Archway Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration 2-Year Results.

PURPOSE: To report 2-year results from the Archway clinical trial of the Port Delivery System with ranibizumab (PDS) for treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, randomized, multicenter, open-label, active-comparator-controlled trial. PARTICIPANTS: Patients with previously treated nAMD diagnosed within 9 months of screening and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to PDS with ranibizumab 100 mg/ml with fixed refill-exchanges every 24 weeks (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). Patients were followed through 4 complete refill-exchange intervals (∼2 years). MAIN OUTCOME MEASURES: Change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline averaged over weeks 44 and 48, weeks 60 and 64, and weeks 88 and 92 (noninferiority margin, -3.9 ETDRS letters). RESULTS: The PDS Q24W was noninferior to monthly ranibizumab, with differences in adjusted mean change in BCVA score from baseline averaged over weeks 44/48, 60/64 and 88/92 of -0.2 (95% confidence interval [CI], -1.8 to +1.3), +0.4 (95% CI, -1.4 to +2.1) and -0.6 ETDRS letters (95% CI, -2.5 to +1.3), respectively. Anatomic outcomes were generally comparable between arms through week 96. Through each of 4 PDS refill-exchange intervals, 98.4%, 94.6%, 94.8%, and 94.7% of PDS Q24W patients assessed did not receive supplemental ranibizumab treatment. The PDS ocular safety profile was generally unchanged from primary analysis. Prespecified ocular adverse events of special interest (AESI) were reported in 59 (23.8%) PDS and 17 (10.2%) monthly ranibizumab patients. The most common AESI reported in both arms was cataract (PDS Q24W, 22 [8.9%]; monthly ranibizumab, 10 [6.0%]). Events in the PDS Q24W arm included (patient incidence) 10 (4.0%) conjunctival erosions, 6 (2.4%) conjunctival retractions, 4 (1.6%) endophthalmitis cases, and 4 (1.6%) implant dislocations. Serum ranibizumab sampling showed that the PDS continuously released ranibizumab over the 24-week refill-exchange interval and ranibizumab serum concentrations were within the range experienced with monthly ranibizumab. CONCLUSIONS: The PDS Q24W showed noninferior efficacy to monthly ranibizumab through approximately 2 years, with approximately 95% of PDS Q24W patients not receiving supplemental ranibizumab treatment in each refill-exchange interval. The AESIs were generally manageable, with learnings continually implemented to minimize PDS-related AEs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Characterization of Serous Retinopathy Associated with Cobimetinib: Integrated Safety Analysis of Four Studies.

INTRODUCTION AND OBJECTIVE: Serous retinopathy can be associated with MEK inhibitors, including cobimetinib. We present results of an integrated safety analysis to further characterize ocular functional and structural changes due to serous retinopathy. METHODS: Four studies evaluating cobimetinib at the approved dose and schedule in combination with other oncology drugs were included. Study CO39721 incorporated standardized ophthalmologic assessments to fully characterize serous retinopathy events over time and was the primary study for analysis. Supporting information was provided by studies GO28141, WO29479, and GO30182. RESULTS: In total, 655 patients received one or more doses of cobimetinib and comprised the safety-evaluable population. Overall, 117 patients (17.9%) had one or more serous retinopathy events, 24 (3.7%) had two or more events, and four (0.6%) had three or more events. Grade 3 events occurred in < 2.5% of patients. In CO39721, the median time to onset was 15 days (range 7-111); median time to resolution of first occurrence was 26 days (range 6-591 + days). Twelve of 25 patients (48.0%) recovered without a dose modification and 4/25 (16.0%) were recovered/recovering following a dose modification. The most frequent presentation of serous retinopathy was focal subretinal fluid on optical coherence tomography (62.8% of cases); in some instances (25.7% of cases), subretinal fluid was multifocal. There was no loss of visual function or visual acuity at serous retinopathy onset or resolution. CONCLUSIONS: Results from this integrated safety analysis indicate that cobimetinib-associated serous retinopathy can be managed with or without a dose modification of cobimetinib at the discretion of the treating physician. No visual loss or permanent retinal damage was identified on comprehensive ophthalmologic assessments. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03178851, NCT01689519, NCT02322814, and NCT02788279.

