Three-Year Outcomes of Individualized
`Ranibizumab Treatment in Patients with
`Diabetic Macular Edema
`
`The RESTORE Extension Study
`
`
`
`Ursula Schmidt-Erfurth, MD,' Gabriele E. Lang, MD,’ Frank G. Holz, MD,’ Reinier O. Schlingemann, MD,*”
`Paolo Lanzetta, MD,°” Pascale Massin, MD, PhD,® Ortrud Gerstner, MSc,’ Abdelkader Si Bouazza,’
`Haige Shen, PhD,'° Aaron Osborne, MD,” Paul Mitchell, MD, PhD,'' on behalf of the RESTORE Extension Study
`Group*
`
`Objective: To evaluate long-term efficacy and safety profiles during 3 years of individualized ranibizumab
`treatment in patients with visual impairment due to diabetic macular edema (DME).
`Design:
`Phaselllb, multicenter, 12-month, randomized core study and 24-month open-label extension study.
`Participants: Of the 303 patients who completed the randomized RESTORE 12-month core study, 240
`entered the extension study.
`Methods:
`In the extension study, patients were eligible to receive individualized ranibizumab treatment as of
`month 12 guided by best-corrected visual acuity (BCVA) and disease progression criteria at the investigators’
`discretion. Concomitant laser treatment was allowed according to the Early Treatment Diabetic Retinopathy
`Study guidelines. Based on the treatments received in the core study, the extension study groups were referred to
`as prior ranibizumab,prior ranibizumab + laser, and laser.
`Main Outcome Measures: Change in BCVA andincidence of ocular and nonocular adverse events (AEs)
`over 3 years.
`Results: Overall, 208 patients (86.7%) completed the extension study. In patients treated with ranibizumab
`during the core study, consecutive individualized ranibizumab treatment during the extension study led to an
`overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year
`extension study (+8.0 letters, —142.1 ym [prior ranibizumab] and +6.7 letters, —145.9 wm [prior ranibizumab +
`laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0
`(mean, 6.0 injections; prior ranibizumab + laser). In the prior laser group, a progressive BCVA improvement (+6.0
`letters) and CRST reduction (—142.7 um) at month 36 were observed after allowing ranibizumab during the
`extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35. Patients in all 3
`treatment groups received a mean of <3 injections in the final year. No cases of endophthalmitis, retinal tear, or
`retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects over 3
`years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were reported during the extension study,
`but none were suspected to berelated to the study drug/procedure.
`Conclusions: Ranibizumab waseffective in improving and maintaining BCVA and CRST outcomes with a
`progressively declining number of injections over 3 years of individualized dosing. Ranibizumab was generally
`well tolerated with no new safety concems over 3 years. Ophthalmology 2014;121:1045-1053
`© 2014 by the American Academy of Ophthalmology. Open access under CC BY-NC-ND license.
`
`=] “Supplemental materialis available at www.aaojournal.org.
`
`Diabetic macular edema (DME)is one of the leading causes of
`visual impairment in the working-age population in developed
`countries.' In addition to DME,patients with diabetes also are
`prone to multiple systemic comorbidities.’ For this large
`population with chronic disease requiring extended lifelong
`therapy in a challenging environment,
`it
`is particularly
`important to identify manageable DMEtreatmentstrategies
`
`that provide long-term safety and efficacy profiles. Although
`focal/grid laser photocoagulation is an established treatment
`option for patients with visual impairment due to DME and is
`known tostabilize vision, it does not appear to be effective in
`improving vision in the majority of patients.” Thus, there is a
`need for treatments that are safe and manageable and that can
`improve vision in patients with DME. Ranibizumab is a
`
`© 2014 by the American Academy of Ophthalmology
`Published by Elsevier Inc. Open access under CC BY-NC-ND license
`
`http://dx.doi.org/10.1016/j.ophtha.2013.11.041
`ISSN 0161-6420/14
`
`1045
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`Page 1
`Regeneron Pharmaceuticals, Inc.
`Exhibit 2058
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc.
