Intravitreal faricimab for previously treated neovascular age-related macular degeneration

Intravitreal faricimab for previously treated neovascular age-related macular degeneration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Intravitreal faricimab for previously treated neovascular age-related macular degeneration Susanna Park, Abraham Hang, Taylor Ngo, Jaipreet Virk, Kareem Moussa, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4255731/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background/Objectives: To report our real-world experience using intravitreal faricimab, a novel anti-vascular endothelial growth factor (anti-VEGF) therapy, in eyes with neovascular age-related macular degeneration (nAMD) previously treated with other anti-VEGF therapy. Subjects/Methods: A retrospective, single-center study of previously treated nAMD eyes treated with faricimab. Results: In 88 eyes (73 patients), mean baseline best-corrected visual acuity (BCVA) was 20/63 (range 20/20 to CF) with mean anti-VEGF injection interval of 6.1 + 2.0 weeks. Mean baseline central subfield thickness (CST) was 291 + 73 µm. During mean follow-up of 30.1 + 13.5 (range 7.0 to 50.3) weeks on faricimab, the eyes received an average of 5.1 + 2.4 injections (range 1 to 11). Mean BCVA remained at 20/63 (p=0.11), but injection interval increased to 7.4 + 2.6 weeks (p<0.001), and CST decreased to 262 + 63 µm (p<0.001). Multiple linear regression analysis revealed that higher number of different anti-VEGF drugs used at baseline was associated with a lower decrease in CST on faricimab (p=0.04) while total number of anti-VEGF injections at baseline (p=0.56) and time on faricimab (p=0.68) were not associated. Faricimab was discontinued in 23 eyes (26.1%), including 8 eyes for poor response, 2 eyes for persistent new floaters and 4 eyes for new vision decrease which reversed after stopping faricimab. Conclusions In previously treated nAMD eyes, intravitreal faricimab was associated with increased mean treatment interval and decreased CST but no improvement in mean BCVA. The benefit of faricimab on CST reduction may be diminished in eyes previously treated with multiple different types of anti-VEGF therapy. Health sciences/Diseases/Eye diseases/Macular degeneration Health sciences/Diseases/Eye diseases/Retinal diseases anti-VEGF therapy intravitreal therapy age-related macular degeneration faricimab Figures Figure 1 Introduction The most common cause of irreversible blindness in the developed world is age-related macular degeneration (AMD). It is projected that by 2040, there will be over 300 million people in the world with AMD. 1 Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become a mainstay in treatment of neovascular age-related AMD (nAMD). It inhibits bleeding and exudation associated with choroidal neovascularization (CNV), thereby limiting vision loss. The number of anti-VEGF medications that can be used as therapy continues to grow, as several new medications have been approved by the Food and Drug Administration (FDA) in recent years. 2 Several other new drugs aiming to increase durability and efficacy are undergoing clinical trials. 2 Intravitreal faricimab is one of the newest anti-VEGF agents to receive FDA approval. In 2022, this drug was approved for treatment of diabetic macular edema (DME) and nAMD; 3 it was also approved for treatment of macular edema associated with retinal vein occlusion (RVO) in 2023. 4 Faricimab is a bispecific antibody that targets VEGF-A and Angiopoetin-2 (Ang-2). Ang-2 is a pro-angiogenic factor that plays a role in vascular leakage and inflammation; it is theorized to play a complementary or even synergistic role with VEGF in nAMD or macular edema from retinal vasculopathy. 3,5 The TENAYA and LUCERNE phase III clinical trials demonstrated non-inferiority of intravitreal faricimab compared to intravitreal aflibercept in treatment of eyes with treatment-naïve nAMD in terms of best corrected visual acuity (BCVA). 6 At week 48, approximately 80% of study eyes treated with faricimab in both trials could have their treatment interval extended to 12 or 16 week. In contrast, eyes treated with aflibercept had treatment interval maintained at 8 weeks for the study duration as per study protocol. Although these studies were not designed to compare durability of faricimab vs aflibercept, the study observations highlight the potential durability of intravitreal faricimab therapy. Since TENAYA and LUCERNE phase III clinical trials included only treatment-naïve eyes with nAMD, this study was conducted to evaluate real-world experience using intravitreal faricimab in treating eyes with nAMD previously treated with other anti-VEGF therapies. This will provide information regarding the relative efficacy and durability of intravitreal faricimab when compared to other available anti-VEGF therapies. This is a single-center retrospective study of all eyes treated with intravitreal faricimab for nAMD after being on other anti-VEGF therapy. We evaluated visual and anatomic outcomes of these eyes on faricimab therapy when compared to baseline. Materials/Subjects and Methods This study included all patients with nAMD that received faricimab therapy between August 2020 and November 2023 at the Department of Ophthalmology and Vision Science, University of California Davis Health, Sacramento, California. Ethical approval of the study protocol and waiver of patient informed consent was obtained from the Office of Human Research (Institutional Review Board) at the University of California, Davis Health. This study complied with accepted-standard research guidelines set forth by the Declaration of Helsinki. The study population included all patients with a diagnosis of nAMD who initiated faricimab therapy, had previously been on another anti-VEGF agent, and had intraretinal and/or subretinal fluid on optical coherence tomography (OCT) within 6 months prior to their first faricimab injection. All eyes with nAMD were treated using a treat-and-extend protocol on anti-VEGF therapy, including faricimab. Patient demographics, including age, sex, and history of concurrent or past retinal conditions were obtained from the electronic medical record. Clinical data collected included BCVA, macular OCT central subfield thickness (CST) and presence or absence of macular fluid, at initial faricimab injection visit and at final visit. Information on the number of faricimab injections and injection interval at the last visit was also collected. To evaluate drug safety, data collected included number and types of ocular adverse effects on faricimab treatment ,in addition to information on all eyes where faricimab was discontinued and reason for discontinuation. Statistical Analysis Summary statistics were generated to describe patient demographic and clinical characteristics of our study population. Paired t-tests were used to compare BCVA and CST before and after starting faricimab. A multiple linear regression model was used to evaluate factors associated with a decrease in CST. Tests for multicollinearity were performed using variance inflation factor values, and tests for clustering were performed by confirming there were no significant changes in results when one eye was removed in a patient with both eyes included in the study. Results Patient Population A total of 123 eyes were identified as having been treated with faricimab at the study center during the study period, and 35 eyes were excluded (Fig. 1 ). Of the 35 excluded eyes, 18 eyes had nAMD but no demonstrated fluid on OCT in the past 6 months, 11 eyes had treatment-naïve nAMD, 5 eyes had pre-existing ocular condition (pars plana vitrectomy, concurrent central retinal vein occlusion, and concurrent uveitic cystoid macular edema), and 1 eye received one faricimab injection without follow-up. After excluding those eyes, 88 eyes (73 patients) fit our study inclusion criteria. All 88 study eyes had intraretinal or subretinal fluid on OCT within 6 months prior to starting faricimab (Table 1 ) and had been treated with other anti-VEGF therapy. 