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.].

Conjunctiva and Tenon's Capsule Handling in the Port Delivery System with Ranibizumab Implant Insertion Procedure: Surgical Pearls.

OBJECTIVES: To describe conjunctiva and Tenon's capsule handling during the Port Delivery System with ranibizumab (PDS) implant insertion procedure including up-front assessments, planning, and instrumentation, with emphasis placed on the peritomy, scleral dissection, and closure steps. METHODS: Surgical pearls based on experience accumulated in the PDS clinical trial program in patients with retinal diseases. RESULTS: Preoperative preparation, specific instruments, and meticulous techniques are key to optimizing surgical outcomes. Before surgery, assessment of factors that affect conjunctival integrity and an in-office conjunctiva examination are conducted. Gentle, purposeful conjunctiva and Tenon's capsule handling with nontoothed forceps and suturing with a BV needle are recommended to prevent tissue damage. The peritomy is 6 mm by 6 mm, centered around the planned implant location in the superotemporal quadrant. A complete sub-Tenon's capsule dissection is achieved using a wide, robust lateral and posterior dissection technique to free tissue from the sclera and minimize tension. The globe is stabilized during scleral cutdown by grasping the sclera with fine-toothed forceps away from the incision edge to prevent tissue delamination. When closing the peritomy, both the conjunctiva and Tenon's capsule are completely captured and sutured with scleral anchoring at the apex of the peritomy to help prevent conjunctival retraction and erosion. Mitigation and detection of adverse events is critical to successful surgical outcomes. CONCLUSIONS: The PDS implant insertion procedure is straightforward, but it requires planned preoperative preparation, specific instruments, and meticulous techniques. The surgical pearls described here offer insights for optimizing outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:266-273.].

Refill-Exchange Procedure of the Port Delivery System With Ranibizumab: Overview and Clinical Trial Experience.

PURPOSE: To describe the Port Delivery System with ranibizumab refill-exchange procedure. METHODS: Procedure based on the clinical trial program in patients with retinal diseases. RESULTS: The refill-exchange procedure is performed under topical anesthesia and strict aseptic conditions. Supplemental task lighting and magnification are recommended throughout the procedure. Ranibizumab is aseptically transferred from the vial with the filter needle and air is removed from the syringe. The filter needle is then replaced with the refill needle; any remaining air is removed from the syringe and the plunger is advanced to the 0.1-mL mark. Targeting the implant septum center, the refill needle is inserted perpendicularly to the globe until the soft stop contacts the conjunctiva (perpendicular orientation and conjunctival contact are maintained throughout the procedure); a cotton-tipped applicator is recommended for globe stabilization. The entire syringe contents are slowly injected over 5-10 seconds while existing solution fills the fluid collection reservoir. Once completed, the needle is carefully withdrawn while maintaining perpendicularity. The procedure can be successfully performed in rare, specific cases, including subconjunctival thickening or fibrous capsule formation, fluid-filled bleb formation, and corneal patch grafts. CONCLUSION: The procedure is straightforward but distinct from intravitreal injections and requires adherence to standardized techniques. With appropriate preparation, the procedure can be performed in specific cases. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:257-265.].

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.

The Port Delivery System with ranibizumab: a new paradigm for long-acting retinal drug delivery.

The Port Delivery System with ranibizumab (PDS) is an innovative intraocular drug delivery system designed for the continuous delivery of ranibizumab into the vitreous for 6 months and beyond. The PDS includes an ocular implant, a customized formulation of ranibizumab, and four dedicated ancillary devices for initial fill, surgical implantation, refill-exchange, and explantation, if clinically indicated. Ranibizumab is an ideal candidate for the PDS on account of its unique physicochemical stability and high solubility. Controlled release is achieved via passive diffusion through the porous release control element, which is tuned to specific drug characteristics to accomplish a therapeutic level of ranibizumab in the vitreous. To characterize drug release from the implant, release rate was measured in vitro with starting concentrations of ranibizumab 10, 40, and 100 mg/mL, with release of ranibizumab 40 and 100 mg/mL found to remain quantifiable after 6 months. Using a starting concentration of 100 mg/mL, active release rate at approximately 6 months was consistent after the initial fill and first, second, and third refills, demonstrating reproducibility between implants and between multiple refill-exchanges of the same implant. A refill-exchange performed with a single 100-µL stroke using the refill needle was shown to replace over 95% of the implant contents with fresh drug. In vitro data support the use of the PDS with fixed refill-exchange intervals of at least 6 months in clinical trials.

