Journal of Clinical Medicine Article Real-World Experience with Brolucizumab in Wet Age-Related Macular Degeneration: The REBA Study Alper Bilgic 1 , Laurent Kodjikian 2,3 , Francesc March de Ribot 4 , Vaishali Vasavada 5 , Jesus H. Gonzalez-Cortes 6 , Amro Abukashabah 2,7 , Aditya Sudhalkar 1,8, * and Thibaud Mathis 2,3 1 Alphavision Augenarztpraxis, 27568 Bremerhaven, Germany; drbilgicalper@yahoo.com 2 Service d’Ophtalmologie, Centre Hospitalier Universitaire de la Croix-Rousse, Hospices Civils de Lyon, Université Claude Bernard Lyon 1, 69004 Lyon, France; laurent.kodjikian@chu-lyon.fr (L.K.); dr.heartaaa@hotmail.com (A.A.); thibaud.mathis@chu-lyon.fr (T.M.) 3 UMR-CNRS 5510, Matéis, Villeurbane, 69004 Lyon, France 4 Department of Ophthalmology, Universitat Autonoma de Barcelona, 08003 Barcelona, Spain; marchfrancesc@gmail.com 5 Raghudeep Eye Hospital, Ahmedabad 380054, India; vaishali@raghudeepeyeclinic.com 6 Department of Ophthalmology, Universitat Autonoma de Ciudad, Mexico City 06720, Mexico; drjesusgzz@gmail.com 7 Ophthalmology Department, King Abdulaziz University, Rabigh 25732, Saudi Arabia 8 MS Sudhalkar Medical Research Foundation, Baroda 390001, India  * Correspondence: adityasudhalkar@yahoo.com; Tel.: +91-265-279-3799  Citation: Bilgic, A.; Kodjikian, L.; Abstract: The aim of the present study was to determine the efficacy and safety of intravitreal March de Ribot, F.; Vasavada, V.; brolucizumab therapy for neovascular age-related macular degeneration (AMD) in the real-world Gonzalez-Cortes, J.H.; Abukashabah, setting. The REBA study (real-world experience with brolucizumab in wet AMD) was a retrospective, A.; Sudhalkar, A.; Mathis, T. observational, multicentric study that included 78 consecutive patients (105 eyes), with neovascular Real-World Experience with AMD, who received brolucizumab therapy. Both treatment-naive and switch-therapy patients were Brolucizumab in Wet Age-Related included. Switch therapy was based either on fluid recurrence, fluid recalcitrance, or inability to Macular Degeneration: The REBA extend beyond q4/q6. All relevant data were collected. The primary outcome measure was change in Study. J. Clin. Med. 2021, 10, 2758. https://doi.org/10.3390/ best-corrected visual acuity (BCVA) over time. Secondary outcome measures included determination jcm10132758 of change in central subfield thickness (CST) and complications. The mean baseline BCVA was 49.4 ± 5.4 letters and 40 ± 3.2 letters, and corresponding mean BCVA gain was +11.9 ± 3.9 letters Academic Editors: María (p = 0.011) and +10.4 ± 4.8 letters (p = 0.014) in the treatment-naive and switch-therapy groups, Isabel López-Gálvez and Margaret respectively. The change in CST was significantly decreased in the treatment-naive (p = 0.021) and the M. DeAngelis switch-therapy (p = 0.013) groups. The mean follow-up was 10.4 months in both groups. One patient in the switch-therapy group developed vascular occlusion and another a macular hole after the fifth Received: 31 May 2021 brolucizumab injection. Both patients recovered uneventfully. In conclusion, patients showed a Accepted: 23 June 2021 very good anatomical and functional response to brolucizumab therapy in the real world, regardless Published: 23 June 2021 of prior treatment status, until the end of the follow-up period. Two significant untoward events were noted. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in Keywords: age-related macular degeneration; anti-vascular endothelial growth factor; brolucizumab; published maps and institutional affil- exudation; switch therapy iations. 1. Introduction Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. Anti-vascular endothelial growth factor (VEGF) agents have been established as This article is an open access article the treatment of choice for neovascular age-related macular degeneration (AMD) [1,2]. distributed under the terms and Monthly injections are rather impractical and negate functional benefits through intense conditions of the Creative Commons follow-up schedules. There are psychological and physical consequences [3] due to the Attribution (CC BY) license (https:// strict schedules and the potential threat of geographic atrophy (although it rarely, if ever, creativecommons.org/licenses/by/ manifests) [4]. One way to reduce the number of treatments is infrequent injections (e.g., pro 4.0/). re nata injections, or some manner of treat-and-inject regimen) [5–9] without compromise J. Clin. Med. 2021, 10, 2758. https://doi.org/10.3390/jcm10132758 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 2758 2 of 12 on visual outcomes. Another approach would be to look at more potent formulations that obviate the need for intense therapy. The HAWK and HARRIER studies established the non-inferiority of the new molecule brolucizumab vis-a-vis aflibercept, with some analyses suggesting a superior anatomic out- come [10]. Nearly 50% of enrolled patients could receive 12-weekly injections, considerably reducing the treatment burden. However, little is known in patients already treated for neovascular AMD who have been switched to brolucizumab therapy. Moreover, concerns about safety with special reference to intraocular inflammation and vasculitis dampened the initial enthusiasm for the drug [11]. As data continues to evolve, the risk of serious adverse events is currently fixed at 4.6% and continues to be updated [12,13]. The current analysis offers a real-world perspective on patients with wet AMD who received brolucizumab either as primary or as switch therapy. 