Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study.

BACKGROUND: Frequent anti-vascular endothelial growth factor A (VEGF-A) injections reduce the risk of rapid and severe vision loss in patients with neovascular age-related macular degeneration (nAMD); however, due to undertreatment, many patients lose vision over time. New treatments that provide sustained suppression of VEGF-A are needed. RGX-314 (currently known as ABBV-RGX-314) is an adeno-associated virus serotype 8 vector that expresses an anti-VEGF-A antigen-binding fragment, which provides potential for continuous VEGF-A suppression after a single subretinal injection. We report results on the safety and efficacy of subretinal injection of RGX-314 in patients with nAMD. METHODS: For this open-label, multiple-cohort, multicentre, phase 1/2a, dose-escalation study conducted at eight sites in the USA, we enrolled participants with nAMD aged 50-89 years who had previously been treated with anti-VEGF injections into five cohorts (with five different doses of RGX-314). To be eligible, participants had to have macular neovascularisation secondary to nAMD with subretinal or intraretinal fluid in the centre subfield, be pseudophakic (after cataract removal), and have a best-corrected visual acuity (BCVA) in the study eye between 20/63 and 20/400 for the first participant in each cohort and between 20/40 and 20/400 for others. Subretinal injection of RGX-314 was done without a pre-bleb by a wet-laboratory-trained vitreoretinal surgeon. Cohort 1 received 3 × 109 genome copies per eye, cohort 2 received 1 × 1010, and cohort 3 received 6 × 1010. Two additional dose cohorts (cohort 4: 1·6 × 1011; cohort 5: 2·5 × 1011) were added. Participants were seen 1 day and 1 week after administration of RGX-314, and then monthly for 2 years (up to week 106). The primary outcome was safety of RGX-314 delivered by subretinal injection up to week 26. This analysis includes all 42 patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT03066258. FINDINGS: Between May 12, 2017, and May 21, 2019, we screened 110 patients for eligibility and enrolled 68. 42 participants demonstrated the required anatomic response to intravitreal ranibizumab and then received a single RGX-314 injection (dose range 3 × 109 to 2·5 × 1011 genome copies per eye) and were followed up for 2 years. There were 20 serious adverse events in 13 participants, of which one was possibly related to RGX-314: pigmentary changes in the macula with severe vision reduction 12 months after injection of RGX-314 at a dose of 2·5 × 1011 genome copies per eye. Asymptomatic pigmentary changes were seen in the inferior retinal periphery several months after subretinal injection of RGX-314 most commonly at doses of 6 × 1010 genome copies per eye or higher. There were no clinically determined immune responses or inflammation beyond that expected following routine vitrectomy. Doses of 6 × 1010 genome copies or higher resulted in sustained concentrations of RGX-314 protein in aqueous humour and stable or improved BCVA and central retinal thickness with few or no supplemental anti-VEGF-A injections in most participants. INTERPRETATION: Subretinal delivery of RGX-314 was generally well tolerated with no clinically recognised immune responses. RGX-314 gene therapy provides a novel approach for sustained VEGF-A suppression in patients with nAMD that has potential to control exudation, maintain vision, and reduce treatment burden after a single administration. Results from this study informed the pivotal programme to evaluate RGX-314 in patients with nAMD. FUNDING: RegenxBio.

Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.

BACKGROUND: The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS: At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS: From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P=0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P=0.003 for aflibercept vs. ranibizumab, and P=0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P=0.40), hospitalization (P=0.51), death (P=0.72), or major cardiovascular events (P=0.56). CONCLUSIONS: Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.).

Efficacy of Ranibizumab in Eyes with Diabetic Macular Edema and Macular Nonperfusion in RIDE and RISE.