14.8% of eyes had no macular fluid on OCT at baseline visit. The indication for starting faricimab therapy was for treatment of recalcitrant macular fluid on OCT and/or desire to extend treatment interval. Average age was 82 ± 9 (range 57–101), and 65.9% were female. The average number and duration of anti-VEGF therapy prior to starting faricimab were 27.5 injections (range 1-127) and 41.9 months (range 1-169), respectively. Among these 88 eyes, 24 eyes (27.3%) had been treated with one anti-VEGF medication prior to starting faricimab, 47 eyes (53.4%) had been on two different anti-VEGF drugs, 12 eyes (13.6%) had been treated with three different anti-VEGF drugs, and 5 eyes (5.7%) had been on four different anti-VEGF drugs at baseline. The four different anti-VEGF medications used prior to starting faricimab included bevacizumab, aflibercept, ranibizumab, and brolucizumab. Prior to switching to faricimab, 63 eyes (71.6%) were on aflibercept, 8 eyes (9.1%) were on ranibizumab, 6 eyes (6.8%) were on bevacizumab, 4 eyes (4.5%) were on brolucizumab, and 7 eyes (8%) were on a monthly treatment alternating between aflibercept and brolucizumab. Table 1 Demographic and baseline clinical feature of eyes with nAMD treated with faricimab Total number of eyes (patients) 88 (73) Mean age, years (SD) 82 ( 9 ) Sex (%) Female 58 (65.9) Male 30 (34.1) Laterality (%) Right 45 (51.1) Left 43 (48.9) Most recent anti-VEGF therapy prior to switch (%) Aflibercept 63 (71.6) Brolucizumab 4 (4.5) Bevacizumab 6 (6.8) Ranibizumab 8 (9.1) Alternating Aflibercept/Brolucizumab 7 (8.0) Mean duration of prior anti-VEGF therapy, months (SD), range 41.9 (39.4) 1-169 Mean number of injections of prior anti-VEGF therapy, (SD), range 27.5 (26.6) 1-127 Indication for switch to faricimab (%) Persistent macular fluid 31 (35.2) Treatment interval extension 35 (40.7) Both 22 ( 25 ) Number of different anti-VEGF therapies used prior to faricimab (%) 1 24 (27.3) 2 47 (53.4) 3 12 (13.6) 4 5 (5.7) Baseline macular fluid status (%) Subretinal fluid (SRF) only 38 (43.2) Intraretinal fluid (IRF) only 24 (27.3) Concurrent SRF and IRF 13 (14.8) No fluid 13 (14.8) Abbreviations : nAMD, neovascular age-related macular degeneration; SD, standard deviation; anti-VEGF, drugs that inhibit vascular endothelial growth factor; SRF, subretinal fluid; IRF, intraretinal fluid; OCT, optical coherence tomography Anatomic and Visual Outcomes Table 2 summarizes the anatomical and visual outcomes in the study eyes before and after starting faricimab. Mean baseline logMAR BCVA prior to starting faricimab was 0.5 ± 0.3 (Snellen equivalent 20/63) with a mean anti-VEGF injection interval of 6.06 ± 2.0 weeks (range 4–15 weeks). On macular OCT, the mean baseline CST was 291 ± 73 µm. All patients had either subretinal or intraretinal fluid on at least one OCT within 6 months prior to starting faricimab. At the baseline visit when faricimab was initiated, 38 (43.2%) patients had subretinal fluid (SRF), 24 (27.3%) had intraretinal fluid (IRF), 13 (14.8%) had both, and 13 (14.8%) had no fluid (Table 1 ). One eye had no OCT done at the baseline visit, so the most recent OCT from the prior visit was used for analysis since the patient had been maintained on the same anti-VEGF therapy. In addition, CST was not available in 1 patient in 2 eyes at both baseline and follow-up due to poor patient cooperation with imaging, resulting in only a 5-line raster scan being obtained. For this OCT, an estimate of the CST was obtained by manual measurements of 5 points from the internal limiting membrane to Bruch’s membrane at the center of the fovea and 0.5 mm superior, inferior, nasal, and temporal, and taking the average. In 1 eye at follow-up, a CST could not be obtained due to poor OCT signal with an erroneous CST reading and was not included in the analysis. Table 2 Anatomical and visual acuity in the study eyes before and after starting faricimab Study eyes on Faricimab (n = 88) Baseline Final follow-up p-value* Mean BCVA (logMAR), (SD) 0.5 ± 0.3 0.5 ± 0.4 0.11 Mean CST (µm), (SD) 291 ± 73 262 ± 63 < 0.001 Mean treatment interval, weeks (SD) 6.06 ± 2.0 7.44 ± 2.6 < 0.001 Mean number of Faricimab injections (SD) 5.1 ± 2.4 Abbreviations : BCVA, best corrected visual acuity; CST, central subfield thickness; SD, standard deviation *p-value based on paired student t test. During a mean follow-up of 30.1 ± 13.5 weeks (range 7.0 to 50.3 weeks) after starting faricimab, the study eyes received a mean of 5.1 ± 2.4 injections (range 1–11). At the latest visit, mean logMAR BCVA remained at 0.5 ± 0.4 (Snellen equivalent 20/63) (p = 0.11), but mean injection interval increased by 1.38 weeks to 7.44 ± 2.6 weeks (p < 0.001), and mean CST decreased to 262 ± 63 µm (p < 0.001) with an average decrease of 28.3 µm in CST (Table 2 ). At last study visit, 25 (28.4%) eyes had SRF, 22 (25.0%) eyes had IRF, 6 (6.8%) had both, 35 (39.8%) had no fluid. Of the 75 eyes with fluid on OCT at baseline, 27 (36%) had complete resolution of macular fluid at the latest visit on faricimab, and 47 (64%) had persistent intraretinal or subretinal fluid. Multiple linear regression analysis revealed that the total number of anti-VEGF injections at baseline was not significantly associated with CST reduction after initiating faricimab (p = 0.56), and neither was the amount of time on faricimab (p = 0.68). However, higher number of different types of anti-VEGF drugs used before starting faricimab was significantly associated with a lesser decrease in CST after starting faricimab (p = 0.04). Safety Faricimab was discontinued in 23 eyes (19 patients) (26%). Eight eyes (35%) were switched to a different anti-VEGF drug due to poor response on faricimab, 2 eyes (9%) were switched due to joining a clinical trial, 2 eyes (9%) were switched due to insurance barriers, 2 eyes (9%) were discontinued due to loss to follow-up, and 1 patient became deceased during this time period. Faricimab was stopped in 8 eyes (9.1%) due to adverse events, including eye irritation (2 eyes in 1 patient), persistent new floaters (2 eyes in 2 patients) and new subjective vision loss (4 eyes in 3 patients). 2 patients (2 eyes) with new floaters had persistent floaters lasting up to 9 to 11 weeks and occurring after the first or second faricimab injection. Both patients declined further treatment with faricimab. All 3 patients with subjective vision loss after starting faricimab had measured vision loss after 1 or 2 faricimab injections with no new change on eye exam or worsening of fluid on OCT to explain the vision loss. All 3 patients had at least partial improvement in vision after stopping faricimab and resuming treatment with other anti-VEGF therapy. These 3 patients are described in more detail below. The first patient is an 81-year-old monocular woman with nAMD in the right eye who received 1 dose of faricimab. She had been treated with monthly alternating dose of brolucizumab and aflibercept and was switched to faricimab to increase treatment interval. When seen 5 weeks later, her BCVA had improved from 20/70 to 20/50, exam was unchanged and macular fluid remained resolved. However, she noted numerous new fixed small spots 360 degrees around her central vision starting a few days after faricimab injection, which were preventing her from reading and seeing properly. She declined further treatment with faricimab and was treated with brolucizmab. When seen the following month, the spots were less visible, but her BCVA dropped to 20/150. She subsequently had cataract surgery and BCVA improved to 20/20 while being maintained on alternating doses of brolucizumab and aflibercept. The spots fully resolved over a couple months after stopping faricimab. The second patient had nAMD OU with end-stage disciform scar in the left eye. The right eye was treated with monthly alternating doses of brolucizumab and aflibercept. Treatment was changed to faricimab for chronic mild residual intraretinal macular fluid and to increase treatment interval. She received 2 doses of faricimab and noted new vision loss 5 weeks after the second dose. Her BCVA in the right eye had dropped to 20/300 from 20/100 baseline. Eye exam and OCT were unchanged. Faricimab was discontinued and the patient was treated with alternating brolucizumab and aflibercept. BCVA returned to baseline 4 weeks later. The third patient is a 94-year-old woman with nAMD in both eyes with trace intraretinal macula fluid in both eyes on aflibercept every 5 weeks. She was started on faricimab OU for residual macular fluid and for extension of treatment interval. She called our office 4 weeks after receiving one dose of faricimab noting new blurry vision in both eyes. When examined 7 weeks after faricimab, her BCVA declined in both eyes to 20/400 from 20/100 OD and 20/150 OS; macular fluid resolved on OCT OU and eye exam was unchanged. Faricimab was discontinued, and she was treated with aflibercept OU monthly. Her BCVA gradually improved to 20/200 OU over 3 months. Discussion Due to advances in drug development, we have a growing number of anti-VEGF drugs that can be administered intravitreally for treatment of nAMD. All of these drugs are effective in reducing vision loss associated with complications of CNV. However, the effects of all anti-VEGF drugs are reversible and require frequent, often indefinite, intravitreal injections to maintain therapeutic effect. In addition, some eyes with nAMD become resistant to anti-VEGF therapy, requiring higher frequency dosing, sometimes as often as 4 weeks. Even then, some eyes with nAMD may become recalcitrant to anti-VEGF therapy with persistent macular fluid on OCT. Persistent residual intraretinal fluid in eyes with nAMD on anti-VEGF therapy has been associated with poorer visual outcome. 