Long-term Outcomes of Ranibizumab
`Therapy for Diabetic Macular Edema: The
`36-Month Results from Two Phase III Trials
`
`RISE and RIDE
`
`
`
`David M. Brown, MD,,5 Quan Dong Nguyen, MD, MSc,?"= Dennis M. Marcus, MD,” David S. Boyer, MD,*
`Sunil Patel, MD, PhD,” Leonard Feiner, MD, PhD,* Patricio G. Schlotmann, MD,’ Amy Chen Rundle, MS,®
`Jiameng Zhang, PhD,* Roman G. Rubio, MD,° Anthony P. Adamis, MD,° Jason S. Ehrlich, MD, PhD,®
`J. Jill Hopkins, MD,° on behalf of the RIDE and RISE Research Group*
`
`Purpose: To report 36-month outcomes of RIDE (NCT00473382) and RISE (NCT00473330), trials of rani-
`bizumabin diabetic macular edema (DME).
`Design:
`PhaseIll, randomized, multicenter, double-masked, 3-year trials, sham injection controlled for
`2 years.
`Participants: Adults with DME (n=759), baseline best-corrected visual acuity (BCVA) 20/40 to 20/320
`Snellen equivalent, and central foveal thickness (CFT) >275 um on optical coherence tomography.
`Methods: Patients were randomized equally (1 eye per patient) to monthly 0.5 mg or 0.3 mg ranibizumab or
`sham injection. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg
`ranibizumab. Macular laser was available to all patients starting at month 3; panretinal laser was available as
`necessary.
`Main Outcome Measures: The proportion of patients gaining >15 Early Treatment Diabetic Retinopathy
`Study letters in BCVA from baseline at month 24.
`Results: Visual acuity (VA) outcomes seen at month 24 in ranibizumab groups were consistent through month
`36; the proportions of patients who gained >15 letters from baseline at month 36in the sham/0.5 mg,0.3 mg, and
`0.5 mg ranibizumab groups were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%,
`respectively, in RISE. In the ranibizumab arms, reductions in CFT seen at 24 months were, on average, sustained
`through month 36.After crossoverto 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg
`group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and
`11.1 letters). Per-injection rates of endophthalmitis remained low over time (~0.06% perinjection). The incidence
`of serious adverse events potentially related to systemic vascular endothelial growth factorinhibition was 19.7% in
`patients whoreceived 0.5 mg ranibizumab compared with 16.8% in the 0.3 mg group.
`Conclusions: The strong VA gains and improvementin retinal anatomy achieved with ranibizumab at month
`24 were sustained through month 36. Delayed treatment in patients receiving sham treatment did not seem to
`result in the same extent of VA improvement observedin patients originally randomized to ranibizumab. Ocular
`and systemic safety was generally consistent with the results seen at month 24.
`Financial Disclosure(s): Proprietary or commercial disclosure may be found after
`Ophthalmology 2013; 120:2013-2022
`
`the references.
`
`© 2013 by the American Academy of Ophthalmology. Open access under CC BY-NC-ND license.
`
`= *Group memberslisted online (available at http://aaojournal.org).
`
`In 1985, the Early Treatment Diabetic Retinopathy Study
`(ETDRS)established macular laser photocoagulation as the
`standard of care for diabetic macular edema (DME).!