PURPOSE: To determine whether there are baseline characteristics that distinguish patients with diabetic macular edema (DME) with coexisting macular nonperfusion (MNP) at baseline and assess these patients' potential to achieve favorable visual acuity (VA), anatomic, and diabetic retinopathy (DR) outcomes over 24 months. DESIGN: Post hoc analysis of RIDE/RISE, 2 phase 3, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov: NCT00473382; NCT00473330). PARTICIPANTS: Study eyes with best-corrected VA (BCVA)/fluorescein angiogram (FA) data at baseline. METHODS: To measure MNP, the Early Treatment for Diabetic Retinopathy Study (ETDRS) grid was overlaid on FAs of the macula. The MNP area was calculated by estimating the percentage of capillary loss in the central, inner, and outer subfields and converting into disc areas (DAs) using a software algorithm. Summary statistics and P values, respectively, were provided for all outcomes and comparisons of interest. MAIN OUTCOME MEASURES: Baseline characteristics; MNP area, BCVA, and central subfield thickness (CST) at months 12 and 24; and incidence of study eyes with ≥2-step DR improvement at months 3, 6, 12, 18, and 24. RESULTS: Baseline MNP was detected in 28.2%, 25.8%, and 26.3% of study eyes in the ranibizumab 0.3 mg (n = 213), ranibizumab 0.5 mg (n = 225), and sham (n = 228) arms, respectively. At baseline, patients with MNP were younger and had shorter diabetes duration, worse vision, increased CST, and worse DR severity (P values < 0.01 vs. those without MNP). In the ranibizumab 0.3 mg arm, eyes with baseline MNP had lower mean baseline BCVA (53.4 vs. 57.2 ETDRS letters for those without baseline MNP; P = 0.05), but mean BCVA gain at month 24 was comparable (+15.6 vs. +13.4 ETDRS letters, respectively; P = 0.2). Eyes with baseline MNP had increased CST at baseline, but experienced a greater decrease in CST by month 24. The proportion of eyes with ≥2-step DR improvement was greater for eyes with versus without baseline MNP in each ranibizumab arm. CONCLUSIONS: Despite having worse vision/increased CST versus those without baseline MNP, eyes with concurrent DME and baseline MNP entering RIDE/RISE experienced robust VA and anatomic improvement with ranibizumab and therefore should not be excluded from therapy.

Infliximab exerts a dose-dependent effect on retinal safety in the albino rabbit.

PURPOSE: To assess the retinal toxicity of an intravitreal injection of infliximab, a monoclonal antibody to tumor necrosis factor α, in a rabbit model. MATERIALS AND METHODS: Two groups of adult albino rabbits (n = 5) received intravitreal injections of infliximab (0.1 ml) in the study eye and balanced salt solution (BSS, 0.1 ml) in the control eye at baseline. Group 1 was administered with 1.5 mg/0.1 ml, and group 2 was injected with 7.5 mg/0.1 ml of infliximab solution. Electroretinography (ERG) was performed at baseline and at 1, 7, 30, and 45 days after the injection. Visual evoked potentials (VEPs) were recorded at 7 and 45 days after the injection. After the last electrophysiological assessment, the rabbits were euthanized and retinal histopathology and immunhistochemistry for glial fibrillary acidic protein (GFAP) were performed. RESULTS: ERG responses demonstrated no significant deficit in retinal function in eyes injected with infliximab. Mean dark-adapted a-wave and b-wave maximal amplitude and semi-saturation constant values at baseline and throughout the 45 days of follow-up after the injection indicated no remarkable difference in outer retinal function between the control and experimental eyes. VEP responses were similar at each time point (7 and 45 days). No difference was seen in retinal histopathology and immunocytochemistry sections in eyes receiving the 1.5 mg/0.1 ml dose compared to the control eyes. However, increased GFAP labeling in retinal Müller cells was detected in rabbit eyes treated with the 7.5 mg/0.1 ml dose. CONCLUSIONS: Intravitreal injection of 1.5 mg/0.1 ml infliximab dose has no toxic effect on the integrity (functional or structural) of the retina in rabbits. A higher dose of 7.5 mg/0.1 ml may be slightly toxic as suggested by positive Müller cell GFAP expression. Additional studies of retinal toxicity at higher doses and after multiple injections are needed to establish the retinal safety of intravitreal infliximab therapy in humans.