`IPR2023-00884
`
`

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`Ophthalmology Volume 121, Number 5, May 2014
`
`humanized monoclonal antibody fragment (Fab) specifically
`designed for ocular use. It binds to vascular endothelial
`growth factor (VEGF)-A with high affinity, inhibits multiple
`isoforms of VEGF-A, and has minimal systemic exposure
`after intravitreal injection.4 Ranibizumab (Lucentis; Novartis,
`Basel, Switzerland and Genentech Inc., South San Francisco,
`CA) is approved in many countries for 4 major indications:
`neovascular age-related macular degeneration, visual impair-
`ment due to DME, visual impairment secondary to macular
`edema in branch or central retinal vein occlusion, and visual
`impairment due to choroidal neovascularization secondary to
`pathologic myopia.5
`Several studies with different dosing regimens and treatment
`algorithms have established the efficacy and safety profiles of
`ranibizumab treatment in patients with DME. Long-term data
`recently became available, allowing the evaluation of continued
`therapy effects and recognizing patterns of chronic disease ac-
`tivity. The Ranibizumab Injection in Subjects with Clinically
`Significant Macular Edema with Center Involvement Second-
`ary to Diabetes Mellitus (RISE [N¼ 377] and RIDE [N ¼ 382])
`studies demonstrated that monthly ranibizumab treatment over
`24 months was well tolerated and associated with superior best-
`corrected visual acuity (BCVA) outcomes compared with
`monthly sham injections.6 Two-year results of the Diabetic
`Retinopathy Clinical Research Network (DRCR.net; N ¼ 691)
`and Ranibizumab for Edema of the mAcula in Diabetes
`(READ-2; N ¼ 126) studies demonstrated that ranibizumab
`alone or in combination with laser (prompt/deferred) provided
`superior and sustained BCVA gains compared with laser
`photocoagulation monotherapy using an individualized dosing
`algorithm.7,8 Of note, the 3-year results of the DRCR.net study
`reported complete BCVA maintenance from year 2 to year 3
`with only 1 to 2 (median) injections in year 3.9 The DRCR.net
`study also permitted less frequent than monthly follow-up for
`patients with stable absence of macular edema. The median
`number of clinic visits in the third year of the DRCR.net study
`was 7 to 8.9 The 3-year outcomes of the READ-2 study sug-
`gested that aggressive retreatment as per individual patient
`needs based on continued or recurrent activity defined by
`intraretinal fluid at the central macula resulted in BCVA
`improvement and reduction in central retinal subfield thickness
`(CRST).10 In contrast to these studies, in the RESTORE study
`ranibizumab
`treatment was
`administered
`using
`an
`individualized dosing regimen based on BCVA stability and
`disease progression criteria,
`in line with the current
`ranibizumab label in European Union (EU).5 The RESTORE
`study aims to address the need to optimally manage patients
`with diabetes by assessing the long-term safety and efficacy
`profiles and the re-treatment needs for ranibizumab.
`The RESTORE core study (registered as NCT00687804 at
`http://clinicaltrials.gov/; accessed June 25, 2013) demonstrated
`that ranibizumab alone or combined with laser provided su-
`perior visual acuity (VA) gains when compared with laser
`monotherapy in patients with visual impairment due to DME
`over 12 months.11 Similar to the core study, in the RESTORE
`extension study, ranibizumab was administered according to
`an individualized dosing regimen based on the investigators’
`discretion;
`treatment was guided by BCVA stability and
`disease progression criteria, with monthly monitoring. All
`patients who completed the core study were eligible to
`
`1046
`
`receive ranibizumab treatment during the extension study.
`The first year
`interim results of
`this extension study
`demonstrated that ranibizumab treatment was well tolerated
`and no new ocular or nonocular safety concerns were
`observed over 2 years. Furthermore,
`the individualized
`dosing regimen was
`successful
`in maintaining (prior
`ranibizumab groups) and improving (prior laser group) the
`BCVA gains observed at the end of the core study over the
`first year of the extension study.12
`The consecutive analysis presented in this article describes
`the extended efficacy and safety findings of individualized
`ranibizumab 0.5 mg treatment based on the complete 3-year
`data of the RESTORE core and extension studies conducted
`in patients with visual impairment due to DME.