`Despite widespread use of macular laser for the past
`quarter century,
`its mechanism of action still
`remains
`largely unknown.In contrast, Folkman’s pioneering work in
`angiogenesis led to the discovery of precise molecular
`mechanisms that could be specifically targeted in cancer,
`macular degeneration, and diabetic retinopathy (DR).” The
`subsequent cloning of vascular endothelial growth factor
`
`(VEGF) A by Ferrara and Henzel’ and the creation of
`highly specific VEGF antagonists led to targeted therapy
`for DME with ranibizumab,
`a monoclonal
`antibody
`fragment (Fab,or antigen binding fragment) that potently
`inhibits VEGF.* Randomizedprospectiveclinical trials have
`demonstrated that
`intravitreal
`inhibition of VEGF with
`ranibizumab, given monthly for up to 24 monthsor less
`frequently using a variety of as needed regimens, results
`in rapid and sustained improvements in vision and retinal
`anatomyin patients with DME.° °
`
`© 2013 by the American Academy of Ophthalmology
`Published by Elsevier Inc. Open access under CC BY-NC-ND license
`
`ISSN 0161-64203
`http://dx.doi.org/10. 1016/j.ophtha.2013.02.034
`
`2013
`
`Page 1
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`Exhibit 2055
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
`

`

`Ophthalmology Volume 120, Number 10, October 2013
`
`RIDE and RISE are phase III, multicenter, randomized
`clinical trials that enrolled a total of 759 patients with vision
`loss from DME (best-corrected visual acuity [BCVA], 20/
`40 20/320 Snellen equivalent, and documented macular
`edema with central subfield thickness 275 mm on time-
`domain optical coherence tomography [OCT]), with the
`objective of evaluating the efficacy and safety of intravitreal
`ranibizumab for DME. The 24-month sham-controlled
`outcomes,
`previously
`published
`in Ophthalmology,
`demonstrated that the response to intravitreal inhibition of
`VEGF was rapid and substantial.7 Compared with the
`control treatment of sham injections plus macular laser per
`protocol-specified criteria, statistically significant improve-
`ments in BCVA and reductions in retinal thickness were
`observed on average as early as 7 days after the first rani-
`bizumab injection; these improvements were maintained to
`24 months. Furthermore, in the first 2 years of RIDE and
`RISE, fewer patients treated with ranibizumab experienced
`significant vision loss (15 ETDRS letters), and fewer
`patients treated with ranibizumab developed proliferative
`DR.10 The ocular safety of ranibizumab in patients with
`DME was consistent with previous phase III studies of
`ranibizumab in DME, age-related macular degeneration,
`and retinal vein occlusion.5,10 14
`Although sham-controlled for only the first 24 months,
`the RIDE and RISE studies continued after the primary
`analysis so that additional questions could be addressed.
`The study design allowed for patients in the sham control
`group to cross over and receive monthly 0.5 mg ranibizu-
`mab injections
`in the third year. Patients originally
`randomized to ranibizumab were maintained in a masked
`fashion on their originally assigned regimens of monthly
`0.3 or 0.5 mg. The additional data provide for evaluation of
`3 important clinical questions: (1) Are the results seen after
`24 months of
`ranibizumab treatment maintained over
`a third year of monthly therapy? (2) What is the effect, if
`any, of delayed initiation of treatment with ranibizumab in
`the sham crossover group? (3) Which tested dose of rani-
`bizumab should be recommended over the long term for
`patients with DME, a population that differs from other
`populations with retinal disease treated with anti-VEGF
`therapy in having a higher likelihood of bilateral disease5
`and an elevated risk of
`cardiovascular events
`and
`mortality?15,16 In this report,
`the ongoing efficacy and
`safety of monthly injections of 0.3 mg and 0.5 mg ranibi-
`zumab for DME through 36 months are presented, and the
`questions are addressed.
`
`Methods
`
`RIDE (registered on ClinicalTrials.gov as NCT00473382; accessed
`September 15, 2012) and RISE (registered on ClinicalTrials.gov as
`NCT00473330; accessed September 15, 2012) are methodologically
`identical, phase III, randomized, multicenter, double masked, 3 year
`trials that were sham injectionecontrolled for the first 2 years.
`Adults with decreased vision due to center involved DME and the
`presence of macular edema documented on OCT were eligible to
`enroll. Both trials were designed and conducted in accordance with
`the principles of the Declaration of Helsinki and in compliance with
`the Health Insurance Portability and Accountability Act. The study
`
`2014
`
`protocols were approved by institutional review boards, ethics
`committees, or as applicable. All patients provided written informed
`consent before enrolling as study participants.
`The study methods have been reported in detail elsewhere.7
`Upon completion of
`the 24 month sham controlled treatment
`period (time point for the primary efficacy outcome), sham patients
`were eligible to cross over to receive treatment with monthly 0.5
`mg ranibizumab. Of note, to preserve study masking, all patients
`were asked if
`they wanted to cross over, but only patients
`randomized to sham injection were actually crossed over by the
`study management computer system. After a protocol amendment
`in 2010, sham patients who met predefined vision loss and OCT
`criteria became eligible for early (before month 25) crossover to
`active treatment with monthly 0.5 mg ranibizumab starting in mid
`2010. Patients with study eyes originally randomized to 0.3 or 0.5
`mg ranibizumab continued on the monthly schedule to which they
`originally had been assigned. All patients remained eligible for per
`protocol macular laser beginning at month 3 and throughout the
`duration of the 36 month treatment period on the basis of pre
`specified subjective and objective criteria.