TREATMENT OF VITREOMACULAR TRACTION WITH INTRAVITREAL PERFLUOROPROPANE (C3F8) INJECTION.

PURPOSE: To assess the posterior vitreous release rates following a single, office-based intravitreal injection of expansile gas in treating vitreomacular traction. METHODS: Thirty eyes of 29 consecutive patients with symptomatic vitreomacular traction received a single, office-based intravitreal injection of up to 0.3 mL of 100% perfluoropropane (C3F8). RESULTS: Overall, vitreomacular traction release occurred in 25 of 30 eyes by the final follow-up visit (83% final release rate); furthermore, 90% (9 of 10 eyes) with diabetes mellitus released, 83% (5 of 6 eyes) with concurrent epiretinal membrane released, and 83% (5 of 6 eyes) previously treated with ocriplasmin released. Vitreomacular traction release occurred overnight in some patients and was documented on spectral domain optical coherence tomography at an average of 13 days (range, 1-62 days). The phakic release rate was 89% (16 of 18 eyes) versus a 75% pseudophakic release rate (9 of 12 eyes) (P = 0.3173). Ellipsoid zone changes on spectral domain optical coherence tomography occurred in 1 of 30 gas-treated eyes. One patient developed pupillary block. CONCLUSION: Office-based intravitreal injection of C3F8 offers an inexpensive and effective treatment for vitreomacular traction, including for patients who underwent previous ocriplasmin administration and in patients with diabetes mellitus or epiretinal membrane.

SYSTEMIC PHARMACOKINETICS AND PHARMACODYNAMICS OF INTRAVITREAL AFLIBERCEPT, BEVACIZUMAB, AND RANIBIZUMAB.

PURPOSE: To evaluate the systemic pharmacokinetics (PKs) of aflibercept, bevacizumab, and ranibizumab in patients with neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), or retinal vein occlusion (RVO). METHODS: Prospective, open-label, nonrandomized clinical trial of patients with AMD, DME, or RVO who were antivascular endothelial growth factor (VEGF) naïve or had not received anti-VEGF for ≥4 months. Patients received 3 monthly intravitreal injections of aflibercept 2.0 mg, bevacizumab 1.25 mg, or ranibizumab (0.5 mg for AMD/RVO, 0.3 mg for DME). The main outcome measures were serum PKs and plasma free-VEGF concentrations after the first and third injections. RESULTS: A total of 151 patients were included. In AMD/DME/RVO, systemic exposure to each drug was highest with bevacizumab, then aflibercept, and lowest with ranibizumab. Ranibizumab cleared from the bloodstream more quickly than bevacizumab or aflibercept. Aflibercept treatment resulted in the greatest reductions in plasma free-VEGF relative to baseline levels, whereas ranibizumab treatment resulted in the smallest decreases in plasma free-VEGF. CONCLUSION: The three anti-VEGF treatments examined in this analysis demonstrated notable differences in systemic PKs. Generally, the reduction in plasma free-VEGF levels correlated with elevated levels of circulating anti-VEGF agents, with the reduction in free-VEGF levels greatest with aflibercept and least with ranibizumab.

Visual and Anatomic Outcomes in Patients with Diabetic Macular Edema with Limited Initial Anatomic Response to Ranibizumab in RIDE and RISE.