2. Materials and Methods The REBA study (real-world experience with brolucizumab in wet AMD) was an observational, retrospective, multicentric study conducted at Alphavision Augenarzt- praxis, Bremerhaven, Germany and the Raghudeep and Sudhalkar group of eye hospitals, Ahmedabad and Baroda, India. A database search was made for patients with macular neovascularization (MNV) who received brolucizumab as intravitreal therapy. This study complied with the tenets of the Declaration of Helsinski and was approved by an inter- national review board (Ethics Committee of the French Society of Ophthalmology, IRB 00008855 Société Française d’Ophtalmologie IRB#1) and by the ethics committee for the Raghudeep Eye Hospital, Ahmedabad, India. Patients provided informed consent for participation in the study. 2.1. Eligibility We looked at the outcomes in treatment-naive patients with neovascular AMD who received intravitreal brolucizumab as well as those who received brolucizumab as switch therapy. Patients who received switch therapy had to have received prior therapy in accor- dance with the treat-and-extend protocol with either ranibizumab or aflibercept to ensure that they had been treated with current guidelines. Therapy switch was based on previ- ously published recommendations [14]. Patients with polypoidal choroidal vasculopathy (PCV) or retinal angiomatous proliferation (RAP) were excluded. 2.2. Definitions Standard definitions in compliance with the latest consensus guidelines [15] are reiterated here for ease of interpretation: • Intraretinal fluid (IRF): accumulation of the fluid in retinal thickening and formation of cystoid spaces. • Subretinal fluid (SRF): leakage in excess of the local capability of removal leading to accumulation of the fluid under the retina. • Retinal pigment epithelial detachment (PED): a clinically evident separation of the retinal pigment epithelium (RPE) monolayer from the underlying Bruch’s membrane. Fluid at the macula was identified as intraretinal or subretinal fluid, whereas its disappearance post-injection was considered to be a ‘fluid-free macula or a complete response’ [7]. PED fluid was noted if present, but it was not considered to be an independent treatment criterion as per the HAWK and HARRIER trials. Baseline images were graded independently by two of the investigators (F.M.R. and A.B.) and adjudicated by a senior colleague (L.K.). 2.3. Grouping Treatment-naive patients with macular neovascularization were assessed separately from those who had received brolucizumab as switch therapy. Switch patients did not receive the loading phase of three injections; therapy was based on clinical signs, symptoms, J. Clin. Med. 2021, 10, 2758 3 of 12 and spectral-domain optical coherence tomography (SD-OCT) scans. Patients in the switch- therapy group were divided into three subgroups according to the reason for the switch: • Recurrent group (subgroup 1): good effectiveness of the previous therapy (>100 µm reduction in fluid on SD-OCT at day 15 with recurrence at day 30). • Recalcitrant group (subgroup 2): no reduction (<100 µm reduction in fluid on SD-OCT at days 15 and 30) or worsening disease. • Inability-to-extend group (subgroup 3): patients for whom the therapy could not be extended after q4/q6 without fluid recurrence. 2.4. Acquisition of Data Data retrieved included patient demographics, the best corrected visual acuity as recorded using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart (also men- tioned in the manuscript in Snellen’s notations for ease of interpretation), the best-corrected visual acuity (BCVA), intraocular pressure (IOP), the details of the ocular examination and special investigations conducted, such as fluorescein angiography (FA) and/or indocyanine angiography (ICGA) and central subfield thickness (CST) as determined by SD-OCT, the type of MNV (type 1/type 2/mixed), the size and location thereof, the anti-VEGF agents used, the number of injections administered, the treatment-free interval, and the need for a therapy switch, if any. BCVA, measurement of IOP, slit-lamp examination, fundoscopy, and SD-OCT were documented at each visit. 2.5. Follow-Up Follow-up was performed according to an in-house protocol for the follow-up of patients under brolucizumab and in accordance with the recommendation for patients under anti-VEGF injections (Stellungn./Empfehlungen DOG). Eyes were examined for detection of ocular-adverse events on days 7, 15, and 30 following the first injection (including OCT scans at day 15) and every month thereafter. After the loading dose, all treatment-naïve patients were assessed at 8 weeks: (i) If no disease activity (i.e., presence of fluid) was observed the patient still had an injection at 12-weeks, and was then reassessed every 12-weeks with another systematic injection (q12w). In cases of disease activity in a follow-up visit, the delay between injections was shortened to 8 weeks. (ii) If fluid was observed, the patient had an injection at 8 weeks and was then reassessed 8-weekly with a systematic injection (q8w). If no fluid was detected at an 