`
`Outcomes
`The primary efficacy outcome measure was the proportion of
`patients who gained 15 ETDRS letters in BCVA score at month
`24 compared with baseline. Secondary outcome measures at month
`36 were analogous to the 24 month outcomes and included the
`proportion of patients who had gained 15 letters from baseline at
`month 36, mean change from baseline in BCVA score over time,
`proportion of patients who lost <15 letters in BCVA score
`compared with baseline, proportion of patients with BCVA Snellen
`equivalent of 20/40 or better, and mean change from baseline in
`central foveal thickness (CFT) over time, as assessed on OCT by
`the central reading center. Exploratory outcomes included the
`proportion of patients with OCT CFT 250 mm and the proportion
`of patients progressing to proliferative DR.
`
`Analysis
`
`The statistical methods used to analyze the data have been
`described in detail elsewhere.7 Analyses for efficacy end points
`were based on the intent to treat (ITT) population, with patients
`grouped according to their assigned treatment. The methods used
`to analyze the 36 month efficacy were the same as those described
`for the analysis of the 24 month end points; however, because most
`patients in the sham group crossed over to receive 0.5 mg ranibi
`zumab monthly in the third year of treatment, analyses of 36 month
`efficacy data consisted of descriptive statistics by treatment group
`with limited formal comparisons made post hoc. Comparisons of
`efficacy at month 36 were between patients actively treated for 3
`years (with monthly 0.3 or 0.5 mg ranibizumab) versus patients
`treated with sham for 2 years followed by treatment for up to 1 year
`with monthly 0.5 mg ranibizumab. Missing data were imputed by
`last observation carried forward.
`Safety analyses were based on the safety evaluable population,
`defined as patients who received at least 1 dose of study drug.
`Patients were grouped according to the treatment received. Patients
`randomized to sham who inadvertently received treatment with the
`active study drug were classified in the active drug treatment
`group. For the sham group, safety outcomes were summarized
`during the 24 month sham controlled period and separately for the
`sham/0.5 mg group during the 36 month study. The sham/0.5 mg
`group consists of patients who received sham only and patients
`who crossed over to receive treatment with monthly 0.5 mg rani
`bizumab in the third year of treatment.
`
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`

`

`Brown et al
`
` Three Years of Ranibizumab for DME
`
`Table 1. Patient Retention and Drug Exposure through Month 36
`
`Category
`
`On study at month 24, n (%)
`On study at month 36, n (%)
`Drug exposure (ranibizumab or
`sham injections)
`Months
`No. of patients
`Total No. of injections
`Per patient
`Mean (SD)
`Median
`
`Sham/0.5 mg
`(N 130)
`
`108 (83.1)
`102 (78.5)
`
`25e36*
`y
`101
`1015
`
`10.0 (1.8)
`11
`
`RIDE
`Ranibizumab
`0.3 mg (N 125)
`0.5 mg (N 127)
`
`105 (84.0)
`98 (78.4)
`
`110 (86.6)
`98 (77.2)
`
`1e36
`125
`3499
`
`1e36
`124
`3765
`
`28.0 (11.2)
`34
`
`30.4 (9.2)
`34
`
`Sham/0.5 mg
`(N 127)
`
`102 (80.3)
`86 (67.7)
`
`25e36*
`y
`89
`881
`
`9.9 (2.3)
`11
`
`RISE
`Ranibizumab
`0.3 mg (N 125)
`0.5 mg (N 125)
`
`105 (84.0)
`98 (78.4)
`
`106 (84.8)
`100 (80.0)
`
`1e36
`125
`3724
`
`1e36
`125
`3562
`
`29.8 (10.2)
`35
`
`28.5 (10.4)
`34
`
`SD standard deviation.
`*Reflects 1 year of ranibizumab 0.5 mg exposure after crossover.
`y
`Number of patients originally randomized to sham who crossed over to ranibizumab 0.5 mg.
`
`Results
`
`Patient Disposition
`
`A total of 594 patients (78.3%) received ranibizumab treatment
`after month 24. At month 36, the proportion of patients remaining
`in the study varied from 67.7% to 80.0% across the treatment
`groups (Table 1). Among the 210 sham patients from both studies
`remaining in the study at month 24 (of 257 originally randomized
`to sham), a total of 190 (91%) crossed over to active treatment with
`monthly 0.5 mg ranibizumab. In the 2 studies, 5 sham patients
`(2.6%) crossed over early, at month 23. The median number of
`ranibizumab injections received by the patients in the sham and
`crossover to 0.5 mg group after crossover (between months 25
`and 36) was 11, whereas patients originally randomized to
`ranibizumab received a median of 34 to 35 injections over their
`3 year treatment period (Table 1).
`
`Visual Acuity Outcomes
`
`Continued treatment with ranibizumab through month 36 resulted
`in maintenance of the efficacy outcomes seen at earlier time points.
