Safety and Efficacy of Subretinally Administered Palucorcel for Geographic Atrophy of Age-Related Macular Degeneration: Phase 2b Study.

PURPOSE: To evaluate safety and successful use of a novel subretinal delivery system and suprachoroidal surgical approach and safety and activity of human umbilical tissue-derived cells (palucorcel) via a novel delivery system in patients with geographic atrophy (GA). DESIGN: Multicenter, open-label phase 2b study. PARTICIPANTS: Participants were 55 to 90 years with GA secondary to age-related macular degeneration (AMD) and best-corrected visual acuity (BCVA) of 20/80 to 20/800. Exclusion criteria included neovascular AMD in the intervention eye, glaucoma with intraocular pressure of 25 mmHg or more, or other significant ophthalmologic conditions. METHODS: Participants received a subretinal injection of palucorcel, 3.0 × 105 cells in 50 µl, using the custom-designed delivery system and surgical procedure. MAIN OUTCOME MEASURES: Safety assessments included treatment-emergent adverse events (AEs), immunologic assessments, and ophthalmologic evaluations. Efficacy was evaluated as change in mean number of BCVA letters from baseline, proportion of participants gaining 15 BCVA letters or more, and growth rate of GA lesions at 12 months. RESULTS: Surgery and palucorcel administration were performed in 21 participants at 8 sites by 8 different surgeons. At baseline, median total area of GA was 13.4 mm2 and median BCVA was 43 letters in the intervention eye. Eye-related AEs occurred in 76% of participants (16/21), including conjunctival hemorrhage (n = 5), retinal hemorrhage (n = 4), and vitreous floaters (n = 4). Most AEs were mild and resolved within 1 month. No serious AEs, no retinal detachment or perforation, and no significant changes in intraocular pressure occurred. At month 12, mean change in BCVA from baseline was -5.9 letters correct (standard deviation, 13.0 letters correct) in the intervention eye and -3.7 letters correct (standard deviation, 9.0 letters correct) in the fellow eye. No participants showed improvement of 15 letters or more in the intervention eye, and 3 participants lost more than 15 letters by month 1. No apparent effect of treatment was observed. CONCLUSIONS: Palucorcel was delivered successfully to the targeted subretinal site using a novel delivery system and suprachoroidal approach for most participants; however, improvement in GA area, retardation of growth, or visual acuity were not demonstrated.

Intravitreal Combined Aflibercept + Anti-Platelet-Derived Growth Factor Receptor ß for Neovascular Age-Related Macular Degeneration: Results of the Phase 2 CAPELLA Trial.

PURPOSE: To compare the efficacy and safety of intravitreal aflibercept + anti-platelet-derived growth factor receptor ß (PDGFRß) combination with intravitreal aflibercept injection (IAI) monotherapy in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN: Phase 2, randomized, double-masked study. PARTICIPANTS: A total of 505 patients (eyes) with nAMD. METHODS: Patients were randomized 1:2:2 to low-dose combination intravitreal anti-PDGFRß 1 mg and aflibercept 2 mg (LD combo), high-dose combination intravitreal anti-PDGFRß 3 mg and aflibercept 2 mg (HD combo), or IAI alone every 4 weeks through week 12. At week 12, patients in the HD combo and IAI groups were re-randomized to continue as assigned or switch to HD combo → IAI or IAI → HD combo and dosed every 4 weeks through week 28. During weeks 28 to 52, patients received treatment as needed per prespecified criteria. This report presents efficacy through week 28 and safety through week 52. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline at week 12 (primary end point). RESULTS: At week 12, mean BCVA gains from baseline were 5.8, 5.8, and 7.5 letters with LD combo, HD combo, and IAI, respectively (P = 0.21 for LD combo and P = 0.10 for HD combo vs. IAI). The corresponding proportions of eyes that gained ≥15 letters were 12%, 19%, and 22%, respectively. Mean reductions in central retinal thickness from baseline were 126.1, 127.1, and 126.9 µm, respectively. Proportions of eyes with complete resolution of fluid from baseline were 35%, 24%, and 42%, respectively. Vision and anatomic outcomes at week 28 were consistent with the week 12 results. Through week 52, the incidence of intraocular inflammation was 1.0%, 7.5%, 2.1%, 2.1%, and 0%, respectively. The incidence of Anti-Platelet Trialists' Collaboration-defined arterial thromboembolic events was 1.9%, 0.9%, 1.1%, 2.1%, and 1.9%, respectively. CONCLUSIONS: Intravitreal aflibercept + anti-PDGFRß did not improve BCVA over IAI alone. Anatomic outcomes evaluating complete fluid resolution favored IAI. Adverse events were consistent with the reported IAI safety profile, except for a higher frequency of intraocular inflammation in the HD combo group.