`
`Methods
`
`Study Design
`
`The RESTORE extension study was a phase IIIb, 24 month, open
`label, multicenter study (month 12 to month 36) conducted in pa
`tients with DME who completed the 12 month RESTORE core study
`(day 1 to month 12; Fig 1, available at www.aaojournal.org). In the
`RESTORE core study, patients were randomized to receive
`ranibizumab, ranibizumab þ laser, or laser alone. In the extension
`study,
`all patients
`could receive
`individualized ranibizumab
`treatment according to the prespecified stability based BCVA and
`the disease progression re treatment criteria. During the extension
`study, the investigators remained masked to the treatment adminis
`tered during the core study. All patients were eligible to receive laser
`pro re nata (PRN) in accordance with Early Treatment Diabetic
`Retinopathy Study (ETDRS) guidelines at the investigators’ discre
`tion. The study was conducted in accordance with the Declaration of
`Helsinki, and every patient provided new written informed consent
`before entering the extension study. The study is registered with
`clinicaltrials.gov (accessed June 25, 2013; NCT00906464).
`
`Patients
`The RESTORE core study enrolled 345 patients aged 18 years with
`type 1 or 2 diabetes mellitus (per American Diabetes Association or
`World Health Organization guidelines), hemoglobin (Hb) A1c10%,
`and visual impairment due to DME with a BCVA letter score between
`78 and 39 letters, based on ETDRS like VA testing charts at a testing
`distance of 4 m (approximate Snellen equivalent 20/32e20/160).
`Patients who completed the randomized 12 month RESTORE
`core study assessments and provided new written informed con
`sents for the extension were included in the RESTORE extension
`study. Key exclusion criteria for the extension study were history
`of stroke or transient ischemic attack; hypersensitivity to ranibi
`zumab or any component of the ranibizumab formulation; uncon
`trolled glaucoma in either eye (intraocular pressure [IOP] >24
`mmHg with medication or according to investigator’s judgment);
`evidence of vitreomacular traction (in either eye) or active prolif
`erative diabetic retinopathy (study eye); use of other investigational
`drugs at the time of enrollment or within 30 days or 5 half lives
`before enrollment, whichever was longer; and ocular conditions
`in the study eye that required chronic concomitant therapy with
`topical ocular corticosteroids.
`
`Objectives
`
`The primary objective of the RESTORE extension study was to
`evaluate the safety profile of ranibizumab 0.5 mg on the basis of
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2058 Page 2
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`Schmidt-Erfurth et al
`
` Long-term Efficacy and Safety Profiles of Ranibizumab in DME
`
`the incidences of ocular and nonocular adverse events (AEs) during
`the 24 month extension study period (i.e., months 12e36). Sec
`ondary objectives were to describe the ocular and nonocular AEs
`over 36 months (i.e., day 1 to month 36) in patients treated with
`ranibizumab 0.5 mg and to evaluate the change in BCVA from
`core baseline over 24 months of the extension study (i.e., months
`12e36) and over 36 months of the entire study period.
`
`Treatment
`
`The RESTORE extension was an open label study. All patients
`enrolled in the extension study were eligible to receive intravitreal
`ranibizumab 0.5 mg injections on the basis of the prespecified
`retreatment criteria, and monthly visits were mandated for each patient.
`Ranibizumab 0.5 mg was administered as an intravitreal in
`jection under aseptic conditions, which includes the use of surgical
`hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid
`speculum. Patients were treated at monthly intervals until stable
`vision was achieved,
`that
`is, no further BCVA improvement
`attributable to treatment was observed compared with the 2 pre
`vious consecutive visits according to the investigator or a BCVA
`letter score of 84 letters (approximate Snellen equivalent of 20/
`20) was observed. If, on the basis of the investigators’ opinion, a
`decrease in BCVA due to DME was observed, monthly ranibizu
`mab treatment was resumed until stable BCVA was reached.