7 It is not entirely clear why certain eyes with nAMD have macular fluid that is resistant to anti-VEGF treatments. A couple of studies have suggested that presence of pigment epithelial detachment, large choroidal neovascular membrane (CNV), and type 1 CNV or non-classic CNV may be associated with poorer response to treatment with ranibizumab or bevacizumab. 8,9 Other studies have shown that nAMD eyes that do not demonstrate a reduction in CST on OCT after 4 weeks on anti-VEGF therapy may have a significant response on OCT that can be detected at 2 or 3 weeks, indicating that the eye is responding to therapy but with shorter duration of effect than expected. 10 The percentage of “non-responders” to intravitreal anti-VEGF therapy is significant and can be as high as 45% depending on the study population, type of anti-VEGF therapy, and how “non-response” is defined. 8,9,11 As such, anti-VEGF agents with greater durability and efficacy are highly desirable for both patients and providers. The TENAYA and LUCERNE phase III clinical trials for faricimab demonstrated non-inferiority of faricimab to aflibercept in terms of BCVA in treating newly diagnosed nAMD. In these trials, 80% of eyes on faricimab had treatment interval extended to 12 or 16 weeks, while all eyes on aflibercept were maintained at a treatment interval of 8 weeks as per study protocol. This finding suggests that faricimab may have long durability. 6 However, TENAYA and LUCERNE studies were not designed to evaluate superiorly of faricimab over aflibercept. In addition, these studies enrolled only treatment-naïve nAMD eyes. It is well-recognized that clinical trial data with well-defined study criteria often result in better outcomes in comparison to real-world data. 12–16 Thus, our study was conducted to evaluate real-world experience using intravitreal faricimab in nAMD eyes previously treated with other anti-VEGF therapies. In our study, we selected only eyes with nAMD that had demonstrated recalcitrant macular fluid on OCT within the 6 months prior to initiation of faricimab. At the time of switching to faricimab, most eyes (85%) had persistent macular fluid on OCT in the study eye on maximum anti-VEGF therapy. After starting faricimab treatment, the number of eyes in our study with no macular fluid increased from 14.8–40.2%. A statistically significant reduction in mean CST was observed at the last follow-up visit on faricimab compared to baseline visit before starting faricimab. We also found a significant increase in the treatment interval at the last visit on faricimab compared to baseline. Faricimab therapy resulted in a mean increase of 1.3 weeks in treatment interval when compared to the treatment interval on other anti-VEGF therapies. These findings support the hypothesis that faricimab may have a longer duration of effect and greater efficacy in treating eyes with nAMD compared to other currently available anti-VEGF therapies. In our study, we used multiple linear regression analysis to identify baseline clinical features that may be associated with improved response on faricimab. We found that the benefit of faricimab in reducing CST in eyes with nAMD previously treated with other anti-VEGF may depend on the number of different anti-VEGF drugs used prior to starting faricimab. In particular, the benefit of faricimab may be diminished in eyes that had been on multiple types of anti-VEGF medications (p = 0.04). This benefit of using faricimab was not affected by the total number of anti-VEGF injections administered prior to switching to faricimab, and was also not affected by the amount of time on faricimab. This is noteworthy because a majority of our study eyes had > 10 anti-VEGF injections, with a mean of 27 injection, prior to starting faricimab; most study eyes had been treated with at least 2 different anti-VEGF drugs before starting faricimab. Eyes treated with multiple other anti-VEGF agents before starting faricimab in our study population likely represent eyes that are most resistant to anti-VEGF therapy. Despite improvement in macular fluid and mean CST on OCT on faricimab, there were no significant changes in BCVA on faricimab therapy when compared to baseline in our study population. This is in contrast to the TENAYA and LUCERNE clinical trials, which showed a mean improvement in BCVA after starting faricimab or aflibercept in treatment-naïve eyes with nAMD. Our study finding is not unexpected, as all the eyes in our study had already been on anti-VEGF therapy. Gain in BCVA on anti-VEGF therapy in eyes with nAMD is usually seen in the first 3 to 4 months after treatment initiation. In eyes with nAMD with chronic macular fluid, it has been shown that vision loss and structural macular damage can result. 17 In addition, prior long-term follow-up studies have demonstrated that in eyes with nAMD being treated with anti-VEGF therapy, BCVA gain that is initially noted with anti-VEGF treatment is often lost due to disease progression and progression of geographic atrophy. 14,16 Our study findings are consistent with a few other real-world outcome studies on faricimab in the treatment of nAMD. These studies also showed that switching to faricimab has a benefit in improving anatomic outcomes through a reduction of CST and intraretinal/subretinal fluid while maintaining BCVA. 18–20 The potential superior efficacy of faricimab in decreasing CST and increasing treatment intervals when compared to other anti-VEGF drugs is attributed to its novel dual inhibition of VEGF and Ang-2. In neovascular diseases, such as nAMD, multiple pro-angiogenic and inflammatory proteins and signaling factors may play a role in pathogenesis. Ang-2 is involved in vascular stability, inflammation, pericyte apoptosis, and changes in the endothelial cell cytoskeleton, which leads to vascular instability. 21–23 Thus, inhibition of Ang-2 is thought to have a complementary, or perhaps synergistic effect to anti-VEGF in decreasing angiogenesis and vascular permeability. Our study also evaluated safety of faricimab therapy in real world patients with nAMD previously treated with other anti-VEGF agents. The TENAYA and LUCERNE trials for nAMD demonstrated a non-inferior safety profile compared to aflibercept for serious ocular adverse events. 6 However, there is a theoretical risk of new adverse events from using faricimab, which blocks new pathways in addition to VEGF-A. 21 In our study, a few patients experienced vision loss or changes soon after starting faricimab. This has not been reported previously in other real-world studies. 18–20,24 These patients had a decrease in BCVA in the treated eye without significant change on OCT or exam to explain the vision loss. Fortunately, all these patients in our study had gradual recovery of vision and resolution of symptoms after stopping faricimab and switching back to their prior anti-VEGF treatment regimen. It is unclear whether these visual changes could be related to effects of faricimab in modulating ang-2. As we gain more real-world experience using faricimab, we can learn more about potential adverse effects of this new therapy. Recently, there was a report of severe vision loss in 3 eyes with nAMD from severe intraocular inflammation after starting faricimab treatment. 25 In our study eyes, no intraocular inflammation was observed. The limitations of our study include the limited sample size as well as the retrospective study design. Although the treat-and-extend regimen was used by all participating retinal specialists, it varied slightly based on the physician as well as the patient’s history of response to prior anti-VEGF therapy. In addition, all study eyes had macular fluid within 6 months of starting faricimab, but only 14.8% of study eyes had no macular fluid on OCT at baseline. Despite this, our study found a significant reduction in mean macular thickness after starting faricimab. In summary, this study provides additional real-world data and insights on treatment outcomes using faricimab in eyes with nAMD previously treated with other anti-VEGF agents. Faricimab demonstrates improved anatomical outcomes in patients with nAMD while decreasing the frequency of injections. The benefit of faricimab over other anti-VEGF therapies may be diminished in eyes with nAMD that have been refractory to multiple different types of anti-VEGF therapies. Faricimab appears to be well tolerated in most eyes, but a few eyes had new vision change or worsening soon after starting faricimab despite stable exam and OCT; these changes appear to resolve after stopping faricimab. Since faricimab is a relatively new therapy for nAMD, future larger studies are important to fully characterize the efficacy, safety, and long-term effects of faricimab in eyes with nAMD. Declarations Conflict of Interest S.S.P. has received contracted research grants via an employer from the industry to investigate anti-VEGF therapy for retinal disorders (Allergan, Greybug, Ophthea Ltd., Roche/Novartis). P.E. is a consultant for Genentech. None of the other authors have any conflicts of interest to report. Funding: This work was supported in part by the Barbara A and Alan M Roth MD Endowed Chair in Visual Science from the University of California Davis (S.S.P.). There was no other funding support. References Vyawahare H, Shinde P. Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment. Cureus. 2022;14(9):e29583. Hang A, Feldman S, Amin AP, Ochoa JAR, Park SS. Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders. Pharmaceuticals (Basel). 2023;16(8). Shirley M. Faricimab: First Approval. Drugs. 2022;82(7):825-30. FDA Approves Genentech’s Vabysmo for the Treatment of Retinal Vein Occlusion (RVO) [press release]. 2023. Khanani AM, Russell MW, Aziz AA, Danzig CJ, Weng CY, Eichenbaum DA, et al. Angiopoietins as Potential Targets in Management of Retinal Disease. Clin Ophthalmol. 2021;15:3747-55. 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Real-world outcomes of treatment resistant neovascular-age related macular degeneration switched from Aflibercept to Faricimab. Ophthalmology Retina. 2023. Pandit SA, Momenaei B, Wakabayashi T, Mansour HA, Vemula S, Durrani AF, et al. Clinical Outcomes of Faricimab in Patients with Previously Treated Neovascular Age-Related Macular Degeneration. Ophthalmology Retina. 2023. Szigiato A, Mohan N, Talcott KE, Mammo DA, Babiuch AS, Kaiser PK, et al. Short-Term Outcomes of Faricimab in Patients with Neovascular Age-Related Macular Degeneration on Prior Anti-VEGF Therapy. Ophthalmology Retina. 2024;8(1):10-7. Larsen HO, Grauslund J, Vergmann AS. Efficacy, Durability and Safety of Faricimab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Oedema: Lessons Learned from Registration Trials. Ophthalmol Ther. 2023;12(5):2253-64. Joussen AM, Ricci F, Paris LP, Korn C, Quezada-Ruiz C, Zarbin M. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021;35(5):1305-16. Regula JT, Lundh von Leithner P, Foxton R, Barathi VA, Cheung CM, Bo Tun SB, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016;8(11):1265-88. Grimaldi G, Cancian G, Rizzato A, Casanova A, Perruchoud-Ader K, Clerici M, et al. Intravitreal faricimab for neovascular age-related macular degeneration previously treated with traditional anti-VEGF compounds: a real-world prospective study. Graefe's Archive for Clinical and Experimental Ophthalmology. 2023. Li Y, Chong R, Fung AT. Association of Occlusive Retinal Vasculitis With Intravitreal Faricimab. JAMA Ophthalmology. 2024. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4255731","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":311430385,"identity":"0f7b40d3-d2ee-4db9-ab4d-b0a7b9231359","order_by":0,"name":"Susanna Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYPCCBDkgYQBGQA5xWoxJ15LYAFVPWIt8/+FnD37uSUvfcPzwxs88BXUM/Ow5Bni1GNxIMzfseZaTu+FMWrE0j8FhBsmeNwS0SPCwSfAcqMjdcIPHQHKGwQGgIQRske8/wyb550BFusENHuOfMwzqGOwJaWE4kMMmzXMgJwGoxUzigwEz0F4i/GIscyDNcOaZtDKLDwaHeSTOPCsg4LDDzx6+OZAsz3f88OYbCX/q5PjbkzfgdxgDAxsKj4eQckwto2AUjIJRMAowAADy0EYNkkx5QAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5911-6671","institution":"UC Davis Eye Center","correspondingAuthor":true,"prefix":"","firstName":"Susanna","middleName":"","lastName":"Park","suffix":""},{"id":311430386,"identity":"3ded4269-a3fe-41b7-8750-5de885e52a7f","order_by":1,"name":"Abraham Hang","email":"","orcid":"","institution":"uc davis","correspondingAuthor":false,"prefix":"","firstName":"Abraham","middleName":"","lastName":"Hang","suffix":""},{"id":311430387,"identity":"dacb80b5-fc65-49a5-9752-ba843c136572","order_by":2,"name":"Taylor Ngo","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Taylor","middleName":"","lastName":"Ngo","suffix":""},{"id":311430388,"identity":"746e2573-4a22-4888-845f-0d7ba9fa64c2","order_by":3,"name":"Jaipreet Virk","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jaipreet","middleName":"","lastName":"Virk","suffix":""},{"id":311430389,"identity":"f661ac76-366f-4283-ab5e-c7532235ada1","order_by":4,"name":"Kareem Moussa","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Kareem","middleName":"","lastName":"Moussa","suffix":""},{"id":311430390,"identity":"fb18de08-9931-4931-9dc9-29bd410d3fa2","order_by":5,"name":"Ala Moshiri","email":"","orcid":"","institution":"Department of Ophthalmology and Vision Science, School of Medicine UC Davis Eye Center","correspondingAuthor":false,"prefix":"","firstName":"Ala","middleName":"","lastName":"Moshiri","suffix":""},{"id":311430391,"identity":"8c364884-2ce2-4cca-9295-005227b6bcca","order_by":6,"name":"Parisa Emami-Naeini","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Parisa","middleName":"","lastName":"Emami-Naeini","suffix":""}],"badges":[],"createdAt":"2024-04-12 06:25:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4255731/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4255731/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":59125255,"identity":"fcb4c99c-4de9-469f-8070-aa99324b9d6e","added_by":"auto","created_at":"2024-06-26 15:27:38","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":180362,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram summarizing the distribution of eyes with neovascular age-related macular degeneration on faricimab identified in the study center and selection of the study eyes.\u003c/p\u003e","description":"","filename":"Figure132924.png","url":"https://assets-eu.researchsquare.com/files/rs-4255731/v1/b07df143c8806676fd1f2855.png"},{"id":63900766,"identity":"371f9337-da68-46aa-a5e8-1f49b94e7515","added_by":"auto","created_at":"2024-09-03 14:18:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":627319,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4255731/v1/1e3701d4-53b3-4680-a4e4-34f54138ba9b.pdf"}],"financialInterests":"There is conflict of interest","formattedTitle":"Intravitreal faricimab for previously treated neovascular age-related macular degeneration","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe most common cause of irreversible blindness in the developed world is age-related macular degeneration (AMD). It is projected that by 2040, there will be over 300\u0026nbsp;million people in the world with AMD.\u003csup\u003e1\u003c/sup\u003e Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy has become a mainstay in treatment of neovascular age-related AMD (nAMD). It inhibits bleeding and exudation associated with choroidal neovascularization (CNV), thereby limiting vision loss. The number of anti-VEGF medications that can be used as therapy continues to grow, as several new medications have been approved by the Food and Drug Administration (FDA) in recent years.\u003csup\u003e2\u003c/sup\u003e Several other new drugs aiming to increase durability and efficacy are undergoing clinical trials.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e Intravitreal faricimab is one of the newest anti-VEGF agents to receive FDA approval. In 2022, this drug was approved for treatment of diabetic macular edema (DME) and nAMD;\u003csup\u003e3\u003c/sup\u003e it was also approved for treatment of macular edema associated with retinal vein occlusion (RVO) in 2023.\u003csup\u003e4\u003c/sup\u003e Faricimab is a bispecific antibody that targets VEGF-A and Angiopoetin-2 (Ang-2). Ang-2 is a pro-angiogenic factor that plays a role in vascular leakage and inflammation; it is theorized to play a complementary or even synergistic role with VEGF in nAMD or macular edema from retinal vasculopathy.\u003csup\u003e3,5\u003c/sup\u003e The TENAYA and LUCERNE phase III clinical trials demonstrated non-inferiority of intravitreal faricimab compared to intravitreal aflibercept in treatment of eyes with treatment-na\u0026iuml;ve nAMD in terms of best corrected visual acuity (BCVA).\u003csup\u003e6\u003c/sup\u003e At week 48, approximately 80% of study eyes treated with faricimab in both trials could have their treatment interval extended to 12 or 16 week. In contrast, eyes treated with aflibercept had treatment interval maintained at 8 weeks for the study duration as per study protocol. Although these studies were not designed to compare durability of faricimab vs aflibercept, the study observations highlight the potential durability of intravitreal faricimab therapy.\u003c/p\u003e \u003cp\u003eSince TENAYA and LUCERNE phase III clinical trials included only treatment-na\u0026iuml;ve eyes with nAMD, this study was conducted to evaluate real-world experience using intravitreal faricimab in treating eyes with nAMD previously treated with other anti-VEGF therapies. This will provide information regarding the relative efficacy and durability of intravitreal faricimab when compared to other available anti-VEGF therapies. This is a single-center retrospective study of all eyes treated with intravitreal faricimab for nAMD after being on other anti-VEGF therapy. We evaluated visual and anatomic outcomes of these eyes on faricimab therapy when compared to baseline.