time (i.e., they had no history of
`photodynamic therapy, nor did they receive the
`treatment during the study) in the study eye. The
`rate of use of this therapy before enrollment and at
`baseline was similar among the treatment groups;
`therapy before enrollment was used for stratifica(cid:173)
`tion at randomization. A history of photodynamic
`therapy was reported at baseline by 24 patients re(cid:173)
`ceiving pegaptanib at 0.3 mg (8 percent), 29 patients
`receiving 1.0 mg (10 percent), 27 patients receiving
`3.0 mg (9 percent), and 18 patients receiving sham
`injections (6 percent).
`The study investigators administered photody(cid:173)
`namic therapy at baseline to 36 patients receiving
`0.3 mg of pegaptanib (12 percent), 31 patients re(cid:173)
`ceiving 1.0 mg (10 percent), 38 patients receiving
`3.0 mg (13 percent), and 40 patients receiving sham
`injections (13 percent). A slightly higher proportion
`of patients receiving sham injections than those re(cid:173)
`ceiving pegaptanib received photodynamic therapy
`after baseline, suggesting a possible bias against
`pegaptanib. After baseline, photodynamic therapy
`was administered to 49 patients receiving 0.3 mg
`of pegaptanib (17 percent), 55 patients receiving
`
`1.0 mg (18 percent), 57 patients receiving 3.0 mg
`(19 percent), and 62 patients receiving sham injec(cid:173)
`tions (21 percent). Therefore, the treatment benefit
`of pegaptanib was present despite the higher rate
`
`Figure 1 (facing page). Mean Change in Scores for Visual
`Acuity.
`Panel A shows the mean changes in visual acuity from
`baseline to week 54 (P<0.002 at every point for the com(cid:173)
`parison of0.3 mg or 1.0 mg of pegaptanib with sham in(cid:173)
`jection at week 54, and P<0.05 at every point for the com(cid:173)
`parison of3.0 mgofpegaptanibwith sham injection at all
`other points after baseline). Panels B, C, and D show the
`mean changes in visual acuity according to the angio(cid:173)
`graphic subtype, visual acuity, and lesion size at baseline,
`respectively. In relation to the visualization of choroidal
`new vessels (classic) in the fluorescein angiogram, a pre(cid:173)
`dominantly classic lesion includes 50 percent or more
`classic choroidal neovascularization, a minimally classic
`lesion includes less than 50 percent classic choroidal neo(cid:173)
`vascu larization, and an occult lesion includes no classic
`choroidal neovascularization. For lesion size, the unit of
`measurement was one optic-disk area, equal to 2.54 mm 2 .
`For this analysis, lesions were categorized as less than
`four optic-disk areas or four or more optic-disk areas in
`size. In Panels B, C, and D, the asterisk denotes P<0.05
`for the comparison of pegaptanib with sham injection,
`the single dagger P<0.001 for the comparison of pegap(cid:173)
`tanib with sham injection, and the double dagger P<0.01
`for the comparison of pegaptanib with sham injection.
`Of a total of 1186 patients, 294 received 0.3 mg of pegap(cid:173)
`tanib, 300 received 1.0 mg of pegaptanib, 296 received
`3.0 mg of pegaptanib, and 296 received sham injection.
`
`2810
`
`N ENGL J MED 351;27 WWW.NEJM.ORG DECEMBER 30, 2004
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
`
`Regeneron Exhibit 1063.006
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`