PURPOSE: To explore the visual acuity and anatomic outcomes over 24 months of patients with diabetic macular edema (DME) who showed a delayed anatomic response after 3 ranibizumab injections in the RIDE and RISE trials. DESIGN: Analysis of data from RIDE and RISE, 2 phase III, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov identifiers, NCT00473382 and NCT00473330). PARTICIPANTS: Patients with DME (n = 681) who received monthly intravitreal ranibizumab 0.3-mg injections, ranibizumab 0.5-mg injections, or sham injections. METHODS: Patients were separated into 3 groups: delayed responders (ranibizumab-treated patients with ≤10% central foveal thickness [CFT] reduction after 3 injections), immediate responders (ranibizumab-treated patients with >10% CFT reduction after 3 injections), and sham recipients. Central foveal thickness was measured by time-domain optical coherence tomography, best-corrected visual acuity (BCVA) was measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores, and diabetic retinopathy (DR) was measured by the standardized ETDRS severity scale (using fundus photographs). MAIN OUTCOME MEASURES: Month-24 CFT, BCVA, and DR severity levels. RESULTS: In RIDE and RISE, 9% to 10% of ranibizumab-treated eyes were delayed responders. At month 24, delayed responders had less CFT reduction (median, -102 µm) from baseline compared with immediate responders (median, -274 µm; P < 0.0001). Delayed responders gained a median of 10 letters at 24 months, similar to immediate responders (14 letters; P = 0.15). At month 24, DR improvement among the delayed responders (31% and 22% of patients with ≥2- or ≥3-step DR improvement, respectively) was comparable with that among immediate responders (42% and 17%, respectively; P = 0.21 and P = 0.48, respectively). CONCLUSIONS: With continued treatment, at month 24, patients with DME with delayed anatomic response (≤10% CFT reduction) after 3 ranibizumab injections had visual acuity gains and DR improvement similar to those of patients with DME who had immediate anatomic response.

Outer retina reflectivity changes on sd-oct after intravitreal ocriplasmin for vitreomacular traction and macular hole.

PURPOSE: To report initial experience with intravitreal ocriplasmin (IVO) and to describe outer retina reflectivity changes observed on spectral domain optical coherence tomography (SD-OCT) after IVO injection in patients with vitreomacular traction (VMT) with or without macular holes (MHs). METHODS: A consecutive retrospective review of patients with VMT and MH who were treated with IVO was performed. Patients underwent complete ophthalmic evaluation, including nonstandardized Snellen visual acuity testing, and SD-OCT at baseline and follow-up visits. RESULTS: A total of 23 patients who received IVO for VMT and/or MH were included for analysis. Patient age ranged from 53 years to 93 years with a mean of 74 years. The mean follow-up was 174 days (range: 20-291 days). Vitreomacular traction release at Day 30 after IVO was achieved in 11 of 23 patients (47.82%), at an average of 14.54 days (range: 1-30 days) after treatment. The mean visual acuity improved from 0.50 to 0.38. At presentation, eight patients had MH associated with VMT. Closure of the MH with ocriplasmin was achieved in two patients, and six patients underwent pars plana vitrectomy for MH repair. Ten of 23 patients (43.47%) presented with changes in the outer retina reflectivity on SD-OCT after IVO, 4 patients of this group experienced a decrease in visual acuity. In 7 of these 10 patients (70%), VMT release was documented on OCT by Day 30 postinjection compared with 4 of 13 patients (30.76%) without outer retina changes post-IVO. Normalization of the outer retina reflectivity was achieved in all cases. CONCLUSION: In this case series of VMT/MH patients treated with ocriplasmin, changes in the SD-OCT outer retina reflectivity were relatively common. Within weeks, the outer retinal reflectivity on SD-OCT improved, as did the visual acuity. Further studies to investigate the association between outer retina reflectivity changes with the use of IVO and long-term visual acuity outcomes are warranted.

A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy.