\u003c/p\u003e"},{"header":"Materials/Subjects and Methods","content":"\u003cp\u003eThis study included all patients with nAMD that received faricimab therapy between August 2020 and November 2023 at the Department of Ophthalmology and Vision Science, University of California Davis Health, Sacramento, California. Ethical approval of the study protocol and waiver of patient informed consent was obtained from the Office of Human Research (Institutional Review Board) at the University of California, Davis Health. This study complied with accepted-standard research guidelines set forth by the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eThe study population included all patients with a diagnosis of nAMD who initiated faricimab therapy, had previously been on another anti-VEGF agent, and had intraretinal and/or subretinal fluid on optical coherence tomography (OCT) within 6 months prior to their first faricimab injection. All eyes with nAMD were treated using a treat-and-extend protocol on anti-VEGF therapy, including faricimab. Patient demographics, including age, sex, and history of concurrent or past retinal conditions were obtained from the electronic medical record. Clinical data collected included BCVA, macular OCT central subfield thickness (CST) and presence or absence of macular fluid, at initial faricimab injection visit and at final visit. Information on the number of faricimab injections and injection interval at the last visit was also collected. To evaluate drug safety, data collected included number and types of ocular adverse effects on faricimab treatment ,in addition to information on all eyes where faricimab was discontinued and reason for discontinuation.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eSummary statistics were generated to describe patient demographic and clinical characteristics of our study population. Paired t-tests were used to compare BCVA and CST before and after starting faricimab. A multiple linear regression model was used to evaluate factors associated with a decrease in CST. Tests for multicollinearity were performed using variance inflation factor values, and tests for clustering were performed by confirming there were no significant changes in results when one eye was removed in a patient with both eyes included in the study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient Population\u003c/h2\u003e \u003cp\u003eA total of 123 eyes were identified as having been treated with faricimab at the study center during the study period, and 35 eyes were excluded (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 35 excluded eyes, 18 eyes had nAMD but no demonstrated fluid on OCT in the past 6 months, 11 eyes had treatment-na\u0026iuml;ve nAMD, 5 eyes had pre-existing ocular condition (pars plana vitrectomy, concurrent central retinal vein occlusion, and concurrent uveitic cystoid macular edema), and 1 eye received one faricimab injection without follow-up.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAfter excluding those eyes, 88 eyes (73 patients) fit our study inclusion criteria. All 88 study eyes had intraretinal or subretinal fluid on OCT within 6 months prior to starting faricimab (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and had been treated with other anti-VEGF therapy. 14.8% of eyes had no macular fluid on OCT at baseline visit. The indication for starting faricimab therapy was for treatment of recalcitrant macular fluid on OCT and/or desire to extend treatment interval. Average age was 82\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;9 (range 57\u0026ndash;101), and 65.9% were female. The average number and duration of anti-VEGF therapy prior to starting faricimab were 27.5 injections (range 1-127) and 41.9 months (range 1-169), respectively. Among these 88 eyes, 24 eyes (27.3%) had been treated with one anti-VEGF medication prior to starting faricimab, 47 eyes (53.4%) had been on two different anti-VEGF drugs, 12 eyes (13.6%) had been treated with three different anti-VEGF drugs, and 5 eyes (5.7%) had been on four different anti-VEGF drugs at baseline. The four different anti-VEGF medications used prior to starting faricimab included bevacizumab, aflibercept, ranibizumab, and brolucizumab. Prior to switching to faricimab, 63 eyes (71.6%) were on aflibercept, 8 eyes (9.1%) were on ranibizumab, 6 eyes (6.8%) were on bevacizumab, 4 eyes (4.5%) were on brolucizumab, and 7 eyes (8%) were on a monthly treatment alternating between aflibercept and brolucizumab.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and baseline clinical feature of eyes with nAMD treated with faricimab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal number of eyes (patients)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e88 (73)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean age, years (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58 (65.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (34.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLaterality (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (51.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeft\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (48.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMost recent anti-VEGF therapy prior to switch (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAflibercept\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63 (71.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrolucizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (4.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBevacizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (6.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRanibizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlternating Aflibercept/Brolucizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (8.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean duration of prior anti-VEGF therapy, months (SD), range\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41.9 (39.4)\u003c/p\u003e \u003cp\u003e1-169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean number of injections of prior anti-VEGF therapy, (SD), range\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.5 (26.6)\u003c/p\u003e \u003cp\u003e1-127\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIndication for switch to faricimab (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePersistent macular fluid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (35.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment interval extension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (40.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of different anti-VEGF therapies used prior to faricimab (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e47 (53.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (13.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (5.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBaseline macular fluid status (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubretinal fluid (SRF) only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (43.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntraretinal fluid (IRF) only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (27.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent SRF and IRF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo fluid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (14.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: nAMD, neovascular age-related macular degeneration; SD, standard deviation; anti-VEGF, drugs that inhibit vascular endothelial growth factor; SRF, subretinal fluid; IRF, intraretinal fluid; OCT, optical coherence tomography\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eAnatomic and Visual Outcomes\u003c/h2\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes the anatomical and visual outcomes in the study eyes before and after starting faricimab. Mean baseline logMAR BCVA prior to starting faricimab was 0.5\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.3 (Snellen equivalent 20/63) with a mean anti-VEGF injection interval of 6.06\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.0 weeks (range 4\u0026ndash;15 weeks). On macular OCT, the mean baseline CST was 291\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;73 \u0026micro;m. All patients had either subretinal or intraretinal fluid on at least one OCT within 6 months prior to starting faricimab. At the baseline visit when faricimab was initiated, 38 (43.2%) patients had subretinal fluid (SRF), 24 (27.3%) had intraretinal fluid (IRF), 13 (14.8%) had both, and 13 (14.8%) had no fluid (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One eye had no OCT done at the baseline visit, so the most recent OCT from the prior visit was