8-week follow-up, extension of injections and follow-up could be done at 12 weeks. For the switch-therapy group, patients were followed monthly after the first injections for possible reinjection in case of disease activity. Once the macula was dry on SD-OCT, all switch patients were assessed at 8 weeks and were reinjected following the above recommendations (Figure 1). Retreatment criteria were based on comparisons with the previous month’s examination and retreatment administered if any one criterion of disease activity was considered to be positive [7,10]. Intravitreal injections were performed using a standardized aseptic technique. Patients had to be followed for a minimum of 9 months to be included in this study. Moreover, for the treatment-naïve group, eyes had to have received at least four intravitreal injections of brolucizumab. J. Clin. Med. 2021, 10, x FOR PEER REVIEW 4 of 12 J. Clin. Med. 2021, 10, 2758 4 of 12 Figure1.1.Our Figure Ourin-house protocol in-house for the protocol for treatment of wetofAMD the treatment with intravitreal neovascular glaucoma injections of brolucizumab. with intravitreal injec- tions of brolucizumab. 2.6. Outcome Measures 2.6. The primary Outcome outcome measure was to determine the change in BCVA from baseline Measures with treatment. Secondary outcome measures included change in CST in SD-OCT, the The primary outcome measure was to determine the change in BCVA from baseline mean number of injections required to achieve repeat resolution, and the complications as- with treatment. Secondary outcome measures included change in CST in SD-OCT, the sociated therewith. We also attempted to determine which factors independently influence mean number of injections required to achieve repeat resolution, and the complications resolution of exudation with a single injection. associated therewith. We also attempted to determine which factors independently influ- ence 2.7. resolution Statistical of exudation with a single injection. Analysis The description of categorical variables was based on absolute (size) and relative 2.7. Statistical Analysis (percentage) frequencies. Quantitative variables were represented as mean and standard The description deviation. The comparison of categorical variables variables of the categorical was based on absolute between (size) of the groups and relative different (percentage) frequencies. Quantitative variables were represented as indications was performed using Fisher’s exact test, and when the pairwise comparisons mean and standard deviation. were The comparison subsequently performed,of the the p-value categorical was variables adjusted usingbetween the the groups of different Benjamini–Hochberg indications method, was performed wherever applicable.using When Fisher’s exacttwo more than test, and when groups were the pairwiseANOVA compared, comparisons was wereAsubsequently used. p-value < 0.05 performed, the p-value was considered was adjusted to be statistically using theQuarterly significant. Benjamini–Hochberg visits were method, wherever considered to make applicable. When up for possible more lost than two groups were compared, ANOVA was follow-ups. used. A p-value < 0.05 was considered to be statistically significant. Quarterly visits were 3.considered Results to make up for possible lost follow-ups. A total of 85 patients (112 eyes) have received intravitreal brolucizumab at our centres 3. Results thus far, of which 78 patients (105 eyes) have completed at least 9 months of follow-up. The remaining A total ofseven patients 85 patients (seven (112 eyes)eyes; haveall switch-therapy received patients) intravitreal did not at brolucizumab complete our cen- 9tres months of follow-up. These 78 patients form the basis for our thus far, of which 78 patients (105 eyes) have completed at least 9 months ofanalysis (68 patients follow- were of Caucasian up. The remainingethnicity and included seven patients in Germany (seven eyes; centers andpatients) all switch-therapy 10 patients did were not com-of south plete Asian 9 monthsethnicity and included of follow-up. These 78 in patients Indian centers). form theOf these basis for78 ourpatients, analysis23 (68patients patients (25 eyes) were of were treatment-naïve Caucasian at baseline ethnicity and included whereas the rest in Germany received centers andswitch therapy. 10 patients Theof were total number of intravitreal procedures carried out in these patients was 572. south Asian ethnicity and included in Indian centers). Of these 78 patients, 23 patients (25 Table 1 lists salient characteristics eyes) were of patients treatment-naïve in both at baseline groupsthe whereas i.e.,rest treatment-naïve received switch and patients therapy. Thewho total received switch therapy. number of intravitreal procedures carried out in these patients was 572. Table 1 lists sali- ent characteristics of patients in both groups i.e., treatment-naïve and patients who re- ceived switch therapy. J. Clin. Med. 2021, 10, 2758 5 of 12 Table 1. Characteristics of patients who received brolucizumab therapy. Characteristic Treatment-Naïve (N = 25) Switch Therapy (N = 80) Mean age, years (SD) 69.2 (4.4) 74.3 (5.8) Male:female 9:14 26:29 Mean follow-up, months (SD) 10.4 (1.5) 10.4 (2.2) * Mean baseline BCVA, letters (SD) 49.4 (4.5) 40.0 (3.2) Mean baseline CST, µm (SD) 428.1 (7.4) 483.2 (59.2) MNV subtype, n: Type 1 14 56 Type 2 7 14 Mixed 4 10 MNV localization, n: Subfoveal 15 56 Juxtafoveal 4 12 Extrafoveal 1 2 Interpapillomacular 5 10 Fluid localization, ** n: IRF 23 57 SRF 12 31 PED 10 24 None 2 0 BCVA, best corrected visual acuity; IRF, intraretinal; MNV, choroidal neovascularization; PED, pigment epithelium detachment; SRF, subretinal fluid. * After initiation of brolucizumab therapy; ** patients could have fluid in more than one compartment. 