`At the 3 year time point, in RIDE, 36.8% of patients receiving 0.3
`mg ranibizumab and 40.2% of patients receiving 0.5 mg ranibi
`zumab had gained 15 ETDRS letters in BCVA from baseline,
`compared with 19.2% of patients treated with sham/0.5 mg
`(P¼0.0026 for comparison of 0.3 mg with sham/0.5 mg, P¼0.0001
`for comparison of 0.5 mg with sham/0.5 mg in post hoc stratified
`calculations; Fig 1 and Table 2).
`In RISE, corresponding
`proportions were 51.2%, 41.6%,
`and 22.0%,
`respectively
`(P < 0.0001 for comparison of 0.3 mg with sham/0.5 mg,
`P¼0.0005 for comparison of 0.5 mg with sham/0.5 mg in post
`hoc stratified calculations; Fig 1 and Table 2).
`Consistent with the maintenance of efficacy measured in terms
`of 15 letter improvement, the average change in BCVA from
`baseline achieved at month 24 was sustained through month 36 in
`patients originally randomized to ranibizumab (Fig 2). In RIDE, the
`mean number of ETDRS letters change from baseline at month 24
`versus change from baseline at month 36 in patients randomized to
`sham, 0.3 mg, and 0.5 mg ranibizumab was 2.3 versus 4.7, 10.9
`versus 10.6, and 12.0 versus 11.4, respectively. In RISE,
`the
`corresponding numbers were 2.6 versus 4.3, 12.5 versus 14.2,
`and 11.9 versus 11.0 (Fig 2). The efficacy of the 0.3 mg and
`
`0.5 mg doses of ranibizumab was similar over 36 months, as
`demonstrated in efficacy data pooled from RIDE and RISE (Fig 3).
`Other measures of BCVA outcome also were consistent with
`the results previously observed at month 24. At month 36, fewer
`patients originally randomized to ranibizumab had lost 15 letters
`from baseline (0.8%e3.9%), compared with patients originally
`randomized to sham (7.7, 8.7%; Fig 1). Likewise, more patients
`treated with ranibizumab from the beginning of
`the study
`completed with a Snellen BCVA equivalent of 20/40 or better,
`and fewer patients originally randomized to ranibizumab
`completed month 36 with a Snellen BCVA of 20/200 or worse
`(Fig 1 and Table 2).
`At baseline, the mean time from first known DME diagnosis to
`study enrollment was 2.3 to 2.4 years in patients randomized to
`sham (comparable to the baseline duration of DME in the groups
`originally randomized to ranibizumab).7 Patients in the sham/
`0.5 mg group thus had DME for approximately 4.5 years before
`initiation of ranibizumab treatment. Because the sham crossover
`group had received only 1 year of
`ranibizumab treatment,
`a comparison was made to assess vision gains achieved after the
`initial 12 months of treatment (Table 3). In pooled data from the
`2 studies, the mean number of letters gained after 12 months of
`monthly ranibizumab was 2.8 letters in the sham/0.5 mg group
`compared with 10.6 and 11.1 letters in the ranibizumab 0.3 mg
`and 0.5 mg groups, respectively. However, the conclusions that
`can be drawn from this observation are limited because the
`groups were no longer fully comparable.
`In evaluating the response of the sham group to delayed rani
`bizumab therapy, it is notable that the average BCVA improve
`ments in the sham group showed relatively little gain after crossover
`to 0.5 mg ranibizumab after month 24 (2.5 letters at month 24 and
`4.5 letters at month 36 in the pooled RIDE/RISE population; Fig 3).
`Because the primary analysis was ITT, the mean BCVA values may
`have been affected by the last observation carried forward method
`of imputing missing data where values from patients who had
`discontinued from the sham group and did not receive treatment
`were
`carried forward. To better understand the potential
`improvements associated with ranibizumab use after 2 years of
`in 70%e74% of
`sham treatment (plus laser, when indicated,
`sham patients through month 247), an analysis was performed in
`the subgroup of patients receiving 1 study drug injection after
`month 24. Sham patients who received at
`least 1 study drug
`injection after month 24 (n¼190) gained on average 7.5 (RIDE)
`
`2015
`
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`

`

`Ophthalmology Volume 120, Number 10, October 2013
`
`RIDE
`
`RISE
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`
`
`
`Figure 1. Thevisual acuity (VA) outcomes at 36 months: percentage of patients who gained >15 or more Early Treatment Diabetic Retinopathy Study
`(ETDRS)letters from baseline VA at 36 months (topleft), percentage of patients who lost >15 ETDRSletters from baseline VA at 36 months (top right),
`percentage ofpatients with vision of the Snellen equivalent of >20/40 at 36 months (bottom left), and percentage of patients with vision of the Snellen
`equivalent of <20/200 at 36 months (bottom right). Vertical bars are 95% confidence intervals for the percentage. Differences shown are unadjusted for
`stratification variables. The last observation carried forward method was used to impute missing data.