used for analysis since the patient had been maintained on the same anti-VEGF therapy. In addition, CST was not available in 1 patient in 2 eyes at both baseline and follow-up due to poor patient cooperation with imaging, resulting in only a 5-line raster scan being obtained. For this OCT, an estimate of the CST was obtained by manual measurements of 5 points from the internal limiting membrane to Bruch\u0026rsquo;s membrane at the center of the fovea and 0.5 mm superior, inferior, nasal, and temporal, and taking the average. In 1 eye at follow-up, a CST could not be obtained due to poor OCT signal with an erroneous CST reading and was not included in the analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAnatomical and visual acuity in the study eyes before and after starting faricimab\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eStudy eyes on Faricimab (n\u0026thinsp;=\u0026thinsp;88)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFinal follow-up\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean BCVA (logMAR), (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean CST (\u0026micro;m), (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e291\u0026thinsp;\u0026plusmn;\u0026thinsp;73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e262\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean treatment interval, weeks (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.06\u0026thinsp;\u0026plusmn;\u0026thinsp;2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.44\u0026thinsp;\u0026plusmn;\u0026thinsp;2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMean number of Faricimab injections (SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e5.1\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbbreviations\u003c/b\u003e: BCVA, best corrected visual acuity; CST, central subfield thickness; SD, standard deviation\u003c/p\u003e \u003cp\u003e*p-value based on paired student t test.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eDuring a mean follow-up of 30.1\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;13.5 weeks (range 7.0 to 50.3 weeks) after starting faricimab, the study eyes received a mean of 5.1\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.4 injections (range 1\u0026ndash;11). At the latest visit, mean logMAR BCVA remained at 0.5\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.4 (Snellen equivalent 20/63) (p\u0026thinsp;=\u0026thinsp;0.11), but mean injection interval increased by 1.38 weeks to 7.44\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.6 weeks (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and mean CST decreased to 262\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;63 \u0026micro;m (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) with an average decrease of 28.3 \u0026micro;m in CST (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). At last study visit, 25 (28.4%) eyes had SRF, 22 (25.0%) eyes had IRF, 6 (6.8%) had both, 35 (39.8%) had no fluid. Of the 75 eyes with fluid on OCT at baseline, 27 (36%) had complete resolution of macular fluid at the latest visit on faricimab, and 47 (64%) had persistent intraretinal or subretinal fluid.\u003c/p\u003e \u003cp\u003eMultiple linear regression analysis revealed that the total number of anti-VEGF injections at baseline was not significantly associated with CST reduction after initiating faricimab (p\u0026thinsp;=\u0026thinsp;0.56), and neither was the amount of time on faricimab (p\u0026thinsp;=\u0026thinsp;0.68). However, higher number of different types of anti-VEGF drugs used before starting faricimab was significantly associated with a lesser decrease in CST after starting faricimab (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eFaricimab was discontinued in 23 eyes (19 patients) (26%). Eight eyes (35%) were switched to a different anti-VEGF drug due to poor response on faricimab, 2 eyes (9%) were switched due to joining a clinical trial, 2 eyes (9%) were switched due to insurance barriers, 2 eyes (9%) were discontinued due to loss to follow-up, and 1 patient became deceased during this time period.\u003c/p\u003e \u003cp\u003eFaricimab was stopped in 8 eyes (9.1%) due to adverse events, including eye irritation (2 eyes in 1 patient), persistent new floaters (2 eyes in 2 patients) and new subjective vision loss (4 eyes in 3 patients). 2 patients (2 eyes) with new floaters had persistent floaters lasting up to 9 to 11 weeks and occurring after the first or second faricimab injection. Both patients declined further treatment with faricimab. All 3 patients with subjective vision loss after starting faricimab had measured vision loss after 1 or 2 faricimab injections with no new change on eye exam or worsening of fluid on OCT to explain the vision loss. All 3 patients had at least partial improvement in vision after stopping faricimab and resuming treatment with other anti-VEGF therapy. These 3 patients are described in more detail below.\u003c/p\u003e \u003cp\u003eThe first patient is an 81-year-old monocular woman with nAMD in the right eye who received 1 dose of faricimab. She had been treated with monthly alternating dose of brolucizumab and aflibercept and was switched to faricimab to increase treatment interval. When seen 5 weeks later, her BCVA had improved from 20/70 to 20/50, exam was unchanged and macular fluid remained resolved. However, she noted numerous new fixed small spots 360 degrees around her central vision starting a few days after faricimab injection, which were preventing her from reading and seeing properly. She declined further treatment with faricimab and was treated with brolucizmab. When seen the following month, the spots were less visible, but her BCVA dropped to 20/150. She subsequently had cataract surgery and BCVA improved to 20/20 while being maintained on alternating doses of brolucizumab and aflibercept. The spots fully resolved over a couple months after stopping faricimab. The second patient had nAMD OU with end-stage disciform scar in the left eye. The right eye was treated with monthly alternating doses of brolucizumab and aflibercept. Treatment was changed to faricimab for chronic mild residual intraretinal macular fluid and to increase treatment interval. She received 2 doses of faricimab and noted new vision loss 5 weeks after the second dose. Her BCVA in the right eye had dropped to 20/300 from 20/100 baseline. Eye exam and OCT were unchanged. Faricimab was discontinued and the patient was treated with alternating brolucizumab and aflibercept. BCVA returned to baseline 4 weeks later. The third patient is a 94-year-old woman with nAMD in both eyes with trace intraretinal macula fluid in both eyes on aflibercept every 5 weeks. She was started on faricimab OU for residual macular fluid and for extension of treatment interval. She called our office 4 weeks after receiving one dose of faricimab noting new blurry vision in both eyes. When examined 7 weeks after faricimab, her BCVA declined in both eyes to 20/400 from 20/100 OD and 20/150 OS; macular fluid resolved on OCT OU and eye exam was unchanged. Faricimab was discontinued, and she was treated with aflibercept OU monthly. Her BCVA gradually improved to 20/200 OU over 3 months.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eDue to advances in drug development, we have a growing number of anti-VEGF drugs that can be administered intravitreally for treatment of nAMD. All of these drugs are effective in reducing vision loss associated with complications of CNV. However, the effects of all anti-VEGF drugs are reversible and require frequent, often indefinite, intravitreal injections to maintain therapeutic effect. In addition, some eyes with nAMD become resistant to anti-VEGF therapy, requiring higher frequency dosing, sometimes as often as 4 weeks. Even then, some eyes with nAMD may become recalcitrant to anti-VEGF therapy with persistent macular fluid on OCT. Persistent residual intraretinal fluid in eyes with nAMD on anti-VEGF therapy has been associated with poorer visual outcome.\u003csup\u003e7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIt is not entirely clear why certain eyes with nAMD have macular fluid that is resistant to anti-VEGF treatments. A couple of studies have suggested that presence of pigment epithelial detachment, large choroidal neovascular membrane (CNV), and type 1 CNV or non-classic CNV may be associated with poorer response to treatment with ranibizumab or bevacizumab.\u003csup\u003e8,9\u003c/sup\u003e Other studies have shown that nAMD eyes that do not demonstrate a reduction in CST on OCT after 4 weeks on anti-VEGF therapy may have a significant response on OCT that can be detected at 2 or 3 weeks, indicating that the eye is responding to therapy but with shorter duration of effect than expected.