3.1. Treatment-Naïve Group A total of 23 patients (25 eyes) were treated for the first time with brolucizumab (all of Caucasian/European ethnicity). The mean time to presentation after onset of symptoms in the treatment-naïve group was 43.2 ± 12.5 days. Baseline BCVA was 49.4 ± 4.5 letters and the mean retinal thickness was 428.1 ± 73.4 µm. Type 1 MNV was the most frequent neovascular lesion (56.0%). The mean neovascular membrane size was 188.4 ± 44.5 µm. Overall, 19/25 (76.0%) eyes showed completely resolved exudation at the end of the loading phase and were planned to undergo injections every 12 weeks (q12w), 13/19 (68.4%) eyes were still treated with q12w dosing at the end of follow-up, and 6/13 (46.1%) eyes did not show any recurrence with the q12w regimen (i.e., no disease activity detected at any time). A total of 6/25 patients were injected at 8-weeks (q8w) after the loading phase. For these patients, none of them experienced fluid at the 4-weeks SD-OCT. In this q8w subgroup, 3/6 eyes were finally extended to q12w dosing at the end of follow-up. The mean final CST decreased significantly to 278.0 ± 47.2 µm (p = 0.021) at the final follow-up. The mean follow-up in the treatment-naïve group was 10.4 ± 1.5 months. Patients received a mean of 2.1 ± 0.8 brolucizumab injections after the three loading- dose injections. 3.2. Visual Gain The mean letter gain was 11.9 ± 3.8 letters in this group (p = 0.011). A total of 15/25 eyes (60%) gained more than 15 letters from baseline at 8 weeks after the loading phase. Of these eyes, 14/25 maintained the 15-letter gain until the end of the follow-up period. Overall, 16/25 (64.0%) patients retained a BCVA of 20/30 or better at the end of the follow-up period. None of the treatment-naive group lost letters from baseline. 3.3. Recurrence A total of 17/25 (68.0%) eyes demonstrated a recurrence in exudation during the whole follow-up period; 7/17 demonstrated a recurrence when treated at 12 weeks whereas 10/17 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 6 of 12 J. Clin. Med. 2021, 10, 2758 6 of 12 tended to have typefluid eyes demonstrated 1 MNV, higherPatients at 8 weeks. MNV size (mean who showed287.4 ± 42.5 µm;tended a recurrence p = 0.03) and peri- to have type papillary MNVs. The presence of IRF was more likely to indicate recurrence (OR-2.31, 1 MNV, higher MNV size (mean 287.4 ± 42.5 µm; p = 0.03) and peripapillary MNVs. The CI 1.7–4.18; p = 0.012). presence of IRF was more likely to indicate recurrence (OR-2.31, CI 1.7–4.18; p = 0.012). 3.4. 3.4. Switch-Therapy Switch-Therapy Group Group AA total total ofof 55 55 patients patients(80 (80eyes; eyes;4545patients patientswere wereofofCaucasian/European, Caucasian/European, and 10 10 and of Asian of Asian ethnicity) received ethnicity) switch received therapy switch from from therapy eithereither aflibercept or ranibizumab aflibercept to brolu- or ranibizumab to cizumab. brolucizumab. All neovascular All neovascular AMDAMD patients receiving patients brolucizumab receiving brolucizumabas switch therapy as switch had therapy been initiated had been on and initiated onreceived and received aflibercept injections aflibercept as primary injections therapy. as primary According therapy. to the According to the of cause cause of the switch, the switch, 25 eyes25were eyesclassified were classified in the subgroup in the subgroup 1 (recurrent), 1 (recurrent), 44 eyes44ineyes the in the subgroup subgroup 2 (recalcitrant), 2 (recalcitrant), and 11 and in the 11subgroup in the subgroup 3 (inability 3 (inability to extend).to extend). The mean The mean number number of of injections injections prior towas prior to switch switch 32.4was 32.4 (±3.4; (±3.4; range rangeThe 12–96). 12–96). The minimum minimum number of number injec- of injections tions prior toprior to the was the switch switch 12.was 12. Baseline BCVA Baseline BCVAwas 40.0±±3.2 was40.0 3.2letters lettersandandthethe mean mean retinal thickness retinal was was thickness ± 59.2 483.2483.2 ± 59.2 µm. Type 1 MNV was the most frequent neovascular lesion (70.0%). µm. Type 1 MNV was the most frequent neovascular lesion (70.0%). Out of the 80 eyes Out of the 80 eyes included in this group, included 27 (33.7%) in this group, 27 were considered (33.7%) to have no disease were considered to haveactivity after activity no disease the first injection, after the 38 (47.5%) first injection,after 38the second (47.5%) afterinjection, the second andinjection, 15 (18.8%) and after the thirdafter 15 (18.8%) injection. None the third of the injection. patients None required of the a fourth patients monthly required a fourthinjection monthly before the extension injection before the at extension 8 weeks. at 8 weeks. The treatment The treatment interval interval waswas extended extended to to 12 12 weeks weeks (q12w) (q12w) in in 25/80 (31.2%) eyes 25/80 (31.2%) eyes atat the the end of the follow-up period and 55/80 (68.8%) eyes were maintained end of the follow-up period and 55/80 (68.8%) eyes were maintained at 8 weeks (q8w). at 8 weeks (q8w). The mean The CST CST mean decreased decreasedsignificantly significantlyto 297.5 ± 53.4 to 297.5 µm (p ± 53.4 µm = (p 0.01) at the = 0.01) at final follow-up. the final The follow-up. mean follow-up in the switch-therapy group was 10.4 ± 2.2 The mean follow-up in the switch-therapy group was 10.4 ± 2.2 months and patients re- months and patients received a meanaof ceived mean4.2 ±of2.1 4.2brolucizumab ± 2.1 brolucizumab injections duringduring injections the follow-up periodperiod the follow-up (Figure 2). 