`
`and 7.8 (RISE) ETDRSletters from baseline (Fig 4, available at
`http://aaojournal.org). However, this is compared with a 12.1 to
`15.6 letters average gain at month 36 in the similar subset of
`patients originally randomized to ranibizumab whoalso received
`at least 1 dose of study drug after month 24 (Fig 3).
`
`Anatomic Outcomes
`
`study drug injection after month 24, observed OCT reductions
`after sham crossover to ranibizumab were greater than those
`seen using the ITT analysis, as shown by the steeper decline in
`the mean OCT CFT curve (Fig 3). Of note, the OCT thicknesses
`at month 36 were more similar among the groups:
`the sham/
`0.5 mg group at month 36 had an average OCT thickness of
`194.1 fm, compared with 223.4 um in the 0.3 mg group and
`201.9 tm in the 0.5 mg group.
`Consistent with the 24 month outcomes,patients randomized to
`ranibizumab were more likely to experience improvements in DR
`severity as measured by the ETDRSretinopathy severity scale and
`less likely to develop proliferative DR (Table 2). The sham
`crossover group also demonstrated improvements in DR severity
`after crossover to ranibizumab therapy (Table 2).
`
`The mean OCT thickness in the sham group at baseline was
`447.4 um in RIDE and 467.3 um in RISE, matching that of the
`originally randomized ranibizumab groups (all >450 pm). All
`groups at baseline also were well matched with respect to mean
`duration of DME (1.6—2.4 years) and prior therapy for DME
`(68.8%—82% in each of the sham, 0.3 mg, and 0.5 mg groups).
`After 12 months of monthly ranibizumabtherapy, the sham/0.5 mg
`group experienced a reduction (SD) of
`984 wm (142.8)
`Use of Macular and Panretinal Laser Treatment
`
`compared with reductions of 237.9 tum (186.1) and=249.3 um
`(194.8) in the 0.3 and 0.5 mg groups, respectively (Table 3).
`Compared with patients who had been randomized to receive rani
`The average OCT CFT at month 24, after sham treatment but
`bizumab, a much greater proportion of sham patients had received
`macular (19.7%—36% vs. 70% and 74%)or panretinal laser (0%—
`before any ranibizumab exposure, was 292.5 |1m in the sham
`1.6% vs. 11% and 12.3%) at month 24.’ These differences were
`group compared with 463.8 and 478.6 tum at baseline in groups
`originally randomized to ranibizumab. This mayreflect the effect
`maintained through 36 months,
`largely as a result of the
`of laser or thinning associated with ongoingretinal cell loss in the
`difference in laser use during the 24 month sham controlled
`diabetic retina. In patients originally randomized to ranibizumab,
`portion of the studies. Through 36 months,
`the proportion of
`the significant reductions in CFT from baseline observed at month
`patients in the sham/0.5 mg group who received macular laser at
`least once over 36 months was 72.3% in RIDE and 74.0% in RISE,
`24 also were maintained through month 36 (Fig 2). By using the
`ITT analysis that carried forward the last observation from sham
`compared with 21.3% to 40.8% of patients originally randomized to
`patients who discontinued the study before month 24, OCT
`ranibizumab (Table 2). The proportion of patients in the sham/0.5
`reductions after crossover
`from sham injection to 0.5 mg
`mg group who underwent panretinal laser was 13.8% in RIDE
`ranibizumab did not seem to be as great at month 36 as in
`and 12.6% in RISE over 36 months compared with 0.0% to 3.2%
`patients originally randomized to ranibizumab (Fig 2). When
`in patients originally randomized to ranibizumab. The proportions