Prevalence and Progression of Macular Atrophy in Eyes with Neovascular Age-Related Macular Degeneration in the Phase 2 Ladder Trial of the Port Delivery System with Ranibizumab.

PURPOSE: To determine whether the rates of macular atrophy (MA) differ between eyes with neovascular age-related macular degeneration (nAMD) treated continuously with the Port Delivery System with ranibizumab (PDS) and those treated with ranibizumab given as a bolus intravitreal injection. DESIGN: A preplanned exploratory analysis of a phase 2, multicenter, randomized, active treatment-controlled, dose-ranging study. PARTICIPANTS: Patients diagnosed with nAMD within 9 months of screening who had received at least 2 previous intravitreal anti-vascular endothelial growth factor injections of any agent and were responsive to the treatment. METHODS: Eyes were randomized (3:3:3:2) to treatment with either the PDS (filled with a customized formulation of ranibizumab at 10, 40, or 100 mg/ml and refilled pro re nata) or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES: The prevalence, incidence, and progression of MA. RESULTS: The analysis population consisted of 220 eyes (58, 62, 59, and 41 eyes in the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg injection arms, respectively). At study baseline, MA was observed in 14.5% (PDS 10-mg/ml), 11.5% (PDS 40-mg/ml), 13.6% (PDS 100-mg/ml), and 7.6% (monthly ranibizumab) of eyes. At the last assessment (mean, 22.1 months), the prevalence of MA had increased to 38.6% (PDS 10-mg/ml), 40.0% (PDS 40-mg/ml), 40.4% (PDS 100-mg/ml), and 45.7% (monthly ranibizumab). In patients without MA at baseline, a higher proportion of eyes in the monthly ranibizumab arm (40.6%) developed MA than in those in the PDS arms (28.6%, 32.1%, and 30.6% of eyes in the PDS 10-, 40-, and 100-mg/ml arms, respectively). The mean change in the area of MA from baseline to the last assessment for the PDS 10-mg/ml, 40-mg/ml, 100-mg/ml, and monthly ranibizumab arms was +2.46, +1.61, +1.09, and +1.15 mm2, respectively. At 9 months, for patients without MA at baseline, the difference in the incidence of MA between the PDS 100-mg/ml and monthly ranibizumab groups was -12% (95% confidence interval, -31% to 7%). CONCLUSIONS: In the phase 2 Ladder trial, there was no evidence of worse MA with the PDS compared with that with monthly intravitreal ranibizumab 0.5-mg injections. Larger trials focusing on MA are needed to confirm this finding.

In-vitro characterization of ranibizumab release from the Port Delivery System.