External Choroidal Drainage Using Direct Visualization.

Laura L. Snyder Shriji N. Patel A woman in her 60s with a functional glaucoma tube shunt presented after vitrectomy for epiretinal membrane peeling with symptomatic choroidal effusions not responsive to medical therapy. She underwent a minimally invasive, transconjunctival choroidal drainage procedure, which was directly visualized under a widefield viewing system to prevent intraocular hemorrhage or retinal penetration of the needle. This allowed for preservation of her conjunctiva, restoration of normal intraocular pressure by temporary blockage of her tube shunt with a viscoelastic, and resolution of her choroidal effusions.

PRN Ranibizumab in the Treatment of Choroidal Neovascularization Secondary to Ocular Histoplasmosis.

BACKGROUND AND OBJECTIVE: Ranibizumab (Lucentis; Genentech, South San Francisco, CA) is used off-label for the treatment of choroidal neovascularization secondary to ocular histoplasmosis syndrome (OHS). This study prospectively evaluates the safety and efficacy of two treatment paradigms utilizing ranibizumab 0.5 mg: one or three initial injections followed by monthly visits with PRN treatment through Month 12. PATIENTS AND METHODS: In this prospective, open-label study, 21 subjects were evaluated monthly and retreated during the pro re nata treatment phase if specific criteria were met, including loss of vision, increase in subretinal fluid, or hemorrhage. Adverse events, best-corrected visual acuity (BCVA), and central subfield retinal thickness (CST) were evaluated. RESULTS: No adverse events were observed. Mean BCVA improved in both groups by approximately 2 lines, and mean CST decreased by approximately 100 µm at month 12. The number of injections was the same (5.7 and 5.8 injections). CONCLUSION: Results suggest that ranibizumab is safe and efficacious for treatment of CNV secondary to OHS. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:20-26.].

INTRAVITREAL AFLIBERCEPT INJECTION FOR CHOROIDAL NEOVASCULARIZATION DUE TO PRESUMED OCULAR HISTOPLASMOSIS SYNDROME: The HANDLE Study.

PURPOSE: To evaluate intravitreal aflibercept injection (IAI) in patients with presumed ocular histoplasmosis syndrome and choroidal neovascularization. METHODS: Open-label randomized Phase I/II study of IAI in patients with presumed ocular histoplasmosis syndrome-related choroidal neovascularization. Thirty-nine eyes from 39 patients were randomized in a 1:1 ratio to 2 groups. The Sustained Group eyes (n = 19) underwent monthly IAI for 3 months, then mandatory IAI every 2 months for 12 months (with an option for monthly PRN dosing, if needed). The PRN Group eyes (n = 20) received 1 IAI at randomization, then monthly PRN IAI for 12 months. RESULTS: Thirty-nine eyes (19 eyes Sustained Group and 20 eyes PRN Group) were randomized. Average age of participants was 50 years (19-75), with 16 men and 23 women. Ten, 12, and 17 eyes demonstrated extrafoveal, juxtafoveal, and subfoveal choroidal neovascularization, respectively. All eyes in both groups received IAI at baseline, with the Sustained and PRN groups receiving on an average 7.5 (5-11) and 4.6 (1-10) injections, respectively, over the 12 months. At baseline, overall average visual acuity was 68 letters (13-87 letters) with Snellen equivalent of 20/42 (20/20-20/160). At 12-month follow-up, Sustained Group's average visual acuity was 84.9 letters (74-94) and Snellen equivalent was 20/21 (20/13-20/32), indicating an average improvement of 12 letters (6 letters loss to 36 letters gain) (P < 0.01). The PRN Group's 12-month average visual acuity was 80.9 letters (60-94) and Snellen equivalent was 20/26 (20/13-20/63), indicating an average gain of 19 letters (4-75) (P < 0.01). Mean baseline central subfield thickness (CST) was 374 µm and mean 1-year CST was 260 µm (P < 0.01) among all study participants. The Sustained Group's mean baseline CST was 383 µm and mean 12-month CST was 268 µm (P < 0.01). Mean baseline CST of the PRN Group was 360.8 µm, with the final mean CST of 260.5 µm (P < 0.01). No reported endophthalmitis, retinal tears, detachments, vitreous hemorrhage, nor adverse thrombotic events were reported. CONCLUSION: Intravitreal aflibercept resulted in improved visual and anatomical outcomes with a favorable safety profile. PRN IAI dosing required less injections with similar visual and anatomical outcomes compared with sustained dosing.