`considering only the subgroup of patients who received >1
`ofpatients receiving macular laser between months 24 and 36 was
`
`2016
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`
`

`

`Brown et al
`
` Three Years of Ranibizumab for DME
`
`Table 2. Key Efficacy Outcomes at Month 36 in the Intent-to-Treat Population
`
`RIDE
`
`Ranibizumab
`
`RISE
`
`Ranibizumab
`
`Sham/0.5 mg
`(N[130)
`
`0.3 mg
`(N[125)
`
`0.5 mg
`(N[127)
`
`Sham/0.5 mg
`(N[127)
`
`0.3 mg
`(N[125)
`
`0.5 mg
`(N[125)
`
`25 (19.2%)
`
`46 (36.8%)
`
`51 (40.2%)
`
`28 (22.0%)
`
`64 (51.2%)
`
`52 (41.6%)
`
`12.5e26.0
`4.7 (13.3)
`
`2.4e7.0
`43 (33.1%)
`
`25.0e41.2
`120 (92.3%)
`
`87.7e96.9
`55 (42.3%)
`33.8e50.8
`9 (6.9%)
`2.6e11.3
`
`28.3e45.3
`10.6 (12.9)
`
`31.6e48.7
`11.4 (16.3)
`
`8.3e12.8
`71 (56.8%)
`
`48.1e65.5
`121 (96.8%)
`
`93.7e99.9
`69 (55.2%)
`46.5e63.9
`4 (3.2%)
`0.1e6.3
`
`8.6e14.3
`80 (63.0%)
`
`54.6e71.4
`122 (96.1%)
`
`92.7e99.4
`75 (59.1%)
`50.5e67.6
`5 (3.9%)
`0.6e7.3
`
`14.8e29.3
`4.3 (14.9)
`
`1.7e7.0
`49 (38.6%)
`
`30.1e47.0
`116 (91.3%)
`
`86.4e96.2
`54 (42.5%)
`33.9e51.1
`14 (11%)
`5.6e16.5
`
`42.4e60.0
`14.2 (12.8)
`
`33.0e50.2
`11.0 (12.9)
`
`12.0e16.5
`87 (69.6%)
`
`61.5e77.7
`124 (99.2%)
`
`97.6e100
`79 (63.2%)
`54.7e71.7
`5 (4.0%)
`0.6e7.4
`
`8.8e13.3
`72 (57.6%)
`
`48.9e66.3
`122 (97.6%)
`
`94.9e100
`74 (59.2%)
`50.6e67.8
`5 (4.0%)
`0.6e7.4
`
`213.2 (193.5)
`
`261.8 (180.8)
`
`266.7 (207.8)
`
`200.1 (215.6)
`
`261.2 (196.5)
`
`269.1 (178.9)
`
`179.6
`246.8 to
`4 (3.2%)
`
`229.8
`293.8 to
`1 (0.9%)
`
`230.2
`303.2 to
`1 (0.8%)
`
`162.3
`238.0 to
`5 (4.3%)
`
`226.4
`296.0 to
`2 (1.7%)
`
`237.4
`300.8 to
`2 (1.7%)
`
`VA Outcomes
`Gaining 15 ETDRS
`letters, n (%)
`95% CI for percentage
`ETDRS letters change
`from baseline, (SD)
`95% CI for mean
`Gaining 10 ETDRS
`letters, n (%)
`95% CI for percentage
`Loss of <15 ETDRS
`letters, n (%)
`95% CI for percentage
`Snellen 20/40, n (%)
`95% CI for percentage
`Snellen 20/200, n (%)
`95% CI for percentage
`Anatomic Outcomes
`Mean change in CFT
`from baseline (SD), mm
`95% CI for percentage
`3-step progression on
`ETDRS scale, n (%)*
`95% CI for percentage
`2 step progression on
`ETDRS scale, n (%)*
`95% CI for percentage
`3-step improvement on
`ETDRS scale, n (%)*
`95% CI for percentage
`2-step improvement on
`ETDRS scale, n (%)*
`95% CI for percentage
`Progression to PDR by
`ophthalmoscopy, n (%)
`95% CI for percentage
`Laser Treatment
`Patients who received
`macular laser, n (%)
`95% CI for percentage
`Patients who received
`PRP laser, n (%)
`95% CI for percentage
`
`0.1e6.3
`11 (8.9%)
`
`3.9e13.9
`5 (4.0%)
`
`0.6e7.5
`29 (23.4%)
`
`15.9e30.8
`18 (13.8%)
`
`7.9e19.8
`
`0.0e2.5
`1 (0.9%)
`
`0.0e2.5
`17 (14.5%)
`
`8.1e20.9
`46 (39.3%)
`
`30.5e48.2
`6 (4.8%)
`
`1.1e8.5
`
`0.0e2.5
`2 (1.7%)
`
`0.0e4.0
`18 (15.1%)
`
`8.7e21.6
`45 (37.8%)
`
`29.1e46.5
`7 (5.5%)
`
`1.5e9.5
`
`0.6e8.1
`11 (9.6%)
`
`4.2e14.9
`3 (2.6%)
`
`0.0e5.5
`28 (24.3%)
`
`16.5e32.2
`22 (17.3%)
`
`10.7e23.9
`
`0.0e4.1
`5 (4.3%)
`
`0.6e7.9
`18 (15.4%)
`
`8.8e21.9
`45 (38.5%)
`
`29.6e47.3
`3 (2.4%)
`
`0.0e5.1
`
`0.0e4.1
`5 (4.3%)
`
`0.6e8.1
`13 (11.3%)
`
`5.5e17.1
`47 (40.9%)
`
`31.9e49.9
`9 (7.2%)
`
`2.7e11.7
`
`94 (72.3%)
`
`46 (36.8%)
`
`27 (21.3%)
`
`94 (74.0%)
`
`51 (40.8%)
`
`47 (37.6%)
`
`64.6e80.0
`18 (13.8%)
`
`7.9e19.8
`
`28.3e45.3
`4 (3.2%)
`
`0.1e6.3
`
`14.1e28.4
`3 (2.4%)
`
`0.0e5.0
`
`66.4e81.6
`16 (12.6%)
`
`6.8e18.4
`
`32.2e49.4
`0
`
`0.0e0.0
`
`29.1e46.1%
`3 (2.4%)
`
`0.0e5.1
`