The Port Delivery System with ranibizumab (PDS) consists of an implant that is a permanent, indwelling drug delivery device that can be refilled through a self-sealing septum and is designed to continuously release a customized formulation of ranibizumab into the vitreous by passive diffusion through a porous titanium release control element. Target release rates of ranibizumab via the implant used in studies of the PDS in patients with neovascular age-related macular degeneration were selected based on clinical and pharmacokinetic (PK) data from previously conducted intravitreal ranibizumab injection studies. In-vitro testing was performed to verify release rates with a range of ranibizumab concentrations before the phase II Ladder (NCT02510794) and phase III Archway (NCT03677934) trials of the PDS. Implants were filled with ranibizumab and were regularly transferred to new buffer-containing tubes to represent ocular ranibizumab clearance and release kinetics. Ranibizumab concentrations were measured and release rates calculated. Release rate data were fit to an exponential model and compared with expected release kinetics of diffusion. Release profiles of the implant releasing ranibizumab at concentrations of 10 mg/mL, 40 mg/mL, and 100 mg/mL were determined in the pre-phase II in-vitro studies. At day 3.5, mean (SD) ranibizumab release rates were 1.75 (0.07), 6.42 (0.35), and 16.69 (0.67) µg/d for PDS 10 mg/mL, 40 mg/mL, and 100 mg/mL, respectively. At month 6, mean (SD) release rates were 1.68 (0.05) and 4.16 (0.05) µg/d for PDS 40 mg/mL and 100 mg/mL, respectively. Measured release rates were within 90% of theoretical release rates during the course of drug release. PDS 100 mg/mL released 73% (SD, 1.92) of drug by month 6. In the pre-phase III in-vitro studies, mean (SD) release rates with PDS 100 mg/mL were 17.97 (0.90), 4.44 (0.11), and 2.45 (0.08) µg/d at 3.5 days, 6 months, and 9 months, respectively. Cumulative release (SD) was 73% (1.92) by month 6 and 87% (1.88) by month 9. The sustained, continuous, and reproducible release from the PDS observed in the in-vitro studies was also observed in Ladder and Archway. In conclusion, in-vitro studies were a powerful tool for characterizing and verifying ranibizumab release from the PDS implant and supported clinical evaluation of the PDS. PDS 100 mg/mL, which was associated with the longest therapeutic-level delivery of ranibizumab among the concentrations tested, was selected for evaluation in the pivotal phase III Archway trial.

Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). DESIGN: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority and equivalence trial. PARTICIPANTS: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. METHODS: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/ml with fixed 24-week (Q24W) refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5-mg injections every 4 weeks (monthly ranibizumab). MAIN OUTCOME MEASURES: Primary end point was change in best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study letter (letters) score from baseline averaged over weeks 36 and 40 (noninferiority margin,-4.5 letters; equivalence margin, ±4.5 letters). RESULTS: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with the PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 letters (PDS Q24W arm) and 75.5 letters (monthly ranibizumab arm; Snellen equivalent, 20/32). Adjusted mean change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 letters (standard error [SE], 0.5 letters) in the PDS Q24W arm and +0.5 letters (SE, 0.6 letters) in the monthly ranibizumab arm (difference, -0.3 letters; 95% confidence interval, -1.7 to 1.1 letters). PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest were reported in 47 patients (19.0%) in the PDS Q24W arm and 10 patients (6.0%) in the monthly ranibizumab arm, which included, in the former arm, 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in the PDS Q24W arm occurred within 1 month of implantation. CONCLUSIONS: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab, with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval.

A custom virtual reality training solution for ophthalmologic surgical clinical trials.

We present a summary of the development and clinical use of two custom designed high-fidelity virtual-reality simulator training platforms. This simulator development program began in 2016 to support the phase III clinical trial Archway (ClinicalTrials.gov identifier, NCT03677934) intended to evaluate the Port Delivery System (PDS) developed by Genentech Inc. and has also been used to support additional clinical trials. The two simulators address two specific ophthalmic surgical procedures required for the successful use of PDS and provide state-of-the-art physical simulation models and graphics. The simulators incorporate customized active haptic feedback input devices that approximate different hand pieces including a custom hand piece specifically designed for PDS implantation. We further describe the specific challenges of the procedure and the development of corresponding training strategies realized within the simulation platform.

Nonclinical Toxicology and Biocompatibility Program Supporting Clinical Development and Registration of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration.

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.

Virtual Reality Becomes a Reality for Ophthalmologic Surgical Clinical Trials.

The Port Delivery System with ranibizumab (PDS) is an innovative, investigational drug delivery system designed for continuous delivery of ranibizumab into the vitreous to maintain therapeutic drug concentrations for extended durations. The phase 2 Ladder trial (NCT02510794) tested the efficacy of three customized formulations of ranibizumab in patients with neovascular age-related macular degeneration, and the phase 3 Archway trial (NCT03677934) will further assess the safety and efficacy of PDS 100 mg/mL with fixed 24-week refills. The insertion of the PDS implant into the vitreous cavity and subsequent refill-exchange of the drug require procedural skills that are not directly transferable from everyday experience for most eye surgeons today. Preoperative practice for the PDS implant insertion and refill-exchange procedures is therefore critical for achieving optimal surgical outcomes. Virtual reality (VR) as a training tool has long been used by the aeronautic industry and more recently adapted for physician training in medicine and surgery, with encouraging results. Besides the primary use of traditional training tools, physicians participating in Archway have an option to practice in computer-simulated environments provided by VR simulators before performing their first PDS implant insertion and refill-exchange procedures on patients. This Perspective article describes the unique advantages and technologic challenges that practice on VR simulators has to offer, and the experience of Archway physicians with VR technology as a first in any ophthalmic clinical trial.

EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL.

PURPOSE: To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant. METHODS: Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated. RESULTS: Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus). CONCLUSION: In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.

The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration: Results from the Randomized Phase 2 Ladder Clinical Trial.

PURPOSE: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) treatment. DESIGN: Phase 2, multicenter, randomized, active treatment-controlled clinical trial. PARTICIPANTS: Patients diagnosed with nAMD within 9 months who had received 2 or more prior anti-vascular endothelial growth factor intravitreal injections and were responsive to treatment. METHODS: Patients were randomized 3:3:3:2 to receive the PDS filled with ranibizumab 10 mg/ml, 40 mg/ml, 100 mg/ml, or monthly intravitreal ranibizumab 0.5-mg injections. MAIN OUTCOME MEASURES: Time to first implant refill assessed when the last enrolled patient completed the month 9 visit (primary efficacy end point), improvement in best-corrected visual acuity (BCVA) and central foveal thickness (CFT), and safety. RESULTS: The primary analysis population was 220 patients, with 58, 62, 59, and 41 patients in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. Median time to first implant refill was 8.7, 13.0, and 15.0 months in the PDS 10-mg/ml, PDS 40-mg/ml, and PDS 100-mg/ml arms, respectively. At month 9, the adjusted mean BCVA change from baseline was ‒3.2 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, ‒0.5 ETDRS letters, +5.0 ETDRS letters, and +3.9 ETDRS letters in the PDS 10-mg/ml, PDS 40-mg/ml, PDS 100-mg/ml, and monthly intravitreal ranibizumab 0.5-mg arms, respectively. At month 9, the adjusted mean CFT change from baseline was similar in the PDS 100-mg/ml and monthly intravitreal ranibizumab 0.5-mg arms. The optimized PDS implant insertion and refill procedures were generally well tolerated. After surgical procedure optimization, postoperative vitreous hemorrhage rate was 4.5% (7/157; 1 event classified as serious). There was no evidence of implant clogging. CONCLUSIONS: In the phase 2 Ladder trial, the PDS was generally well tolerated and demonstrated a dose response across multiple end points in patients with nAMD. The PDS 100-mg/ml arm showed visual and anatomic outcomes comparable with monthly intravitreal ranibizumab 0.5-mg injections but with a reduced total number of ranibizumab treatments. The PDS has the potential to reduce treatment burden in nAMD while maintaining vision.

Sickle cell maculopathy: Identification of systemic risk factors, and microstructural analysis of individual retinal layers of the macula.

PURPOSE: To identify systemic risk factors for sickle cell maculopathy, and to analyze the microstructure of the macula of Sickle Cell Disease (SCD) patients by using automated segmentation of individual retinal layers. METHODS: Thirty consecutive patients with SCD and 30 matched controls underwent spectral-domain optical coherence tomography (SD-OCT) and automated thickness measurement for each retinal layer; thicknesses for SCD patients were then compared to normal controls. Demographic data, systemic data, and lab results were collected for each SCD patient; multivariate logistic regression analysis was used to identify potential risk factors for sickle cell maculopathy. RESULTS: Ongoing chelation treatment (p = 0.0187) was the most predictive factor for the presence of sickle cell maculopathy; the odds were 94.2% lower when chelation was present. HbF level tended to influence sickle cell maculopathy (p = 0.0775); the odds decreased by 12.9% when HbF increased by 1%. Sickle cell maculopathy was detected in 43% of SCD patients as patchy areas of retinal thinning on SD-OCT thickness map, mostly located temporally to the macula, especially in eyes with more advanced forms of sickle cell retinopathy (p = 0.003). In comparison to controls, SCD patients had a subtle thinning of the overall macula and temporal retina compared to controls (most p<0.0001), involving inner and outer retinal layers. Thickening of the retinal pigment epithelium was also detected in SCD eyes (p<0.0001). CONCLUSIONS: Chronic chelation therapy and, potentially, high levels of HbF are possible protective factors for the presence of sickle cell maculopathy, especially for patients with more advanced forms of sickle cell retinopathy. A subtle thinning of the overall macula occurs in SCD patients and involves multiple retinal layers, suggesting that ischemic vasculopathy may happen in both superficial and deep capillary plexi. Thinning of the outer retinal layers suggests that an ischemic insult of the choriocapillaris may also occur in SCD patients.