The Role of Anti-VEGF Therapy in the Treatment of Diabetic Macular Edema.

Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults. DR often leads to diabetic macular edema (DME), which often goes unnoticed until a patient presents with vision loss. However, treatment options and data for DME are continually improving. We know that vascular endothelial growth factor (VEGF) plays a key role in DME progression; therapies that act by inhibiting VEGF production seem to improve visual acuity in patients with DME. Of the anti-VEGF therapies available, two have been approved by the U.S. Food and Drug Administration to treat DME: ranibizumab (Lucentis; Genentech, South San Francisco, CA) and aflibercept (Eylea; Regeneron, Tarrytown, NY). Bevacizumab (Avastin; Genentech, South San Francisco, CA), which is approved for the treatment of certain types of cancer, is occasionally used off-label to treat DME. Anti-VEGF therapy can stop vision loss and even improve visual acuity. Other treatments remain effective, and these various treatment options fuel a need for new data and discussion. This roundtable discussion, which took place during the 2015 annual meeting of the American Academy of Ophthalmology, outlines the current protocols used to treat DME and provides clinical opinions about selecting and treating with an appropriate anti-VEGF therapy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:S5-14.].

Comprehensive Review of Ocular and Systemic Safety Events with Intravitreal Aflibercept Injection in Randomized Controlled Trials.

PURPOSE: To assess the ocular and systemic safety of intravitreal aflibercept injection (IAI) compared with controls in IAI trials in neovascular age-related macular degeneration (nAMD), macular edema following central retinal vein occlusion (MEfCRVO), macular edema following branch retinal vein occlusion (MEfBRVO), and diabetic macular edema (DME). DESIGN: Comprehensive review of 10 phase II and III trials of IAI in retinal diseases. PARTICIPANTS: Patients were included from IAI trials in nAMD (CLEAR-IT 2 [52 weeks], VIEW 1 [96 weeks], VIEW 2 [96 weeks], VIEW 1 extension [208 weeks]); MEfCRVO (COPERNICUS [100 weeks], GALILEO [76 weeks]); MEfBRVO (VIBRANT [52 weeks]); and DME (DA VINCI [52 weeks], VIVID [100 weeks], VISTA [100 weeks]). METHODS: Rates were calculated as events/100 person-years at risk (PYR). When applicable, rate ratios (RRs) and 95% confidence intervals (CIs) were provided. MAIN OUTCOME MEASURES: Outcomes included rates for intraocular inflammation, endophthalmitis, serious adverse events (SAEs), wound-healing complications, hypertension (HTN), adjudicated Anti-Platelet Trialists' Collaboration (APTC)-defined arterial thromboembolic events (ATEs) (nonfatal myocardial infarction, nonfatal stroke, and vascular death), and death from all causes. RESULTS: More than 4000 patients contributed >7000 PYR. For all outcomes, there were no meaningful differences between evaluated adverse event rates for IAI and controls. Overall intraocular inflammation rates were 2.37 (control) and 2.06 (IAI); overall RR was 0.87 (95% CI, 0.61-1.27). Overall endophthalmitis rates were 0.52 (control) and 0.22 (IAI); overall RR was 0.42 (95% CI, 0.18-1.03). Overall SAE rates were 23.09 (control) and 20.80 (IAI); overall RR was 0.90 (95% CI, 0.80-1.02). Overall rates of wound-healing complications were 0.17 (control) and 0.15 (IAI); overall RR was 0.85 (95% CI, 0.24-3.86). Overall HTN rates were 14.87 (control) and 11.27 (IAI), with an overall RR of 0.76 (95% CI, 0.65-0.89); HTN rates were highest in MEfBRVO and lowest in nAMD. For adjudicated APTC-defined ATEs, rates were 2.04 (control) and 2.19 (IAI), with an RR of 1.07 (95% CI, 0.73-1.61). Overall death rates were 1.16 (control) and 1.49 (IAI); overall RR was 1.28 (95% CI, 0.80-2.15). CONCLUSIONS: Rates of selected ocular and systemic adverse events with IAI were similar to those of controls and similar across disease states in evaluated IAI trials. Intravitreal aflibercept injection was generally well tolerated in the patients evaluated.