`Ranibizumab injection at the baseline of the extension study (i.e.,
`month 12) was not mandated, and a maximum of 24 monthly
`ranibizumab injections could be administered during the extension
`study (months 12e35). Also, patients previously treated with laser
`monotherapy who entered the extension study did not mandatorily
`receive the 3 initial injections that were administered to patients in
`the ranibizumab groups at the beginning of the core study. During
`the 2 year extension study, all patients also were eligible to receive
`laser treatment (recorded as concomitant medication during the
`extension study) at a minimum interval of 90 days, according to the
`ETDRS guidelines at the investigators’ discretion. Decisions on
`treatment with laser were independent of decisions to inject rani
`bizumab and vice versa. If in the opinion of the investigator, both
`ranibizumab and laser treatment were required on the same day,
`laser was always administered before ranibizumab injection.
`
`Efficacy and Safety Assessments
`Efficacy Assessments. The BCVA of the study eye (evaluated
`through the change vs. baseline of core and extension studies, pro
`portion of patients gaining and losing 10 and 15 BCVA letters,
`respectively, and the proportion of patients with BCVA score >78
`and <39 ETDRS letters was assessed at every visit as described
`previously.11 The VA measurements were taken in a sitting position
`using the ETDRS like VA testing charts at a testing distance starting
`at 4 m. The VA was assessed by certified personnel to ensure
`standardized BCVA assessments at each visit before applying any
`potential new dose of ranibizumab.
`Anatomic end points included change in CRST (assessed by
`Stratus Optical Coherence Tomography; Carl Zeiss Meditec Inc.,
`Dublin, CA), proportion of patients with a 3 step change from
`baseline in the ETDRS severity score, and retinal ischemia (re
`ported as change from baseline in foveal avascular zone, evaluated
`through the central subfield capillary loss variable) and were
`assessed as described previously.11 These end points were assessed
`by the Central Reading Center.
`The patients’ subjective assessment of visual functioning was
`assessed using the National Eye Institute Visual Functioning
`questionnaire 25 (NEI VFQ 25). The assessed end points included
`change in NEI VFQ 25 scores (composite, general vision, near
`activities, and distance activities).
`
`Treatment Exposure. The number and frequency of ranibizu
`mab injections and active laser treatments (recorded as concomitant
`medication during the extension study) were evaluated during the
`extension study. Reasons for ranibizumab treatment interruption in
`the extension study were documented.
`Safety Assessments. Safety assessments included monitoring
`and recording all ocular and nonocular AEs and serious AEs
`(SAEs). Safety was assessed by standard ophthalmic examinations,
`IOP measurements, vital signs, and laboratory parameters, as
`previously.11 Laboratory
`described
`assessments
`for
`safety
`parameters were performed by a certified central laboratory. All
`ocular/nonocular AEs and SAEs, including information on their
`relationship to study drug/procedure, were recorded at every visit.
`Adverse events were summarized by the proportion of patients
`experiencing any type of AEs and grouped per the standardized
`Medical Dictionary for Regulatory Activities system organ classes
`and preferred terms.
`The AEs of potential safety concerns (hypersensitivity, hyper
`tension, nonocular hemorrhage, proteinuria, myocardial infarction,
`venous thromboembolic events, and other arterial thromboembolic
`events), identified on the basis of prior experience with ranibizu
`mab in clinical trials, were recorded.
`
`Statistical Analysis
`All analyses in the extension study were presented by treatment
`groups as in the core study, namely, ranibizumab, ranibizumab þ
`laser, and laser alone, and are now referred to as prior ranibizumab,
`prior ranibizumab þ laser, and prior laser groups, respectively. No
`comparison of treatment groups by means of statistical hypothesis
`testing was intended. Data were summarized for 2 time periods: (1)
`24 month analysis (analysis of data from the extension study, i.e.,
`months 12e36) and (2) 36 month analysis (analysis of data from
`the core and extension studies, i.e., day 1 to month 36).
`All analyses were performed on the safety set, consisting of all
`patients who entered and had at least 1 safety assessment in the
`extension study. Adverse events were summarized by the number
`and proportion of patients experiencing AEs by system organ
`classes and preferred terms. Descriptive statistics (including num
`ber of observations, mean, and standard deviation or standard er
`ror) were provided separately for each treatment group. A last
`observation carried forward approach was used for imputation of
`missing data in the BCVA, CRST, ETDRS severity score, retinal
`ischemia, and NEI VFQ 25 analysis. All comparisons between day
`1 and month 36 and month 12 and month 36 results in this article
`are made only for the 240 patients who participated in both the core
`and extension studies.