\u003csup\u003e10\u003c/sup\u003e The percentage of \u0026ldquo;non-responders\u0026rdquo; to intravitreal anti-VEGF therapy is significant and can be as high as 45% depending on the study population, type of anti-VEGF therapy, and how \u0026ldquo;non-response\u0026rdquo; is defined.\u003csup\u003e8,9,11\u003c/sup\u003e As such, anti-VEGF agents with greater durability and efficacy are highly desirable for both patients and providers.\u003c/p\u003e \u003cp\u003eThe TENAYA and LUCERNE phase III clinical trials for faricimab demonstrated non-inferiority of faricimab to aflibercept in terms of BCVA in treating newly diagnosed nAMD. In these trials, 80% of eyes on faricimab had treatment interval extended to 12 or 16 weeks, while all eyes on aflibercept were maintained at a treatment interval of 8 weeks as per study protocol. This finding suggests that faricimab may have long durability.\u003csup\u003e6\u003c/sup\u003e However, TENAYA and LUCERNE studies were not designed to evaluate superiorly of faricimab over aflibercept. In addition, these studies enrolled only treatment-na\u0026iuml;ve nAMD eyes.\u003c/p\u003e \u003cp\u003eIt is well-recognized that clinical trial data with well-defined study criteria often result in better outcomes in comparison to real-world data.\u003csup\u003e12\u0026ndash;16\u003c/sup\u003e Thus, our study was conducted to evaluate real-world experience using intravitreal faricimab in nAMD eyes previously treated with other anti-VEGF therapies. In our study, we selected only eyes with nAMD that had demonstrated recalcitrant macular fluid on OCT within the 6 months prior to initiation of faricimab. At the time of switching to faricimab, most eyes (85%) had persistent macular fluid on OCT in the study eye on maximum anti-VEGF therapy. After starting faricimab treatment, the number of eyes in our study with no macular fluid increased from 14.8\u0026ndash;40.2%. A statistically significant reduction in mean CST was observed at the last follow-up visit on faricimab compared to baseline visit before starting faricimab. We also found a significant increase in the treatment interval at the last visit on faricimab compared to baseline. Faricimab therapy resulted in a mean increase of 1.3 weeks in treatment interval when compared to the treatment interval on other anti-VEGF therapies. These findings support the hypothesis that faricimab may have a longer duration of effect and greater efficacy in treating eyes with nAMD compared to other currently available anti-VEGF therapies.\u003c/p\u003e \u003cp\u003eIn our study, we used multiple linear regression analysis to identify baseline clinical features that may be associated with improved response on faricimab. We found that the benefit of faricimab in reducing CST in eyes with nAMD previously treated with other anti-VEGF may depend on the number of different anti-VEGF drugs used prior to starting faricimab. In particular, the benefit of faricimab may be diminished in eyes that had been on multiple types of anti-VEGF medications (p\u0026thinsp;=\u0026thinsp;0.04). This benefit of using faricimab was not affected by the total number of anti-VEGF injections administered prior to switching to faricimab, and was also not affected by the amount of time on faricimab. This is noteworthy because a majority of our study eyes had\u0026thinsp;\u0026gt;\u0026thinsp;10 anti-VEGF injections, with a mean of 27 injection, prior to starting faricimab; most study eyes had been treated with at least 2 different anti-VEGF drugs before starting faricimab. Eyes treated with multiple other anti-VEGF agents before starting faricimab in our study population likely represent eyes that are most resistant to anti-VEGF therapy.\u003c/p\u003e \u003cp\u003eDespite improvement in macular fluid and mean CST on OCT on faricimab, there were no significant changes in BCVA on faricimab therapy when compared to baseline in our study population. This is in contrast to the TENAYA and LUCERNE clinical trials, which showed a mean improvement in BCVA after starting faricimab or aflibercept in treatment-na\u0026iuml;ve eyes with nAMD. Our study finding is not unexpected, as all the eyes in our study had already been on anti-VEGF therapy. Gain in BCVA on anti-VEGF therapy in eyes with nAMD is usually seen in the first 3 to 4 months after treatment initiation. In eyes with nAMD with chronic macular fluid, it has been shown that vision loss and structural macular damage can result.\u003csup\u003e17\u003c/sup\u003e In addition, prior long-term follow-up studies have demonstrated that in eyes with nAMD being treated with anti-VEGF therapy, BCVA gain that is initially noted with anti-VEGF treatment is often lost due to disease progression and progression of geographic atrophy.\u003csup\u003e14,16\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur study findings are consistent with a few other real-world outcome studies on faricimab in the treatment of nAMD. These studies also showed that switching to faricimab has a benefit in improving anatomic outcomes through a reduction of CST and intraretinal/subretinal fluid while maintaining BCVA.\u003csup\u003e18\u0026ndash;20\u003c/sup\u003e The potential superior efficacy of faricimab in decreasing CST and increasing treatment intervals when compared to other anti-VEGF drugs is attributed to its novel dual inhibition of VEGF and Ang-2. In neovascular diseases, such as nAMD, multiple pro-angiogenic and inflammatory proteins and signaling factors may play a role in pathogenesis. Ang-2 is involved in vascular stability, inflammation, pericyte apoptosis, and changes in the endothelial cell cytoskeleton, which leads to vascular instability.\u003csup\u003e21\u0026ndash;23\u003c/sup\u003e Thus, inhibition of Ang-2 is thought to have a complementary, or perhaps synergistic effect to anti-VEGF in decreasing angiogenesis and vascular permeability.\u003c/p\u003e \u003cp\u003eOur study also evaluated safety of faricimab therapy in real world patients with nAMD previously treated with other anti-VEGF agents. The TENAYA and LUCERNE trials for nAMD demonstrated a non-inferior safety profile compared to aflibercept for serious ocular adverse events.\u003csup\u003e6\u003c/sup\u003e However, there is a theoretical risk of new adverse events from using faricimab, which blocks new pathways in addition to VEGF-A.\u003csup\u003e21\u003c/sup\u003e In our study, a few patients experienced vision loss or changes soon after starting faricimab. This has not been reported previously in other real-world studies.\u003csup\u003e18\u0026ndash;20,24\u003c/sup\u003e These patients had a decrease in BCVA in the treated eye without significant change on OCT or exam to explain the vision loss. Fortunately, all these patients in our study had gradual recovery of vision and resolution of symptoms after stopping faricimab and switching back to their prior anti-VEGF treatment regimen. It is unclear whether these visual changes could be related to effects of faricimab in modulating ang-2. As we gain more real-world experience using faricimab, we can learn more about potential adverse effects of this new therapy. Recently, there was a report of severe vision loss in 3 eyes with nAMD from severe intraocular inflammation after starting faricimab treatment.\u003csup\u003e25\u003c/sup\u003e In our study eyes, no intraocular inflammation was observed.\u003c/p\u003e \u003cp\u003eThe limitations of our study include the limited sample size as well as the retrospective study design. Although the treat-and-extend regimen was used by all participating retinal specialists, it varied slightly based on the physician as well as the patient\u0026rsquo;s history of response to prior anti-VEGF therapy. In addition, all study eyes had macular fluid within 6 months of starting faricimab, but only 14.8% of study eyes had no macular fluid on OCT at baseline. Despite this, our study found a significant reduction in mean macular thickness after starting faricimab.\u003c/p\u003e \u003cp\u003eIn summary, this study provides additional real-world data and insights on treatment outcomes using faricimab in eyes with nAMD previously treated with other anti-VEGF agents. Faricimab demonstrates improved anatomical outcomes in patients with nAMD while decreasing the frequency of injections. The benefit of faricimab over other anti-VEGF therapies may be diminished in eyes with nAMD that have been refractory to multiple different types of anti-VEGF therapies. Faricimab appears to be well tolerated in most eyes, but a few eyes had new vision change or worsening soon after starting faricimab despite stable exam and OCT; these changes appear to resolve after stopping faricimab. Since faricimab is a relatively new therapy for nAMD, future larger studies are important to fully characterize the efficacy, safety, and long-term effects of faricimab in eyes with nAMD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eS.S.P. has received contracted research grants via an employer from the industry to investigate anti-VEGF therapy for retinal disorders (Allergan, Greybug, Ophthea Ltd., Roche/Novartis). P.E. is a consultant for Genentech. None of the other authors have any conflicts of interest to report.