2). (Figure Figure 2. A 74-year-old male with neovascular AMD was switched to brolucizumab after demonstrating worsening of Figure 2. A 74-year-old male with neovascular AMD was switched to brolucizumab after demonstrating worsening of anatomical changes despite six consecutive injections of aflibercept followed by six consecutive injections of ranibizumab. anatomical changes despite six consecutive injections of aflibercept followed by six consecutive injections of ranibizumab. (A–D) Multimodal imaging showing the baseline situation before any anti-VEGF therapy. (E) SD-OCT showing the con- (A–D) dition ofMultimodal imaging showing the retina immediately prior tothe baseline initiation of situation before brolucizumab any anti-VEGF therapy. therapy. Large pigment (E) SD-OCT epithelium showing detachment the (PED) condition of the retina immediately prior to initiation of brolucizumab therapy. Large pigment epithelium was present, associated with persistent subretinal fluid (SRF). (F) SD-OCT demonstrating significant improvement after detachment (PED) the firstwas present, associated intravitreal withinjection brolucizumab persistent andsubretinal fluid (SRF). further resolution (F) SD-OCT of PED and SRF.demonstrating significant (G) SD-OCT after improvement the second injection. afterpatient The the first intravitreal has continuedbrolucizumab injection to receive therapy in theand q12w further dosingresolution regimen.of PED and SRF. (G) SD-OCT after the second injection. The patient has continued to receive therapy in the q12w dosing regimen. 3.5. Visual Gain The mean letter gain was 10.4 ± 4.8 letters in this group (p = 0.014). A total of 8/80 eyes (10%) gained more than 15 letters from baseline at the end of follow-up. Overall, 9/80 J. Clin. Med. 2021, 10, 2758 7 of 12 J. Clin. Med. 2021, 10, x FOR PEER REVIEW 3.5. Visual Gain 7 of 12 The mean letter gain was 10.4 ± 4.8 letters in this group (p = 0.014). A total of 8/80 eyes (10%) gained more than 15 letters from baseline at the end of follow-up. Overall, 9/80 (11.2%) patients retained retained aa BCVA BCVAof of20/30 20/30 or better at the end of thethe follow-up follow-up period, and 2/80(2.5%) 2/80 (2.5%)eyes eyesininthe theswitch-therapy switch-therapygroup grouplost lostletters lettersfrom from baseline. baseline. According to the cause cause of of switch, switch, the thevisual visualgain gainwaswas10.9 ± 3.3 letters, 10.9± letters, 8.6 ± 1.2 8.6 ± 1.2 letters, letters, and 7.2 ±±2.1 2.1letters lettersfor forthe thesubgroup subgroup1,1,2,2,and and3,3,respectively respectively(p(p==0.051; 0.051;ANOVA). ANOVA). 3.6. Adverse 3.6. Adverse Events Events A total of two A total of two patients were noted patients were noted to to have have had had untoward untoward events events after after switching switching to to brolucizumab. A 78-year-old male patient (Figure 3) developed a macular brolucizumab. A 78-year-old male patient (Figure 3) developed a macular hole 15 days hole 15 days after receiving after receivinghishis5th 5thbrolucizumab brolucizumabinjection injection (and (and 55th 55th injection injection overall). overall). TheThe patient patient un- derwent uneventful macular hole surgery with C2F6 intraocular gas tamponade andand underwent uneventful macular hole surgery with C 2 F 6 intraocular gas tamponade re- recovered covered well; well; hisBCVA his BCVAwaswas20/80 20/80prior priortotothe thedevelopment developmentof ofmacular macularhole. hole. The The BCVA BCVA had dropped had dropped to to 20/200 when he 20/200 when he was was detected detected toto have have aa macular macular hole. hole. Post Post vitrectomy vitrectomy and and gas tamponade, his BCVA recovered to 20/100 and has been stable for 4 months (until the gas tamponade, his BCVA recovered to 20/100 and has been stable for 4 months (until the last follow-up) after surgery. He has been switched to aflibercept therapy (six injections last follow-up) after surgery. He has been switched to aflibercept therapy (six injections overall) and has been maintained on q8w dosing. overall) and has been maintained on q8w dosing. Figure 3. A 78-year-old male patient had been treated for neovascular AMD with aflibercept and ranibizumab and had Figure 3. A 78-year-old male patient had been treated for neovascular AMD with aflibercept and ranibizumab and had received 50 injections overall prior to switch to brolucizumab. (A–C) Multimodal imaging at baseline showing a large received 50 injections overall prior to switch to brolucizumab. (A–C) Multimodal imaging at baseline showing a large subfoveal