VISUALIZATION OF MACULAR PUCKER BY MULTICOLOR SCANNING LASER IMAGING.

PURPOSE: To compare the visualization of the epiretinal membrane (ERM) using multicolor imaging (MCI) (Heidelberg Engineering, Carlsbad, CA) and conventional white light flood color fundus photography (FP) (Topcon). METHODS: The paired images of patients with ERM who underwent same-day MCI and FP examinations were reviewed. Visibility of the ERM was graded using a scale (0: not visible, 1: barely visible, and 2: clearly visible) by masked readers, and surface folds were counted to quantify the membrane visibility for each method. Images from individual color channels in MCI (green, blue, and infrared) were also graded using the same method to further investigate MCI images. RESULTS: Forty-eight eyes of 42 patients were included. The average ERM visibility score was 1.8 ± 0.37 for MCI and 1.01 ± 0.63 for FP (P < 0.001). The number of the surface folds detected per quadrant was signifi8cantly higher in MCI than that in FP (6.79 ± 3.32 vs. 2.85 ± 2.81, P < 0.001). The ERM was graded with similar scores on the two modalities in 43.8% of the eyes; in 56.2%, the ERM was better visualized on MCI than that on FP. Conventional FP failed to detect ERM in 11.4% of eyes when the mean central retinal thickness was <413 microns. Analysis of laser color reflectance revealed that green reflectance provided better detection of surface folds (5.54 ± 2.12) compared to blue reflectance (4.2 ± 2.34) and infrared reflectance (1.2 ± 0.9). CONCLUSION: Multicolor scanning laser imaging provides superior ERM detection and delineation of surface folds than conventional FP, primarily due to the green channel present in the combination-pseudocolor image in MCI.

Outer Retinal Tubulation in Subretinal Neovascularization Associated with Macular Telangiectasia Type 2.

PURPOSE: To describe characteristics of outer retinal tubulation (ORT) in eyes with subretinal neovascular membrane (SRNVM) associated with Macular Telangiectasia type 2 (MacTel type 2). METHODS: A retrospective analysis of longitudinal spectral domain optical coherence tomography (SD-OCT) scans of 46 eyes of 30 patients with SRNVM associated with MacTel type 2 was performed. To identify ORTs, each B-scan image of the macular cube (512 X 128) scan on the Cirrus® SD-OCT was reviewed. Changes in ORT characteristics, including location, size, reflectivity of the borders, and internal reflectivity, were noted during an average follow-up period of 18 months. RESULTS: Ten ORTs were detected in 7 of 46 eyes (15.2%); SRNVM showed no activity in six of these seven eyes. ORT was seen as round or ovoid hyporeflective spaces with hyperreflective borders, and measured 56 to 206 µm in height and 120 to 357 µm in width. An average of 1 bevacizumab injection (range: 0-2) was administered before at least one ORT was diagnosed. The mean interval between the last injection and detection of ORT was 10.2 months (range: 1-48 months). Over the 18-month follow-up period, ORTs were unchanged in four eyes, while in the remaining three eyes ORTs underwent structural changes. Five ORTs disappeared, four new ORTs appeared, and one ORT disappeared and reappeared. The size and the shape of ORT did not change, except in one case. CONCLUSION: Outer retinal tubulation can develop in eyes with MacTel type 2 associated SRNVM, with similar characteristics to ORT found in other degenerative diseases. ORTs may undergo dynamic structural modifications over time, with or without ongoing bevacizumab treatment.