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was supported in part by the Barbara A and Alan M Roth MD Endowed Chair in Visual Science from the University of California Davis (S.S.P.). There was no other funding support.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eVyawahare H, Shinde P. Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment. Cureus. 2022;14(9):e29583.\u003c/li\u003e\n \u003cli\u003eHang A, Feldman S, Amin AP, Ochoa JAR, Park SS. Intravitreal Anti-Vascular Endothelial Growth Factor Therapies for Retinal Disorders. Pharmaceuticals (Basel). 2023;16(8).\u003c/li\u003e\n \u003cli\u003eShirley M. Faricimab: First Approval. Drugs. 2022;82(7):825-30.\u003c/li\u003e\n \u003cli\u003eFDA Approves Genentech\u0026rsquo;s Vabysmo for the Treatment of Retinal Vein Occlusion (RVO) [press release]. 2023.\u003c/li\u003e\n \u003cli\u003eKhanani AM, Russell MW, Aziz AA, Danzig CJ, Weng CY, Eichenbaum DA, et al. Angiopoietins as Potential Targets in Management of Retinal Disease. Clin Ophthalmol. 2021;15:3747-55.\u003c/li\u003e\n \u003cli\u003eHeier JS, Khanani AM, Quezada Ruiz C, Basu K, Ferrone PJ, Brittain C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet. 2022;399(10326):729-40.\u003c/li\u003e\n \u003cli\u003eCore JQ, Pistilli M, Hua P, Daniel E, Grunwald JE, Toth CA, et al. Predominantly Persistent Intraretinal Fluid in the Comparison of Age-related Macular Degeneration Treatments Trials. Ophthalmol Retina. 2022;6(9):771-85.\u003c/li\u003e\n \u003cli\u003eSuzuki M, Nagai N, Izumi-Nagai K, Shinoda H, Koto T, Uchida A, et al. Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration. Br J Ophthalmol. 2014;98(9):1186-91.\u003c/li\u003e\n \u003cli\u003eLux A, Llacer H, Heussen FM, Joussen AM. Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions. Br J Ophthalmol. 2007;91(10):1318-22.\u003c/li\u003e\n \u003cli\u003eBontzos G, Bagheri S, Ioanidi L, Kim I, Datseris I, Gragoudas E, et al. Nonresponders to Ranibizumab Anti-VEGF Treatment Are Actually Short-term Responders: A Prospective Spectral-Domain OCT Study. Ophthalmol Retina. 2020;4(12):1138-45.\u003c/li\u003e\n \u003cli\u003eKrebs I, Glittenberg C, Ansari-Shahrezaei S, Hagen S, Steiner I, Binder S. Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration. Br J Ophthalmol. 2013;97(11):1443-6.\u003c/li\u003e\n \u003cli\u003eSchmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201.\u003c/li\u003e\n \u003cli\u003eBrown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57-65.e5.\u003c/li\u003e\n \u003cli\u003eMaguire MG, Martin DF, Ying GS, Jaffe GJ, Daniel E, Grunwald JE, et al. Five-Year Outcomes with Anti-Vascular Endothelial Growth Factor Treatment of Neovascular Age-Related Macular Degeneration: The Comparison of Age-Related Macular Degeneration Treatments Trials. Ophthalmology. 2016;123(8):1751-61.\u003c/li\u003e\n \u003cli\u003eKhanani AM, Gahn GM, Koci MM, Dang JM, Brown SM, Hill LF. Five-year outcomes of intravitreal drug therapy for neovascular age-related macular degeneration in eyes with baseline vision 20/60 or better. Clin Ophthalmol. 2019;13:347-51.\u003c/li\u003e\n \u003cli\u003eRofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292-9.\u003c/li\u003e\n \u003cli\u003eMetrangolo C, Donati S, Mazzola M, Fontanel L, Messina W, D\u0026apos;Alterio G, et al. OCT Biomarkers in Neovascular Age-Related Macular Degeneration: A Narrative Review. J Ophthalmol. 2021;2021:9994098.\u003c/li\u003e\n \u003cli\u003eRaimondi R, Falfeli T, Bogdanova-Bennet A, Varma D, Habib M, Kotagiri A, et al. Real-world outcomes of treatment resistant neovascular-age related macular degeneration switched from Aflibercept to Faricimab. Ophthalmology Retina. 2023.\u003c/li\u003e\n \u003cli\u003ePandit SA, Momenaei B, Wakabayashi T, Mansour HA, Vemula S, Durrani AF, et al. Clinical Outcomes of Faricimab in Patients with Previously Treated Neovascular Age-Related Macular Degeneration. Ophthalmology Retina. 2023.\u003c/li\u003e\n \u003cli\u003eSzigiato A, Mohan N, Talcott KE, Mammo DA, Babiuch AS, Kaiser PK, et al. Short-Term Outcomes of Faricimab in Patients with Neovascular Age-Related Macular Degeneration on Prior Anti-VEGF Therapy. Ophthalmology Retina. 2024;8(1):10-7.\u003c/li\u003e\n \u003cli\u003eLarsen HO, Grauslund J, Vergmann AS. Efficacy, Durability and Safety of Faricimab in Neovascular Age-Related Macular Degeneration and Diabetic Macular Oedema: Lessons Learned from Registration Trials. Ophthalmol Ther. 2023;12(5):2253-64.\u003c/li\u003e\n \u003cli\u003eJoussen AM, Ricci F, Paris LP, Korn C, Quezada-Ruiz C, Zarbin M. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021;35(5):1305-16.\u003c/li\u003e\n \u003cli\u003eRegula JT, Lundh von Leithner P, Foxton R, Barathi VA, Cheung CM, Bo Tun SB, et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol Med. 2016;8(11):1265-88.\u003c/li\u003e\n \u003cli\u003eGrimaldi G, Cancian G, Rizzato A, Casanova A, Perruchoud-Ader K, Clerici M, et al. Intravitreal faricimab for neovascular age-related macular degeneration previously treated with traditional anti-VEGF compounds: a real-world prospective study. Graefe\u0026apos;s Archive for Clinical and Experimental Ophthalmology. 2023.\u003c/li\u003e\n \u003cli\u003eLi Y, Chong R, Fung AT. Association of Occlusive Retinal Vasculitis With Intravitreal Faricimab. JAMA Ophthalmology. 2024.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"anti-VEGF therapy, intravitreal therapy, age-related macular degeneration, faricimab","lastPublishedDoi":"10.21203/rs.3.rs-4255731/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4255731/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eBackground/Objectives:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eTo report our real-world experience using intravitreal faricimab, a novel anti-vascular endothelial growth factor (anti-VEGF) therapy, in eyes with neovascular age-related macular degeneration (nAMD) previously treated with other anti-VEGF therapy.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eSubjects/Methods:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eA retrospective, single-center study of previously treated nAMD eyes treated with faricimab.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eResults:\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn 88 eyes (73 patients), mean baseline best-corrected visual acuity (BCVA) was 20/63 (range 20/20 to CF) with mean anti-VEGF injection interval of 6.1\u003cu\u003e+\u003c/u\u003e2.0 weeks. Mean baseline central subfield thickness (CST) was 291\u003cu\u003e+\u003c/u\u003e73 µm. During mean follow-up of 30.1\u003cu\u003e+\u003c/u\u003e13.5 (range 7.0 to 50.3) weeks on faricimab, the eyes received an average of 5.1\u003cu\u003e+\u003c/u\u003e2.4 injections (range 1 to 11). Mean BCVA remained at 20/63 (p=0.11), but injection interval increased to 7.4\u003cu\u003e+\u003c/u\u003e2.6 weeks (p\u0026lt;0.001), and CST decreased to 262\u003cu\u003e+\u003c/u\u003e63 µm (p\u0026lt;0.001). Multiple linear regression analysis revealed that higher number of different anti-VEGF drugs used at baseline was associated with a lower decrease in CST on faricimab (p=0.04) while total number of anti-VEGF injections at baseline (p=0.56) and time on faricimab (p=0.68) were not associated. Faricimab was discontinued in 23 eyes (26.1%), including 8 eyes for poor response, 2 eyes for persistent new floaters and 4 eyes for new vision decrease which reversed after stopping faricimab.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConclusions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eIn previously treated nAMD eyes, intravitreal faricimab was associated with increased mean treatment interval and decreased CST but no improvement in mean BCVA. The benefit of faricimab on CST reduction may be diminished in eyes previously treated with multiple different types of anti-VEGF therapy.\u003c/p\u003e","manuscriptTitle":"Intravitreal faricimab for previously treated neovascular age-related macular degeneration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-26 15:27:33","doi":"10.21203/rs.3.rs-4255731/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ee0294f8-3e61-4221-aad3-39ca371f38a8","owner":[],"postedDate":"June 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":32916650,"name":"Health sciences/Diseases/Eye diseases/Macular degeneration"},{"id":32916651,"name":"Health sciences/Diseases/Eye diseases/Retinal diseases"}],"tags":[],"updatedAt":"2024-09-03T14:10:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-26 15:27:33","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4255731","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4255731","identity":"rs-4255731","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}