lesion. (D) SD-OCT immediately prior to initiation of brolucizumab therapy. (E) SD-OCT 8 weeks after the first subfoveal brolucizumablesion. (D) SD-OCT injection showingimmediately prior toofinitiation a total resorption of brolucizumab the subretinal therapy. fluid but also (E) SD-OCT an evident 8 weeksadherence vitreomacular after the first brolucizumab injection showing a total resorption of the subretinal fluid but also an evident vitreomacular (arrows). (F) SD-OCT 15 days after receiving his 5th brolucizumab injection, showing macular hole. SD-OCT after the adherence (arrows). (F) SD-OCT macular hole 15 days surgery. (G) after C-late receiving phase FFA. his 5th brolucizumab injection, showing macular hole. SD-OCT after the macular hole surgery. (G) C-late phase FFA. A 71-year-old female developed branch arterial occlusion 7 days after receiving her A 71-year-oldinjection 5th brolucizumab female developed branch and presented arterial within 4 hocclusion 7 days of onset of after receiving symptoms. Her BCVA her 5th brolucizumab injection and presented within 4 h of onset of symptoms. Her prior to this event was 20/60; it dropped to 20/200 secondary to the arterial occlusion. Her BCVA prior to this perimetry event showed analysis was 20/60; it dropped field corresponding to 20/200 secondary defects. She was to the arterialreferred immediately occlusion. to Her perimetry analysis showed corresponding field defects. She was immediately the stroke clinic in Bremerhaven, Germany and received low molecular weight heparin. referred to the She strokecomplete showed clinic in Bremerhaven, Germanywith recovery, as confirmed and her received low molecular restoration of BCVAweight (20/60) hep- and complete disappearance of all field defects (Figure 4). The indication for switch to brolu- cizumab was an inability to extend the treatment-free interval beyond 4 weeks. With ini- tiation of brolucizumab therapy itself, the interval could be extended to 8 weeks. She has J. Clin. Med. 2021, 10, 2758 8 of 12 arin. She showed complete recovery, as confirmed with her restoration of BCVA (20/60) J. Clin. Med. 2021, 10, x FOR PEER REVIEW and complete disappearance of all field defects (Figure 4). The indication for switch 8 of to 12 brolucizumab was an inability to extend the treatment-free interval beyond 4 weeks. With initiation of brolucizumab therapy itself, the interval could be extended to 8 weeks. She has had not not had any adverse any adverse eventevent sincesince andbeen and has has been continued continued on aflibercept on aflibercept therapy therapy on a on q4w a q4w schedule. She has been asked to maintain a close watch on her vision. We schedule. She has been asked to maintain a close watch on her vision. We did not note anydid not note any instance instance of intraocular of intraocular inflammation, inflammation, such such as as anterior anterior chamber chamber reaction, reaction, vitritis,vitritis, or vascu-or vasculitis, nor vasculitic occlusion in any of the litis, nor vasculitic occlusion in any of the patients.patients. Figure 4. A 71-year-old woman with neovascular AMD had received 70 injections prior to initiation of brolucizumab Figure 4. A 71-year-old woman with neovascular AMD had received 70 injections prior to initiation of brolucizumab therapy. (A–C) Multimodal imaging showing the baseline situation before any anti-VEGF therapy. (D) SD-OCT immedi- therapy. (A–C) Multimodal imaging showing the baseline situation before any anti-VEGF therapy. (D) SD-OCT immediately ately prior to initiation of brolucizumab therapy. (E) SD-OCT after the first brolucizumab injection showing total resorp- prior tion oftosubretinal initiation of brolucizumab fluid and decrease therapy. of the (E) SD-OCT pigment after the detachment. epithelium first brolucizumab injection The patient showing total complained resorption of loss of visionof7 subretinal fluid and decrease of the pigment epithelium detachment. The patient complained of loss days after the fifth brolucizumab injection. (F–I) Multimodal imaging showing an retinal arterial occlusion in herof vision 7 days leftafter eye the fifth brolucizumab injection. (F–I) Multimodal imaging showing an retinal arterial occlusion in (arrow); perimetry analysis demonstrates a corresponding superior scotoma. She had presented within 4 h of onset ofher left eye (arrow); perimetry symptomsanalysis and wasdemonstrates immediatelyareferred corresponding superior scotoma. to the emergency Shereceived room and had presented within 4 hweight low molecular of onset of symptoms heparin. and (J,K) Post- heparin was analysis showing immediately perimetry referred to recovering the emergency roomand andarterial reperfusion. received low molecular weight heparin. (J,K) Post-heparin analysis showing perimetry recovering and arterial reperfusion. 