`confidence interval; ETDRS
`central foveal thickness; CI
`CFT
`Early Treatment Diabetic Retinopathy Study; PDR
`proliferative diabetic reti-
`nopathy; PRP
`panretinal photocoagulation; VA visual acuity.
`The last observation carried forward method was used to impute missing data. Stratification variables in stratified analyses: baseline VA (55 or >55 letters),
`baseline hemoglobin A1c (8%, >8%), and prior treatment for DME (yes, no).
`*N 124, 117, and 119 (RIDE) and 115, 117, and 115 (RISE) for sham/0.5 mg, 0.3 mg, and 0.5 mg groups, respectively.
`
`5.5% to 9.4% across all treatment groups among patients who
`received at least 1 dose of study drug after month 24. Likewise,
`the proportions of patients who had received at least 1 dose of
`study drug after month 24 and underwent panretinal laser between
`months 25 and 36 was 0% to 2.2% among all groups.
`
`Safety Outcomes
`
`Safety data collected through month 36 were evaluated to
`assess whether the longer term safety profile of ranibizumab
`
`was consistent with that initially observed and to further assess
`the relative long term safety of ongoing monthly 0.3 mg and 0.5
`mg ranibizumab doses. Because the majority of patients in the
`sham group crossed over
`to monthly 0.5 mg ranibizumab
`dosing after month 24 and received 12 months of exposure
`compared with 36 months of exposure in the originally
`randomized groups, comparisons between the groups need to be
`interpreted with caution because the populations are not directly
`comparable with respect
`to the duration of
`ranibizumab
`exposure.
`
`2017
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2055 Page 5
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`

`

`Ophthalmology Volume 120, Number 10, October 2013
`
`2
`
`4
`
`6
`
`8
`
`ToT TT TT TT TT tt Tt TT
`10
`12
`14 16
`18 20 22
`24 26 28
`30 32 34 36
`Month
`
`from T
`letters MeanBCVAchange
`
`
`baseline,
`
`
` MeanchangeinCFT,pm
`
`0
`
`TT rr
`2
`4
`6
`8
`10
`12
`14 16
`18 20
`Month
`
`22 24 26 28
`
`T
`30 32
`
`T
`34 36
`
`Figure 2. Mean change in best-corrected visual acuity (BCVA) and central foveal thickness (CFT) from baseline over time. Vertical bars are 95%
`confidence intervals. Missing data were imputed bylast observation carried forward.
`
`—t—Sham —%r—Sham/0.5 mg -=-O== Ranibizumab 0.3 mg ==: Ranibizumab 0.5 mg
`
`Ocular Safety
`
`Key study eye ocular safety data are summarized in Table 4
`(available at http://aaojoumal.org). The ocular safety profile was
`consistent with the sham controlled safety observations from the
`24 month analysis. In particular, rates of procedure related serious
`adverse events (SAEs), such as endophthalmitis and traumatic
`cataract, remained low. The total number of patients in the rani
`bizumabtreatment groups experiencing endophthalmitis or trau
`matic cataract in the study eye over the 36 month treatment period
`across both studies was 6 (1.2%) and 4 (0.8%), respectively. The
`per injection rate of endophthalmitis was approximately 0.06%,
`whereas the perinjection rate of traumatic cataract was 0.03%
`(Table 5, available at http://aaojournal.org). Similar proportions of
`the patients randomized to ranibizumab reported an adverse event
`(AE) of increased intraocular pressure at months 24 and 36
`(Table 4, available at http://aaojournal.org). The mean pre dose
`intraocular pressure in the study eye at month 36 in the sham
`and crossover to 0.5 mg, 0.3 mg, and 0.5 mg groups was
`15.4 mmHg, 15.5 mmHg, and 14.9 mmHg,respectively.