PURPOSE: Multicenter, open-label, single-dose, dose-escalation Phase Ia study to determine the safety, tolerability, maximum tolerated dose, and immunogenicity of FCFD4514S, an antigen-binding fragment from a humanized monoclonal antibody directed against complement factor D, in patients with geographic atrophy. METHODS: Eighteen patients with geographic atrophy (lesion size: ≥ 0.75 disk areas; best-corrected visual acuity: 20/125-20/400 Snellen equivalent) were sequentially enrolled and received 1 of 6 escalating doses of intravitreal FCFD4514S subject to dose-limiting toxicity criteria. Follow-up assessments (clinical examination, best-corrected visual acuity, intraocular pressure) were conducted at postadministration Days 1, 3, 7, 14, 30, 60, and 90. Serum pharmacokinetics, immunogenicity, and complement activity were also evaluated. RESULTS: All patients completed the study with no reported FCFD4514S-related dose-limiting toxicities or ocular or systemic adverse events. The maximum tolerated dose for this study was 10 mg, the highest dose tested. No antitherapeutic antibody response or adverse effects on systemic complement activity were observed. Time to maximum serum concentration was 1 day to 3 days postdosing; serum terminal half-life was 5.9 days. CONCLUSION: Single-dose intravitreal FCFD4514S administrations were safe and well tolerated and not associated with any study drug-related ocular or systemic adverse events. These data support a multidose safety and tolerability assessment of FCFD4514S in geographic atrophy.

Supplemental Intravitreal Ranibizumab Injections in Eyes Treated with the Port Delivery System with Ranibizumab in the Archway Trial.

PURPOSE: To determine the proportion and characteristics of eyes with neovascular age-related macular degeneration (nAMD) treated with the Port Delivery System (PDS) with ranibizumab that receive supplemental intravitreal ranibizumab injections because of changes in best-corrected visual acuity (BCVA) or central subfield thickness (CST), or both, and to investigate the safety and efficacy of supplemental injections in eyes with the PDS. DESIGN: Post hoc analyses of data from the phase III, randomized, multicenter, open-label, active-comparator Archway trial (NCT03677934). PARTICIPANTS: Adults with nAMD diagnosed within 9 months of screening previously responsive to anti-VEGF therapy. INTERVENTION: Four hundred eighteen patients were randomized to the PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (Q24W) or monthly intravitreal ranibizumab 0.5 mg for 96 weeks. RESULTS: Of the 246 eyes treated with the PDS Q24W and assessed for supplemental treatment criteria, the vast majority (94.6%-98.4%) did not receive supplemental treatment during each retreatment interval, with 87.4% not receiving supplemental treatment at any point during the trial. Of the 31 eyes receiving supplemental treatment, 58.1% received 1 injection and 32.3% received 2. At baseline, eyes receiving supplemental treatment were significantly more likely to have thicker retinas (mean CST, 370.5µm vs. 304.4µm; P = 0.0001), subretinal fluid (54.8% vs. 21.2%; P < 0.0001), and larger pigment epithelial detachment height (215.7 µm vs. 175.9 µm; P = 0.003). These features have previously been associated with difficult-to-treat nAMD. Although BCVA and CST generally remained constant throughout the trial in eyes without supplemental treatment, the small number of eyes receiving supplemental treatment on average lost 1 line of vision from baseline to week 96 (mean, -5.7 ETDRS score letters) and CST continued to increase over time. Absolute BCVA at week 96 was similar irrespective of supplemental treatment status (71.1 and 73.7 letters). Best-corrected visual acuity and CST generally improved within 28 days of supplemental treatment. CONCLUSIONS: Although the PDS Q24W effectively maintains vision and retinal stability in most eyes with nAMD, a small proportion of patients with features of difficult-to-treat nAMD may benefit from supplemental intravitreal anti-VEGF injections and initial close monitoring is recommended. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

BILATERAL PERIPAPILLARY CHOROIDAL NEOVASCULARIZATION IN AN OTHERWISE HEALTHY TEENAGER TREATED WITH ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS.

PURPOSE: This case report describes the presentation, diagnostic reasoning, and successful management of a 14-year-old teenage boy found to have bilateral peripapillary choroidal neovascularization. METHODS: This is a case of a teenage boy with an unremarkable ocular and systemic history presenting with decreased visual acuity, macular edema, and bilateral peripapillary choroidal neovascularization. RESULTS: After intravitreal antivascular endothelial growth factor injections, the patient's visual acuity improved. Imaging further revealed that the initially present macular edema, subretinal fluid, and peripapillary choroidal neovascularizations markedly improved after treatment. CONCLUSION: Peripapillary choroidal neovascularizations are often not trivial to diagnose. As this report illustrates, work-up with different modalities is extremely valuable, and antivascular endothelial growth factor injections may help decrease exudation and improve visual outcomes.