`
`Results
`
`Patient Disposition and Demographics
`
`Of the 303 patients with DME who completed the core study, 240
`provided signed informed consent and were enrolled in the
`extension study. Although the reasons for nonenrollment into the
`extension study were not formally documented, the majority of the
`remaining 63 patients could not be enrolled into the extension
`study because of administrative reasons, such as late approvals
`from the institutional review board/independent ethics committee
`or late contract agreements. All analyses were performed on the
`safety set, which comprised 83 (prior ranibizumab), 83 (prior
`ranibizumab þ laser), and 74 (prior laser) patients. Of the 240
`enrolled patients, 208 (86.7%) completed the extension study (Fig
`2, available at www.aaojournal.org). The proportion of patients
`who completed the study and the month 36 visit was similar
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`Ophthalmology Volume 121, Number 5, May 2014
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`Figure 3. Mean of the change in best-corrected visual acuity (BCVA) letter score from baseline (day 1) to month 36 (A) and mean of the change in central
`retinal subfield thickness (CRST) score from baseline to month 36 (B) (safety set [last observation carried forward]). ETDRS
`early treatment diabetic
`retinopathy study; PRN pro re nata; SE
`standard error.
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`across all the prior treatment groups (prior ranibizumab: 88.0%,
`ranibizumab þ laser: 86.7%, and prior
`prior
`laser: 85.1%).
`Withdrawal of consent (4.6%), death (3.3%), and AEs (2.5%)
`were the most common reasons for patient discontinuation of the
`extension study across all
`the prior treatment groups (Fig 2,
`available at www.aaojournal.org).
`The core baseline demographics and disease characteristics (at day
`1) for patients entering the extension study were similar across all the
`prior treatment groups (Table 1, available at www.aaojournal.org). At
`the baseline of
`the extension study (month 12),
`the disease
`characteristics of patients treated with laser and those treated with
`ranibizumab in the core study were comparable except for BCVA,
`which was slightly lower in patients treated with laser alone in the
`core study (Table 2, available at www.aaojournal.org).
`
`Efficacy Profile
`Best-Corrected Visual Acuity. The mean of the change in BCVA
`from baseline over 3 years is shown in Figure 3A. In patients
`
`treated with ranibizumab in the core study, the mean BCVA gain
`(letters  standard error) at month 12 (7.9  0.81 [prior
`ranibizumab]; 7.1  0.80 [prior ranibizumab þ laser]) was in
`general maintained from month 12 to 36 (prior ranibizumab: 8.0
` 1.11; prior ranibizumab þ laser: 6.7  1.05 at month 36). Of
`note, prior laser treated patients, who were eligible to receive
`ranibizumab treatment in the extension study, showed a progres
`sive improvement of BCVA from 2.3  1.11 letters at month 12 to
`6.0  1.09 letters at month 36.
`At month 36, 42.2% of patients in the prior ranibizumab group,
`28.9% of patients in the prior ranibizumab þ laser group, and 17.6%
`of patients in the prior laser group had a BCVA score >78 letters,
`whereas only 1 patient (1.2%), 1 patient (1.2%), and 2 patients
`(2.7%), respectively, had a BCVA of <39 letters at month 36. Over
`the 3 year study period, a similar proportion of patients gained 10
`and 15 BCVA letters across the 3 groups (Fig 4). However, at
`month 36, a greater proportion of patients treated with laser alone
`in the core study lost 10 letters (prior ranibizumab: 2.4%; prior
`ranibizumab þ laser: 4.8%; prior laser: 8.1%) and 15 letters (prior
`
`1048
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`

`

`Schmidt-Erfurth et al
`
` Long-term Efficacy and Safety Profiles of Ranibizumab in DME
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`Figure 4. Categorized change in best-corrected visual acuity (BCVA) from
`baseline (day 1) to month 36 (safety set [last observation carried forward]).