27 patients (27 eyes) receiving switch therapy were on IOP-lowering medications at 27 patients the time (27toeyes) of switch receiving switch brolucizumab. therapy The switch in were on IOP-lowering therapy medications did not adversely at affect IOP the timeinofany control switch to brolucizumab. of these The switch 27 patients. None of the in therapy did not treatment-naïve adversely patients wereaffect IOP on prior control in therapy anyIOP-lowering with of these 27 patients. Noneeither medications of the at treatment-naïve patients the time of first were on intravitreal prior broluci- zumab injection or during the follow-up period. There was no rise in IOP noted at any point in time during the course of follow-up in any of the patients included in the study. The seven eyes excluded from the analysis received a mean of 3.2 (±0.8) injections after switch therapy and did not report any untoward event until the end of follow-up. J. Clin. Med. 2021, 10, 2758 9 of 12 therapy with IOP-lowering medications either at the time of first intravitreal brolucizumab injection or during the follow-up period. There was no rise in IOP noted at any point in time during the course of follow-up in any of the patients included in the study. The seven eyes excluded from the analysis received a mean of 3.2 (±0.8) injections after switch therapy and did not report any untoward event until the end of follow-up. None of the eyes were switched from brolucizumab to aflibercept (except for the two patients with ocular-adverse events described above). 4. Discussion The current analysis demonstrates very good anatomical, and to a significant extent, visual outcomes following the administration of intravitreal brolucizumab in treatment- naïve or switch-therapy patients in routine practice. Therefore, the primary aim of the study was to describe a real-world cohort of patients with lower baseline BCVA (in comparison to randomized control trials), that showed significant letter gain despite having undergone several treatments in the past. A significant proportion of treatment-naïve and switch patients demonstrated excellent visual and anatomical outcomes that were maintained until the end of the follow-up period. A sizeable proportion of eyes in the treatment-naïve group and the switch-therapy group were maintained on q12w dosing. The visual gains reported in the present study are higher than what was reported in the HAWK or HARRIER protocols [10]. In our study, treatment-naïve patients had a significantly lower baseline BCVA compared to the HAWK and HARRIER studies, and this could explain the greater visual gain. The ‘ceiling effect’ may thus account for the difference of visual gain when baseline BCVA are not similar. The switch-therapy groups demonstrated very good outcomes, and this could also be explained by the lower baseline BCVA than other series described in the literature. A recent paper on real-world evidence with brolucizumab reported no significant changes in BCVA at final follow-up for a cohort of patient who were mainly switched from another anti-VEGF therapy. However, the baseline BCVA reported in the study was higher than ours at 64.1 letters [11]. Another explanation for the high visual gain in the switch group is the presence of fluid, both IRF and SRF, within the retina at baseline in the majority of patients in this group. Brolucizumab injections efficiently treated the fluid in all cases with one to three injections before the total disappearance of the fluid, making an increase in visual acuity possible. Despite a proactive and intensive protocol with historical anti-VEGF molecules, this subgroup of patients had no or low or an ill-sustained response to the previous therapy. The visual gain provided by brolucizumab injections is probably explained by a greater drying effect on the retina and most importantly, it was also sustained in most patients at 8 weeks. However, it should be noted that the comparison in visual gain, according to the cause of switch, did not show any differences, although there was a trend to better visual gain in eyes with fluid at the time of switch in comparison to patients switched for the inability to extend beyond q6/q8 with previous therapy. This point should be investigated further in a larger cohort of patients. The smaller size of the brolucizumab molecule means a larger concentration of the drug can be delivered intraocularly. This probably accounts for improved efficacy and durability but may account for a higher incidence of hypersensitivity-like reactions. The incidence of vascular occlusion has been estimated to be 3.4/10000 injections [16]. Biological agents are known to cause hypersensitivity reactions [17]. Overall, enthusiasm for the drug on account of its increased efficacy has been offset somewhat by reports of increased propensity towards inflammatory adverse events [18,19]. Notwithstanding, the drug is a useful alternative to currently available anti-VEGF agents for wet AMD and indeed can eventually be the drug of choice given its potency. As regards complications, both adverse events were noted in patients receiving switch therapy and occurred after the loading phase. Treatment-naïve patients did not demonstrate adverse events until the last follow-up. One patient developed vascular occlusion after the fifth brolucizumab injection and this was reversed through timely intervention. There were no residual deficits noted, J. Clin. Med. 2021, 10, 2758 10 of 12 either in terms of visual acuity or perimetric changes. The time to development of this adverse event is contrary to past reports on vasculitis associated with brolucizumab that suggest that such adverse events are noted later (day 30) in the course of the follow-up. Additionally, this occurred after the fifth injection