Active aspiration of suprachoroidal hemorrhage using a guarded needle.

BACKGROUND AND OBJECTIVE: To describe a novel technique using a guarded needle to drain suprachoroidal hemorrhage. PATIENTS AND METHODS: A guarded needle is used to drain suprachoroidal hemorrhage under direct microscope visualization. A scleral buckling sleeve is used to create a guarded 26-gauge needle to avoid over-penetration of the needle beyond the suprachoroidal space. Active extrusion can be used to drain suprachoroidal blood. RESULTS: The authors report two cases in which active aspiration using a guarded needle was successful in draining suprachoroidal hemorrhage without complications. In both cases, the vitreous cavity could be restored, allowing for subsequent pars plana vitrectomy. CONCLUSION: The technique of active aspiration using a guarded needle optimizes surgeon control of suprachoroidal hemorrhage drainage and also has the added benefit of easy transition to secondary vitrectomy after drainage has been completed.

Neovascular AMD with marked macular fluid and rapid response to anti-VEGF therapy.

The authors describe the clinical management and spectral-domain optical coherence tomography (SD-OCT) findings of three unusual cases of neovascular age-related macular degeneration (AMD). Each patient presented with decreased vision and a diagnosis of neovascular AMD, with SD-OCT findings of marked macular fluid. Macular fluid was noted to be subretinal fluid, pigment epithelial detachment, or both. In each case, visual acuity improved and the fluid resolved rapidly with monthly anti-vascular endothelial growth factor therapy.

A pharmacogenetics study to predict outcome in patients receiving anti-VEGF therapy in age related macular degeneration.

PURPOSE: To ascertain whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth factor (VEGFA), Complement Factor H (CFH), and LOC387715 genes could predict outcome to anti-VEGF therapy for patients with age related macular degeneration (AMD). METHODS: Patients with "wet" AMD were identified by chart review. Baseline optical coherence tomography (OCT) and visual acuity (VA) data, and at least 6 months of clinical follow up after 3 initial monthly injections of bevacizumab or ranibizumab were required for inclusion. Based on OCT and VA, patients were categorized into two possible clinical outcomes: (a) responders and (b) non-responders. DNA was extracted from saliva and genotyped for candidate SNPs in the VEGFA, LOC387715, and CFH genes. Clinical outcomes were statistically compared to patient genotypes. RESULTS: 101 patients were recruited, and one eye from each patient was included in the analysis. 97% of samples were successfully genotyped for all SNPs. We found a statistically significant association between the LOC387715 A69S TT genotype and outcome based on OCT. CONCLUSION: Genetic variation may be associated with outcome in patients receiving anti-VEGF therapy.

Modified external needle drainage of subretinal fluid in the management of rhegmatogenous retinal detachment using a "guarded needle" approach.

External needle drainage of subretinal fluid is a useful technique to assist with retinal detachment surgery. This technique provides the ability to directly visualize the removal of subretinal fluid in a controlled manner. The major difficulty in learning this technique is the potential for overpenetration with the needle. Using a "guarded needle" approach can reduce this risk and increase the adoption of this useful method.

Peripapillary choroidal neovascularization associated with kenny syndrome.

PURPOSE: To report a case of Kenny-Caffey syndrome with peripapillary choroidal neovascularization. METHODS: An observational case report with clinical findings demonstrated by wide-field retinal photographic and angiographic evaluation of a patient with Kenny-Caffey syndrome. RESULTS: Wide-field retinal photography and fluorescein angiography showed characteristic findings seen in Kenny-Caffey syndrome (crowded optic nerves, retinal vascular tortuosity). In addition, the previously undocumented finding of peripapillary choroidal neovascularization is demonstrated. CONCLUSION: The development of peripapillary choroidal neovascularization can occur in patients with Kenny-Caffey syndrome. The development of this finding may be secondary to abnormalities of the optic nerve inherent in this rare disorder.

Triamcinolone acetonide preparations: impact of crystal size on in vitro behavior.