`
`ranibizumab: 1.2%; prior ranibizumab þ laser: 1.2%; prior laser:
`2.7%) when compared with patients primarily treated with
`ranibizumab in both the core and extension studies.
`Central Retinal Subfield Thickness. In patients treated with
`ranibizumab in the core and extension studies, the mean CRST
`reductions observed at
`the
`end of
`the
`core
`study (prior
`127.8 mm; prior ranibizumab þ laser:
`139.7 mm at
`ranibizumab:
`month 12) were maintained at month 36 (prior ranibizumab:
`142.1
`mm; prior ranibizumab þ laser: 145.9 mm). At month 12, a relatively
`lower mean reduction in CRST ( 63.3 mm) was observed in the prior
`laser treated patients compared with patients in the prior ranibizumab
`group. A progressive reduction of 79.4 mm was observed in the prior
`laser treated patients with the allowance of ranibizumab treatment from
`month 12 to 36 (mean change from baseline to month 36, 142.7 mm;
`Fig 3B).
`Retinal Ischemia. The mean of the changes in the size of the
`foveal avascular zone from baseline to month 36 were 0.027 mm2
`(median, 0.049 mm2; prior ranibizumab), 0.051 mm2 (median, 0.027
`mm2; prior ranibizumab þ laser), and
`0.399 mm2 (median,
`0.013
`mm2; prior laser).
`Early Treatment Diabetic Retinopathy Study Severity
`Score. At month 36, 14.8% of patients in the prior ranibizumab
`group, 28.3% of patients in the prior ranibizumab þ laser group,
`and 16.0% of patients in the prior laser group had an improvement
`in ETDRS severity score (3 steps) from baseline, whereas 1.6%,
`7.5%, and 4.0% of patients, respectively, had a worsening of
`ETDRS score (3 steps) from baseline to month 36.
`Visual Functioning Questionnaire. Over 3 years, patients
`treated with ranibizumab in both the core and extension studies
`showed an overall improvement of NEI VFQ 25 scores at month
`36 when compared with the core baseline (composite scores: 5.0
`[prior ranibizumab], 4.3 [prior ranibizumab þ laser]; general
`vision: 6.0 [prior ranibizumab], 7.1 [prior ranibizumab þ laser];
`near activities: 12.2 [prior ranibizumab], 7.8 [prior ranibizumab þ
`laser]; distance activities: 2.6 [prior
`ranibizumab], 4.1 [prior
`ranibizumab þ laser]). In both the prior ranibizumab and prior
`ranibizumab þ laser groups, the initial gains in the NEI VFQ 25
`scores observed at month 12 were mostly maintained for the
`composite (prior ranibizumab: 6.5 [month 12] and 5.0 [month 36];
`prior ranibizumab þ laser: 4.8 [month 12] and 4.3 [month 36]),
`general vision (prior ranibizumab: 8.7 [month 12] and 6.0 [month
`36]; prior ranibizumab þ laser: 8.0 [month 12] and 7.1 [month
`36]), distance activity (prior ranibizumab: 6.4 [month 12] and 2.6
`[month 36], and near activity (prior ranibizumab: 10.7 [month 12];
`12.2 [month 36]; prior ranibizumab+laser: 9.3 [month 12]; 7.8
`[month 36]) prior ranibizumab þ laser: 4.5 [month 12] and 4.1
`[month 36]) subscale scores until month 36. After allowance of
`
`ranibizumab treatment as of month 12, patients in the prior laser
`group showed a progressive improvement in near activities (month
`12: 1.9; month 36: 8.4), general vision (month 12: 1.6; month 36:
`8.1), distance activities (month 12: 1.8; month 36: 3.5), and
`composite scores (month 12: 2.4; month 36: 3.9) from months 12
`to 36.