of brolucizumab and the 75th injection overall (including past therapy). Whereas a recently published study comprising 172 eyes receiving brolucizumab and 6 months of follow-up reported 14 instances of intraocular inflammation, only one serious adverse event (vasculitic occlusion) was reported [12]. In the remaining 13 eyes in the study, the vast majority of eyes showed spontaneous resolution whereas some eyes needed intervention in the form of topical or subtenon steroid therapy. The incidence of serious adverse events matches our analysis. Moreover, we report for the first time, to the best of our knowledge, macular hole formation after brolucizumab therapy. The patient responded well to surgery. Macular hole formation has been noted earlier with ranibizumab and bevacizumab [20,21]. A combination of alterations in retinal tractional forces and contracture of the choroidal neovascular membrane consequent to VEGF withdrawal along with altered vitreous dynamics consequent to repeat violations of the milieu interior of the vitreous cavity leads to macular hole formation. Whether the higher molecular concentration of brolucizumab plays any role in its incidence merits further investigation. The retrospective nature of our study is an obvious limitation in that follow-ups are liable to be missed. This is evolving data as it is a new drug. We attempted to analyze response by ethnicity but the numbers are too small (especially for south Asian ethnicity) to permit meaningful analysis. Notwithstanding, this current analysis is, in our opinion, an accurate portrayal of the current status of intravitreal brolucizumab therapy for neovascular AMD and the challenges associated therewith in the real world as opposed to the setting of a randomized trial. Brolucizumab was effective both in treatment-naïve patients and those receiving switch therapy in terms of visual gain and anatomical resolution of MNV associated exudation and in extension of the treatment interval. There was significant improvement in vision from baseline in both groups, thereby demonstrating its efficacy even in patients who had received multiple injections earlier and in patients with low baseline BCVA. Our findings correspond to early reports on the use of brolucizumab [22] but additionally, we also report on patients receiving switch therapy. The current general consensus the world over is one of reduction in the treatment burden. The FLUID study, for example also looks at how much fluid can be tolerated without much compromise of final vision [23] whereas our recent publication looks at a particular subset of patients who do well with one injection over a considerable period of time [24]. This is also important in reducing treatment costs. Finally, our short case series on the efficacy of brolucizumab in patients with MNV and RPE rip reaffirms to some extent the visual gains reported in the present analysis, albeit a very small number of patients [25]. To conclude, intravitreal brolucizumab therapy is effective in both treatment-naïve patients and patients who receive the drug as switch therapy. There is a small but definite risk associated with the drug (1.9% overall in our series; 0.95% as far as vascular occlusion is concerned). Notwithstanding the small risk of untoward events, intravitreal brolucizumab therapy is a useful addition to the retinal surgeon’s armamentarium and should establish itself as an effective form of primary therapy that can do well with infrequent administra- tion. A high index of suspicion maintained both by the physician and the patient can help avert disastrous complications. Author Contributions: Conceptualization, A.B., L.K., A.S. and T.M.; methodology, A.B., L.K., A.S. and T.M.; validation, A.B., L.K., F.M.d.R., V.V., J.H.G.-C., A.A., A.S. and T.M.; formal analysis, A.B., L.K., F.M.d.R., V.V., J.H.G.-C., A.A., A.S. and T.M.; investigation, A.B., L.K., A.S. and T.M.; writing— original draft preparation, A.B., A.S. and T.M.; writing—review and editing, A.B., L.K., F.M.d.R., V.V., J.H.G.-C., A.A. and A.S.; supervision, L.K. and T.M. All authors have read and agreed to the published version of the manuscript. Funding: Novartis had no role in the conceptualization, design, conduct, or analysis of the manuscript but will support open access fees for this manuscript. J. Clin. Med. 2021, 10, 2758 11 of 12 Institutional Review Board Statement: This study complied with the tenets of the Declaration of Helsinski and was approved by an international review board (Ethics Committee of the French Society of Ophthalmology, IRB 00008855 Société Française d’Ophtalmologie IRB#1). Patients gave their informed consent to participate in the study. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Data Availability Statement: All data are available upon request to the corresponding author. Conflicts of Interest: Laurent Kodjikian is a consultant for Allergan/Abbvie, Bayer, Horus, Novartis, Roche and Théa; Thibaud Mathis is a consultant for Allergan/Abbvie, Bayer, GSK, Horus and Novartis. Other authors have no conflicts of interest to declare. References 1. Rosenfeld, P.J.; Brown, D.M.; Heier, J.S.; Boyer, D.S.; Kaiser, P.; Chung, C.Y.; Kim, R.Y. Ranibizumab for Neovascular Age-Related Macular Degeneration. N. Engl. J. 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