`
`Systemic Safety
`
`The long term systemic safety of ranibizumab in DME was eval
`uated using 2 methods. As in previous studies of intravitreal
`ranibizumab across several retinal vascular diseases, we first
`assessed rates of arterial thromboembolic events (ATEs) using the
`AntiplateletTrialists’ Collaboration (APTC) classification,'” which
`is based on a specific and well defined spectrum of ATE AEs:
`vascular deaths (including deaths of unknown cause), nonfatal
`myocardial
`infarction, and nonfatal stroke (Table 6). Overall
`APTC classified AEs occurred in 7.2%, 10.8%, and 10.4% of
`patients in the sham/0.5 mg, 0.3 mg, and 0.5 mg groups, respec
`tively. Among APTCclassified events occurring over 36 months,
`deaths of vascular and unknown causesoccurred in 2%, 3.6%, and
`3.6% of patients in the sham/0.5 mg, 0.3 mg, and 0.5 mg
`
`2018
`
`ranibizumab groups, respectively. The overall incidence of deaths
`through 36 months, including deaths from nonvascular causes, was
`4.4% (11 patients) in the monthly 0.3 mg group, 6.4% (16 patients)
`in the 0.5 mg group, and 2.8% (7 patients) in the sham/0.5 mg
`group (Table 7, available at http://aaojournal.org). Causes of death,
`listed in Table 7, were mostly consistent with those typical of
`patients with advanced complications of diabetes.'* Rates of
`stroke over 3 years were higher in the 0.5 mg group (12 [4.8%])
`compared with the 0.3 mg group (5 [2.0%]) or sham/0.5 mg
`group (6 [2.4%])
`(Table 6). The incidence of myocardial
`infarction through month 36 was 18 (7.2%) in the 0.3 mg group
`and 9 (3.6%) in the 0.5 mg group (Table 6).
`Although the APTC classification system provides useful insight
`into the systemic safety of intraocular anti VEGF therapy, a more
`thorough understanding of systemic anti VEGF safety has devel
`oped over the last several years, primarily because of the use of
`intravenous agents in oncology. As clinical experience with
`systemic anti VEGF agents has grown, additional types and cate
`gories of systemic AEs potentially associated with the use of
`systemic anti VEGF treatment have been identified. These are
`considered “class” effects related to systemic VEGFinhibition.'®
`Categories of these anti VEGF class related AEs include hyper
`tension, proteinuria, arterial and venous thromboembolic events,
`bleeding/hemorrhage (central nervous system and cerebrovascular,
`non—central nervous system), congestive heart failure, fistulae,
`gastrointestinal perforation, and wound healing complications.
`Categorizing SAEs using this second broader approach demon
`strated that the overall incidence of SAEs potentially related to
`systemic VEGF inhibition was higher in patients who received
`0.5 mg ranibizumab compared with 0.3 mg ranibizumab or sham/
`0.5 mg: 49 of 249 (19.7%) versus 42 of 250 (16.8%) and 33 of 251
`(13.1%) (Table 8, available at http://aaojoumal.org). The incidence
`of several categories (central nervous system and cerebrovascular
`hemorrhage, congestive heart failure, hypertension, gastrointestinal
`perforation, proteinuria, and wound healing complications) ap
`peared to increase in a dose dependent fashion in patients with
`
`Page 6
`Regeneron Pharmaceuticals,Inc.
`Exhibit 2055
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals,Inc.
`IPR2023-00884
`
`

`

`Brown et al
`
`+ Three Years of Ranibizumab for DME
`
`RIDE and RISE Pooled
`
`20) RIDE RISE Pooled
`
`
`
`changeinCFT,pm$e8es8
`
` 50) RIDE RISE Pooled Mean
`
`MeanBCVAchange,ETDRSletters
`
`
`
`
`
` MeanBCVAchangefrombaseline,
`
`
`letters
`
` MeanchangeinCFT,pm
`
`
`
`
`
`
`
`
`
`—t—Sham —t—Sham/0.5mg -—O== Ranibizumab 0.3 mg ‘=fRanibizumab 0.5 mg
`
`Figure 3. Mean change in best-corrected visu