`
`Treatment Exposure
`Ranibizumab Injections. Patients who received ranibizumab pre
`viously in the core study and continued with individualized ranibi
`zumab treatment in the extension study (prior ranibizumab and prior
`ranibizumab þ laser) received a median of 12.0 (mean: prior rani
`bizumab [14.2]; prior ranibizumabþlaser: [13.5]) ranibizumab in
`jections over 3 years (day 1 to month 35; Table 3 and Table 4,
`available
`at www.aaojournal.org). The mean
`number
`of
`ranibizumab injections administered over 2 years of the extension
`study (months 12e35) was similar across the 3 groups, with a
`progressive reduction in re treatment need from the first to the
`second year and the third year (median, 6.0; mean, 6.8 [prior
`ranibizumab]; median, 4.0; mean, 6.0 [prior ranibizumab þ laser],
`and median, 4.0; mean, 6.5 [prior laser]). A similar proportion of
`patients across the 3 groups did not receive any injections over
`months 12 to 35 (prior ranibizumab: 19.3%; prior ranibizumab þ
`laser: 25.3%; and prior
`laser: 20.3%; Table 4, available at
`www.aaojournal.org). Therefore, 59 of the 74 prior laser treated
`patients (79.7%) received an average of 8.1 ranibizumab injections
`from months 12 to 35.
`In the 24 month extension study (months 12e35), disease
`improvement was the most frequent reason for treatment inter
`ruption/stop. In the prior laser treated patients, ranibizumab in
`jections over months 12 to 35 resulted in disease improvement and
`subsequent treatment interruption in 93.2% of patients (Table 5,
`available at www.aaojournal.org).
`Laser Treatment. The mean number of
`treatments
`laser
`administered to the study eye during the extension study (months
`12e36; recorded as concomitant medication) ranged from 0.1 to
`0.4 across the prior treatment groups (median, 0.0 for all treatment
`groups). In the extension study, the majority of patients (75.9%e
`91.6%) across all groups did not require/receive laser treatment
`(Table 6, available at www.aaojournal.org).
`
`Safety Profile
`Serious Adverse Events. Overall, ocular SAEs (study eye) were
`reported in 8 patients (3.3%; Table 7, available at www.
`aaojournal.org) over the 3 year study period (day 1 to month
`36); the most frequently observed ocular SAE was cataract (prior
`ranibizumab þ laser: 3 [3.6%], prior laser: 2 [2.7%]). The most
`frequently occurring ocular SAEs in the extension study (months
`
`Table 3. Mean Number of Ranibizumab Treatments Received
`over 3 Years (Day 1 to Month 35, Safety Set)
`
`Mean No. of Ranibizumab Injections
`Prior
`Ranibizumab
`0.5 mg þ Laser
`(n
`83)
`
`Prior Ranibizumab
`0.5 mg (n
`83)
`
`Prior
`Laser
`(n
`74)
`
`14.2
`7.4
`3.9
`2.9
`
`13.5
`7.5
`3.5
`2.5
`
`6.5*
`0.0
`4.1
`2.4
`
`Treatment Period
`
`Day 1 to month 35
`Day 1 to month 11
`Months 12e23
`Months 24e35
`
`*Includes ranibizumab 0.5 mg injections given over months 12e35 only.
`
`1049
`
`Regeneron Pharmaceuticals, Inc. Exhibit 2058 Page 5
`Samsung Bioepis Co., Ltd. v. Regeneron Pharmaceuticals, Inc. IPR2023-00884
`
`

`

`Ophthalmology Volume 121, Number 5, May 2014
`
`Table 9. Most Frequent Ocular (Study Eye) and Nonocular Adverse Events in the Extension Study (Months 12e36;
`5% in Any Group, Safety Set)
`
`Preferred Terms
`
`Ocular AEs (study eye), total
`Eye pain
`Cataract
`Dry eye
`Lacrimation increased
`Macular fibrosis
`Nonocular AEs, total
`Nasopharyngitis
`Influenza
`Hypertension
`Back pain
`Dizziness
`Renal failure
`
`Prior
`Ranibizumab 0.5 mg (n [83)
`
`Prior
`Ranibizumab 0.5 mg D Laser
`(n [ 83)
`
`47 (56.6)
`9 (10.8)
`7 (8.4)
`3 (3.6)
`2 (2.4)
`1 (1.2)
`61 (73.5)
`12 (14.5)
`7 (8.4)
`7 (8.4)
`3 (3.6)
`2 (2.4)
`0 (0.0)
`
`47 (56.6)
`6 (7.2)
`12 (14.5)
`3 (3.6)
`3 (3.6)
`2 (2.4)
`61 (73.5)
`12 (14.5)
`6 (7.2)
`7 (8.4)
`2 (2.4)
`0 (0.0)
`2 (2.4)
`
`Prior
`Laser
`(n [ 74)
`
`37 (50.0)
`9 (12.2)
`8 (10.8)
`5 (6.8)
`5 (6.8)
`4 (5.4)
`53 (71.6)
`15 (20.3)
`7 (9.5)
`5 (6.8)
`5 (6.8)
`4 (5.4)
`4 (5.4)
`
`adverse event.