Implant Insertion Procedure of the Port Delivery System With Ranibizumab: Overview and Clinical Pearls.

OBJECTIVE: To describe the Port Delivery System with ranibizumab implant insertion procedure. METHODS: A surgical procedure based on the clinical trial program in patients with retinal diseases. RESULTS: An infusion line is placed in the infero-temporal quadrant; a superotemporal quadrant corneal traction suture is recommended. The superotemporal quadrant peritomy of 6 × 6 mm is executed with gentle, purposeful tissue handling. Generous posterior and lateral sub-Tenon's capsule dissection creates laxity for the subsequent closure. Adequate scleral hemostasis is achieved with wet-field cautery to maintain a clean field. The implant is filled under magnification with a customized formulation of ranibizumab. A precise 3.5-mm-long scleral incision (4 mm posterior and parallel to the limbus) is created to ensure proper implant fit. The exposed pars plana undergoes laser ablation to reduce vitreous hemorrhage risk. A pars plana incision is made, and the implant is inserted perpendicular to the globe and seated flush against the sclera. Complete closure of both the conjunctiva and Tenon's capsule with scleral anchoring and mild tissue overhang at the anterior limbus is performed to reduce conjunctival erosion and retraction risks. CONCLUSION: The procedure is straightforward yet requires precise preoperative and intraoperative preparation and standardized surgical techniques. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:249-256.].

Pharmacokinetics of the Port Delivery System with Ranibizumab in the Ladder Phase 2 Trial for Neovascular Age-Related Macular Degeneration.

INTRODUCTION: Ladder was a phase 2 trial that evaluated the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration. Serum and aqueous humor samples were collected to characterize the pharmacokinetics (PK) of ranibizumab delivered through the PDS. METHODS: Ladder was a multicenter, randomized, active treatment-controlled, phase 2 clinical trial. Patients with neovascular age-related macular degeneration (n = 220) were randomized (3:3:3:2) to PDS 10 mg/ml, PDS 40 mg/ml, PDS 100 mg/ml, or monthly intravitreal ranibizumab 0.5 mg. Serum PK samples were collected in all arms and analyzed for ranibizumab concentration using an enzyme-linked immunosorbent assay. The main PK analyses were conducted in the PK-evaluable population (n = 68), which excluded patients who received fellow eye intravitreal treatment, supplemental ranibizumab treatment, or had previous treatment with bevacizumab in either eye within 9 months of randomization. RESULTS: In the PDS 10 mg/ml arm, median serum ranibizumab concentrations were below the serum trough concentration (Ctrough; 130 pg/ml) expected with monthly intravitreal ranibizumab 0.5 mg at all time points. In the PDS 40 mg/ml and 100 mg/ml arms, median serum ranibizumab concentrations were above the Ctrough expected with monthly intravitreal ranibizumab 0.5 mg (130 pg/ml) through month 3 and month 12 after implantation, respectively, and remained above the lower limit of quantification through month 15 and month 16 after implantation, respectively. CONCLUSIONS: These PK data indicate that the implant in the PDS 100 mg/ml arm maintained ranibizumab concentrations within the range of monthly intravitreal ranibizumab 0.5 mg injections (130-2220 pg/ml) through month 12 after implantation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02510794.

Management of Key Ocular Adverse Events in Patients Implanted with the Port Delivery System with Ranibizumab.