PURPOSE: To characterize the in vitro behavior of three preparations of triamcinolone acetonide (TA). METHODS: Three preparations of TA were mixed with Balanced Salt Solution Plus: commercially available TA (Kenalog 40, Bristol-Myers Squibb, Princeton, NJ), compounded preservative-free triamcinolone acetonide (PFTA, New England Compounding Center, Framingham, MA), and triamcinolone acetonide injectable suspension (TAIS, TRIESENCE, Alcon, Inc., Fort Worth, TX). We determined the mean number of crystalline aggregates per high-power deconvolution microscopy field, largest aggregate area, and spectroscopic photometric absorption. RESULTS: Preservative-free triamcinolone acetonide had larger mean number of aggregates compared with TA (time 0 P = 0.002, 10 minutes P < 0.001) and TAIS (time 0 P < 0.001, 10 minutes P = 0.003). Aggregate size varied at both 0 and 10 minutes: TAIS > TA > PFTA. Spectroscopic photometric absorption decreased in direct correlation to aggregate size over time for all three preparations. CONCLUSION: In vitro, PFTA in Balanced Salt Solution Plus had more aggregates of smaller size than either TA or TAIS. By contrast, TAIS had much larger aggregate size than both PFTA and TA, and this increased over time. These findings correlate with the clinical observations that PFTA and TA tend to disperse throughout the vitreous, whereas TAIS tends to conglomerate and gravitate toward the most dependent portion of the eye in a globular fashion.

Retinal breaks observed during pars plana vitrectomy.

PURPOSE: To quantitate the frequency and features of retinal breaks discovered at the time of vitrectomy and to evaluate the outcomes with prophylactic treatment. DESIGN: A consecutive, single-surgeon, retrospective, observational case series from a two-year period. METHODS: Medical records were reviewed for all patients who underwent primary, standard, three-port pars plana vitrectomy (PPV) between January 1, 2000, and December 31, 2001. Intraoperative findings recorded included the number, location, and categorization of retinal breaks and their method of management. Postoperative features recorded included the presence or absence of a retinal detachment (RD). RESULTS: There were 65 retinal breaks found in 48 (11.6%) of 415 eyes and included 30 (7.2%) eyes with definite breaks, nine (2.2%) with suspicious breaks, and nine (2.2%) with probably preexisting breaks. Breaks that were described as being large (n = 5) were more commonly associated with the right-hand sclerotomy (P = .041), although other categories of breaks were not. After surgery, the overall incidence of RD was 2.2% (nine of 415 eyes). The rate of RD among the 48 eyes with retinal breaks (of any category) was also 2.1% (one eye). All RDs in this series occurred more than three months after initial vitrectomy and, accordingly, were probably unrelated to retinal breaks that occurred during surgery. CONCLUSIONS: Recognition of retinal breaks and intraoperative treatment with retinopexy and air-fluid exchange during vitrectomy reduces the postoperative risk of RD to that among eyes without observed intraoperative retinal breaks.

Indocyanine green-assisted internal limiting membrane peeling for macular holes: toxicity?

BACKGROUND: Indocyanine green (ICG) staining facilitates definitive internal limiting membrane (ILM) peeling during macular hole surgery (MHS), but might cause toxicity. PURPOSE: To determine if ICG to assist in ILM peeling has an effect on anatomic or visual results in MHS with ILM peeling. METHODS: Retrospective, comparative review including primary analysis of 173 cases undergoing MHS. Visual acuity >or=20/50, or=20/50 visual acuity. CONCLUSIONS: ICG usage during macular hole surgery was not associated with worse visual outcomes, suggesting possible toxic effects reported are not clinically significant. If the ILM cannot be peeled effectively, ICG should be considered a safe option.

Idiopathic macular hole with extensive subretinal fluid: clinical and optical coherence tomography features before and after surgery.

PURPOSE: To report clinical and optical coherence tomography (OCT) features in patients with idiopathic macular hole and extensive subretinal fluid (extending at least 1 disk diameter from the center of the hole). DESIGN: Retrospective, consecutive, noncomparative case series. METHODS: The case records of two patients with idiopathic macular holes with extensive subretinal fluid were reviewed. RESULTS: Both patients presented with reduced visual acuity (20/200 and 20/400). OCT demonstrated attachment of the posterior hyaloid to the inner retina, a full-thickness macular hole, cystoid macular edema (CME), and extensive subretinal fluid. After surgery, both patients achieved macular hole closure and improvement in visual acuity (20/60 and 20/30). Postoperatively, OCT showed a normal foveal contour, complete hole closure, and resolution of the CME and subretinal fluid. CONCLUSIONS: In patients with macular hole and extensive subretinal fluid, improved visual acuity and hole closure can be achieved. Preoperative OCT in these patients demonstrates vitreoretinal interface abnormalities, CME, and extensive subretinal fluid. These changes resolve postoperatively.