`AE
`Data are no. (%). Preferred terms are sorted in descending frequency, as reported in ranibizumab 0.5 mg column; a subject with multiple occurrences of an
`AE under 1 treatment is counted only once in the AE category for that treatment.
`
`12e36)
`at www.
`(available
`8
`in Table
`presented
`are
`aaojournal.org). During the extension study (months 12e36),
`cataract was observed as an ocular SAE in 1 patient in the prior
`ranibizumab þ laser group. Over the 3 year study period, none
`of the ocular SAEs of the study eye were suspected by the
`investigator to be related to the study drug or procedure.
`Overall, 88 patients (36.7%) experienced nonocular SAEs
`(Table 7, available at www.aaojournal.org) over 3 years (prior
`ranibizumab: 30 [36.1%], prior ranibizumab þ laser: 31 [37.3%],
`and prior laser: 27 [36.5%]). The key nonocular SAEs reported
`over this 3 year period included coronary artery disease (prior
`ranibizumab: 3 [3.6%]; prior laser: 1 [1.4%]), angina pectoris (prior
`ranibizumab: 2 [2.4%]; prior ranibizumab þ laser: 1 [1.2%]), cardiac
`failure (each prior ranibizumab group: 1 [1.2%]; prior laser: 4
`[5.4%]), cerebrovascular accident (prior ranibizumab: 2 [2.4%];
`prior ranibizumab þ laser: 1 [1.2%]; prior laser: 1 [1.4%]), and
`myocardial infarction (prior ranibizumab þ laser: 3 [3.6%]; prior
`laser: 3 [4.1%]). Nonocular SAEs reported during the extension
`study (months 12e36) are presented in Table 8 (available at
`www.aaojournal.org), and those suspected by the investigator to
`be related to the study drug/procedure over 2 years are indicated.
`Of the 240 patients entering the extension, 8 deaths were reported
`during the 24 month extension study, that is, over months 12 to 36 (2
`in the prior ranibizumab group and 3 each in the prior ranibizumab þ
`laser and prior laser groups); none were suspected to be related to the
`study drug or procedure. Nonocular SAEs reported during the
`extension study (months 12e36) are presented in Table 8 (available at
`www.aaojournal.org), and those suspected by the investigator to be
`related to the study drug/procedure over 2 years are indicated.
`Adverse Events. The most frequently observed ocular AEs in the
`study eye during the extension study (months 12e36) were cataract (27
`[11.3%]) and eye pain (24 [10.0%]); the most frequently occurring
`ocular AEs in the study eye during the extension study (months 12e36;
`5% in any group) are summarized in Table 9. The most frequent
`ocular AEs (5% in any group; summarized in Table 10, available
`at www.aaojournal.org) in the study eye across the treatment groups
`over the 3 years were cataract (39 [16.3%]), eye pain (37 [15.4%]),
`conjunctival hyperemia (21 [8.8%]), and conjunctival hemorrhage
`(18 [7.5%]). Of the 240 patients entering the extension study,
`increased IOP in study eye was observed in 9 patients (3.8%) only
`
`1050
`
`across the prior ranibizumab treatment arms over 3 years. The most
`frequent ocular AEs in the study eye suspected by the investigator to
`be related to study drug/procedure across all treatment groups over
`the 3 years (day 1 to month 36) and during the extension study
`(months 12e36) were eye pain and conjunctival hemorrhage (the
`latter was observed only in patients who received ranibizumab in the
`core or extension studies) (Tables 11 and 12, availabl