PURPOSE: To provide strategies for the management of key ocular adverse events (AEs) that may be encountered with the Port Delivery System with ranibizumab (PDS) in practice and provide recommendations that may mitigate such AEs based on clinical trial experiences and considerations from experts in the field. DESIGN: Safety evaluation based on the phase 2 Ladder (NCT02510794) and phase 3 Archway (NCT03677934) trials of the PDS. METHODS: The PDS implant is a permanent, indwelling, and refillable ocular drug delivery system that requires standardized procedural steps for its insertion and refill-exchange procedures, which evolved during the PDS clinical program. We described identified AEs that may arise after implant insertion or refill-exchange procedures, including conjunctival retraction, conjunctival erosion, endophthalmitis, implant dislocation, conjunctival blebs or conjunctival filtering bleb leaks, wound leaks, hypotony, choroidal detachment, vitreous hemorrhage, rhegmatogenous retinal detachment, cataract, and septum dislodgement. RESULTS: Adverse events related to the PDS were well understood, were manageable by trial investigators, and did not prevent patients from achieving optimal outcomes in most cases. CONCLUSIONS: Surgeons using the PDS should be aware of potential ocular AEs and identify them early for optimal management. As with any new surgical procedure, it is important to provide surgeons with appropriate training, ensure adherence to optimal surgical techniques, and continually refine the procedure to mitigate complications and improve outcomes.

Intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion.

PURPOSE: To evaluate the safety and efficacy of intravitreal ranibizumab for macular edema secondary to central retinal vein occlusion. METHODS: Patients with macular edema secondary to perfused central retinal vein occlusion were enrolled in this ongoing, prospective, open-label study. Treatment was initiated with monthly intravitreal ranibizumab for 3 months. In the first year, additional injections were administered for edema in quarterly intervals as needed (PRN) for Cohort 1 (n = 10) and monthly PRN for Cohort 2 (n = 10). In the second year of treatments, all patients received monthly PRN treatment. Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central retinal thickness, fundus photographs, and fluorescein angiograms were evaluated, and the incidence and severity of adverse events were documented. RESULTS: Mean change in best-corrected visual acuity and central retinal thickness improved during the induction phase in both groups. During the remainder of the first year for Cohort 1, initial gains were lost during quarterly treatment but returned with monthly PRN treatment in the second year. For Cohort 2, improvement in best-corrected visual acuity and central retinal thickness from the induction phase was maintained through Month 24. Nineteen of 20 patients experienced a reduction in intraretinal hemorrhage, optic nerve swelling, and/or venous diameter after treatment. One myocardial infarction, one cerebrovascular accident, and no serious ocular adverse events were reported. Iris neovascularization was developed in none of the eyes. CONCLUSION: Ranibizumab was well tolerated and associated with a greater reduction in macular edema and improvement in visual acuity in the monthly PRN regimen compared with quarterly treatment. Vision lost during the quarterly PRN injection intervals in the first year of Cohort 1 could be regained by switching to monthly PRN dosing.

Evaluation of Port Delivery System with ranibizumab for the treatment of neovascular age-related macular degeneration.

Current treatment of neovascular age-related macular degeneration involves periodic intravitreal injections of anti-VEGF medication, creating a burden to patients and physicians, resulting in nonadherence to recommended dosing schedules. The Port Delivery System with ranibizumab offers a long-term solution that involves implantation of a device into the pars plana and provides continuous release of anti-VEGF medication into the vitreous, thus requiring fewer office visits. The Port Delivery System has demonstrated comparable visual and anatomic outcomes to monthly injections and shows promise in alleviating the patient burden in the treatment of neovascular age-related macular degeneration, making possible better long-term real-world visual outcomes.

Retrospective Study of Ellipsoid Zone Integrity Following Treatment with Intravitreal Ocriplasmin (OZONE Study).