`

`PEGAPTAN IB FOR AGE-RELATED MACULAR DEGENERATION
`
`~ \:~:~: ...... •-•--=•=,---o ~ LO m, ec,ap<aoob
`
`- -. A·---·-·-·.6·- - --□---:: 0
`- --.o,__ __ _
`"' _ 0.3 mg Pegaptanib
`,,_
`3.0 mg Pegaptanib
`
`CJ
`
`-+ _
`............... + ____ ____
`
`----+ ___ ___
`
`--- - + ----+ ........ ___
`
`-~'~s
`
`z;(cid:173)
`·;;
`u
`<(
`oi-
`
`-~ t >::::
`
`,:..!:!
`·- 4--
`0J 0
`bJl
`.
`s:: 0
`"'s::
`..s::-u
`s::
`"' OJ
`::i:
`
`+ "-,
`'
`
`'+--
`
`- A -
`
`-
`
`-]
`8
`=9
`-10
`-11
`-12
`-13
`-14
`~-+
`-15
`Sham injection
`-16
`-17 -+ - - -~ -~~ -~ - -~ - -~ - -~ -~ - -~ - -~
`0
`12
`18
`24
`30
`36
`42
`48
`54
`
`A
`
`B
`
`C
`
`Weeks
`
`No. at Risk
`0.3 mg Pegaptanib 294
`1.0 mg Pegaptanib 300
`3.0 mg Pegaptanib 296
`Sham injection
`296
`
`286
`292
`286
`291
`
`289
`291
`283
`288
`
`269
`291
`281
`287
`
`273
`287
`283
`281
`
`271
`285
`278
`282
`
`265
`278
`273
`278
`
`271
`270
`267
`275
`
`266
`267
`259
`269
`
`271
`275
`264
`275
`
`■ 0.3 mg Pegaptanib D 1.0 mg Pegaptanib D 3.0 mg Pegaptanib D Sham injection
`
`18
`
`16
`
`-~
`::,
`u
`14
`<(
`oi
`: : , - 12
`·- ~ > OJ
`"'"'
`-=] 10
`OJ4--
`8
`"' 0
`"' OJ ci
`~-C
`~ s::
`s::
`"' OJ
`::i:
`
`6
`
`4
`
`2
`
`-
`
`--
`
`*
`
`.:!:..
`
`J.
`
`0
`
`-
`
`Predominantly
`Classic Lesion
`
`Minimally
`Classic Lesion
`
`Occult with No
`Classic Lesion
`
`■ 0.3 mg
`Pegaptanib
`
`D 1.0mg
`Pegaptanib
`
`D 3.0 mg
`Pegaptanib
`
`D Sham
`injection
`
`■ 0.3 mg
`Pegaptanib
`
`D 1.0mg
`Pegaptanib
`
`D 3.0 mg
`Pegaptanib
`
`D Sham
`injection
`
`D
`
`z;-
`·;;
`u
`<(
`oi
`: : , -
`
`OJ4--
`
`-~ ~ >~ 12
`-=1 10
`"' 0
`"' ci
`8
`~ u
`s::
`6
`OJ-
`C
`s::
`"'
`OJ
`::i:
`
`20
`
`18
`16
`
`14
`
`4
`
`2
`0
`
`1
`
`18-
`
`16-
`
`14-
`
`12-
`
`10-
`
`8-
`
`6-
`
`4-
`
`2-
`
`*
`1
`
`2:54 Letters
`
`0 -~
`<4 Optic-Disk
`Areas
`
`2:4 Optic-Disk
`Areas
`
`-
`
`* r <54 Letters
`
`N ENGL J MED 351;27 WWW.NEJM.0RG DECEMBER 30, 2004
`
`2811
`
`The New England Journal of Medicine
`Downloaded from nejm.org on July 14, 2020. For personal use only. No other uses without permission.
`Copyright© 2004 Massachusetts Medical Society. All rights reserved.
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`Regeneron Exhibit 1063.007
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`

`The NEW ENGLAND JOURNAL oJMEDICINE
`
`of use of photodynamic therapy among patients re(cid:173)
`ceiving sham injections.
`On the two angiographic examinations, there
`was a slowing in the growth of the total area of a
`lesion, the size of choroidal neovascularization, and
`the severity ofleakage in the groups receiving pe(cid:173)
`gaptanib as compared with the sham-injection
`group (Table 4). A difference was evident at weeks
`30and 54.
`The rate of discontinuation of therapy due to
`adverse events was 1 percent in the pegaptanib
`groups and 1 percent in the sham-injection group.
`The reasons for discontinuation were diverse and
`were not clustered in relation to a particular system
`or organ. No systemic adverse events were defini(cid:173)
`tively attributed by the independent data manage(cid:173)
`ment and safety monitoring committee to the study
`drug, nor were any observed for any organ system
`in all three treatment groups. In a comparison of
`rates of adverse events (for all doses of pegaptanib
`as compared with sham injection), no significant
`difference was observed in the rates of vascular hy(cid:173)
`pertensive disorders (10 percent in all groups); hem(cid:173)
`orrhagic adverse events (2 percent and 3 percent,
`respectively); thromboembolic events (6 percent in
`all groups), and gastrointestinal perforations (0 in
`all groups). The baseline laboratory values were
`
`Table 4. Changes in Size of Lesion, Extent of Choroid al Neovascularization
`(CNV), and Leakage over Time in 1186 Patients.
`
`Variable'~
`
`Total size of lesion
`
`Baseline
`
`Wk 30
`
`Wk 54
`
`Total size ofCNV
`
`Baseline
`
`Wk 30
`
`Wk 54
`
`Total size of leakage
`
`Baseline
`
`Wk 30
`
`Wk 54
`
`3.0mg
`1.0mg
`0.3 mg
`Pegaptanib Pegaptanib Pegaptanib
`(N=294)
`(N=300)
`(N=296)
`
`Sham
`Injection
`(N=296)
`
`3.7
`
`4.9
`
`5.5t
`
`3.1
`
`4.0
`
`4.7
`
`3.3
`
`4.0t
`4.3
`
`4.0
`
`5.0
`
`5.8t
`
`3.5
`
`4.2
`
`4.7t
`
`3.4
`
`3.6t
`3.9t
`
`3.7
`
`5.2
`
`6.2
`
`3.2
`
`4.2
`
`5.0
`
`3.4
`
`4.2
`
`4.6
`
`4.2
`
`5.7
`
`6.7
`
`3.7
`
`4.9
`
`5.8
`
`3.6
`
`4.9
`
`5.2
`
`'' The total size of a lesion, choroidal neovascularization, or leakage was mea(cid:173)
`sured as the number of optic-disk areas, each of which is equal to 2.54 mm 2.
`t P<0.01 for the comparison of the change from baseline with that in the sham(cid:173)
`injection group.
`
`similar in all groups, and median changes in all lab(cid:173)
`oratory values from baseline were small and not
`clinically meaningful. The death rate was 2 percent
`in all groups, which is similar to that seen in other
`studies of age-related macular degeneration in this
`population. 21 No antibodies against pegaptanib
`were detected. There were also no reports oflocal
`or systemic hypers