PURPOSE: To assess generalized (GD) and focal ellipsoid zone disruption (FD) in patients with symptomatic vitreomacular adhesion (sVMA) using spectral domain optical coherence tomography (SD-OCT) following ocriplasmin. PATIENTS AND METHODS: OZONE was a Phase 4, retrospective study of patients with sVMA treated with a single intravitreal injection of ocriplasmin (0.125 mg). Data from adult patients with at least 6-month follow-up after ocriplasmin were included. SD-OCT was performed at baseline (within 30 days before ocriplasmin), before Day 21 post-injection (early observation, EO), and by last observation (LO) which was maximally 6 months post-injection. The main outcome measure was the development of new and the evolution of existing FD/GD at EO and LO. RESULTS: The study enrolled 134 eyes/patients from 22 sites in the USA. At baseline, 87 eyes (64.9%) had FD, 21 eyes (15.7%) had GD and 26 eyes (19.4%) had no FD/GD. Among the eyes without FD/GD at baseline, 13 (50%) and 8 (30.8%) developed FD or GD, respectively, by EO. By LO, FD/GD improvement or resolution was seen in >80% of these eyes. Among the eyes with FD/GD at baseline, <40% had improving/resolving EZ integrity at LO. The absence of FD/GD at baseline was associated with less persistent FD/GD at LO (P<0.0005). The presence of FD with MH at baseline was associated with persistent FD at LO (P=0.027). CONCLUSION: The fact that a large majority of eyes had FD/GD prior to ocriplasmin was unexpected and demonstrates that EZ disruptions are common in sVMA. This suggests that loss of EZ integrity may be part of the natural history of this disorder. It is hypothesized that the status of the EZ at baseline is a contributing, ocriplasmin independent modulator of subsequent EZ changes after ocriplasmin. Prospective analyses which include a sham control group would be required to test this hypothesis.

Phase 1 Study of the Anti-HtrA1 Antibody-binding Fragment FHTR2163 in Geographic Atrophy Secondary to Age-related Macular Degeneration.

PURPOSE: FHTR2163 is a novel antigen-binding fragment (Fab) directed against high-temperature requirement protein A1 (HtrA1). HTRA1 inhibition may preserve retinal integrity and slow disease progression in geographic atrophy (GA) secondary to age-related macular degeneration (AMD). This study examined the safety, pharmacokinetics, immunogenicity, and changes in the HTRA1-specific substrate Dickkop-related protein 3 (DKK3) in patients with GA who received FHTR2163. DESIGN: Phase I, open-label, single ascending dose escalation and multiple-dose expansion study. METHODS: Adults aged ≥ 50 years with GA secondary to AMD with best corrected visual acuity ranging between Snellen 20/125 and 20/400 were enrolled. In the first stage, a single intravitreal injection of FHTR2163 was given in 5 dose-escalation cohorts ranging from 1 to 20 mg (n = 3 patients/cohort; n = 15 total patients). The second stage evaluated the maximum tested dose of 20 mg administered every 4 weeks for 3 doses (n = 13 patients). RESULTS: No dose limiting toxicities or ocular serious AEs were reported. The most frequently reported AEs in the study eye were conjunctival hemorrhage (n = 7), conjunctival hyperemia (n = 4), and eye pain (n = 2). No non-ocular or ocular AEs were assessed as drug related. There were no clinically significant changes in ocular exams. A sustained pharmacodynamic effect of anti-HtrA1 was observed in the aqueous humor, as measured by levels of cleaved DKK3. CONCLUSIONS: FHTR2163, a novel Fab directed against HtrA1, was well tolerated with no DLTs or significant ocular AEs. The molecule when injected intravitreally for 3 doses showed a sustained pharmacodynamic effect at the maximum tested dose of 20 mg.

Understanding seizure risk with wide field fundus photography: Implications for screening guidelines in the era of COVID-19 and telemedicine.

PURPOSE: To report two cases of photosensitive seizures due to fundus photography flash. OBSERVATIONS: Two patients with seizure history present to a retina clinic for routine follow up. While obtaining imaging, these patients experienced a seizure triggered by fundus camera flash. CONCLUSIONS: Fundus photography is essential and ubiquitous amongst optometry and ophthalmology practices, especially in the rising era of telemedicine in the setting of the recent COVID-19 pandemic. To our knowledge, there are no other reports in the literature of seizures triggered by fundus photography flash. However, we believe this to be an under-reported phenomenon and suggest that all eye care providers screen patients for a history of seizures or epilepsy prior to fundus photography.