Phase I DAVIO Trial: EYP-1901 Bioerodible, Sustained-Delivery Vorolanib Insert in Patients With Wet Age-Related Macular Degeneration.

Purpose: To evaluate safety and tolerability of EYP-1901, an intravitreal insert containing vorolanib, a pan-VEGF receptor inhibitor packaged in a bioerodible delivery technology (Durasert E™) for sustained delivery, in patients with wet age-related macular degeneration (wAMD) previously treated with anti-VEGF therapy. Design: Phase I, multicenter, prospective, open-label, dose-escalation trial. Participants: Patients with wAMD and evidence of prior anti-VEGF therapy response. Methods: Patients received a single intravitreal injection of EYP-1901. Main Outcome Measures: The primary objective was to evaluate safety and tolerability of EYP-1901. Secondary objectives assessed biologic activity of EYP-1901 including best-corrected visual acuity (BCVA) and central subfield thickness (CST). Exploratory analyses included reduction in anti-VEGF treatment burden and supplemental injection-free rates. Results: Seventeen patients enrolled in the 440 µg (3 patients), 1030 µg (1 patient), 2060 µg (8 patients), and 3090 µg (5 patients) dose cohorts. No dose-limiting toxicity, ocular serious adverse events (AEs), or systemic AEs related to EYP-1901 were observed. There was no evidence of ocular or systemic toxicity related to vorolanib or the delivery technology. Moderate ocular treatment-emergent AEs (TEAEs) included reduced visual acuity (2/17) and retinal exudates (3/17). One patient with reduced BCVA had 3 separate reductions of 17, 18, and 16 letters, and another had a single drop of 25 letters. One severe TEAE, neovascular AMD (i.e., worsening/progressive disease activity), was reported in 1 of 17 study eyes but deemed unrelated to treatment. Mean change from baseline in BCVA was -1.8 letters and -5.4 letters at 6 and 12 months. Mean change from baseline in CST was +1.7 µm and +2.4 µm at 6 and 12 months. Reduction in treatment burden was 74% and 71% at 6 and 12 months. Of 16 study eyes, 13, 8, and 5 were injection-free up to 3, 6, and 12 months. Conclusion: In the DAVIO trial (ClinicalTrials.gov identifier, NCT04747197), EYP-1901 had a favorable safety profile and was well tolerated in previously treated eyes with wAMD. Measures of biologic activity remained relatively stable following a single EYP-1901 injection. These preliminary data support ongoing phase II and planned phase III trials to assess efficacy and safety. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Inhibition of Complement Factor 3 in Geographic Atrophy with NGM621: Phase 1 Dose-Escalation Study Results.

PURPOSE: To evaluate the safety and tolerability of single and multiple intravitreal injections of NGM621 in patients with geographic atrophy (GA) and to characterize the pharmacokinetics and immunogenic potential. DESIGN: Multicenter, open-label, single- and multiple-dose phase 1 study. METHODS: Fifteen patients enrolled at 4 sites in the United States. Participants had GA secondary to age-related macular degeneration, lesion size ≥2.5 mm2, best-corrected visual acuity of 4 to 54 letters (20/80 to 20/800 Snellen equivalent) in the study eye, and no history of choroidal neovascularization in either eye. Patients who met eligibility criteria were treated in a single ascending-dose phase (2 mg, 7.5 mg, and 15 mg) or received 2 doses of NGM621 (15 mg) 4 weeks apart in the multidose phase and were monitored for 12 weeks (85 days). Assessments included adverse events, best-corrected visual acuity, low-luminance visual acuity, vital signs, clinical laboratory evaluations, GA lesion area as measured by fundus autofluorescence, spectral domain optical coherence tomography, and pharmacokinetic, immunogenicity, and pharmacodynamic assessments. RESULTS: All 15 participants completed the 12-week study. There were no serious adverse events, no drug-related adverse events, and no choroidal neovascularization developed in either eye. Mean visual acuity and GA lesion area appeared stable through week 12 for all cohorts. Pharmacokinetic analyses indicated that NGM621 serum exposures appeared to be dose proportional, and no antidrug antibodies were identified at any of the evaluated time points. CONCLUSIONS: In this small, open-labeled, 12-week phase 1 study, NGM621 was safe and tolerable when administered intravitreally up to 15 mg..

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.

Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial.

PURPOSE: The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME). DESIGN: The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States. PARTICIPANTS: The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 µm or more. METHODS: Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability. MAIN OUTCOME MEASURES: The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment. RESULTS: The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals. CONCLUSIONS: The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.

Isolated choroidal melanocytosis: a distinct clinical entity?

PURPOSE: The objective was to describe a distinct, limited form of congenital ocular melanocytosis that involves the choroid only. METHODS: A retrospective descriptive case series study of 11 patients with similar appearing broad-based but entirely flat melanotic choroidal lesions was carried out. RESULTS: All 11 lesions were homogeneously dark brown in color with at least one striated margin. They were located in various regions of the fundus from the macula and juxtapapillary area to the periphery. They ranged in size from 6 to 23 mm in the largest basal diameter, but all 11 were completely flat. The youngest patient was only 2 months old when the lesion was first detected, but the oldest was 82 years old. None of the 7 lesions that were re-evaluated over a median follow-up of 4 years enlarged or changed appreciably otherwise. CONCLUSIONS: The choroidal lesions described in this report may be a distinct, limited form of congenital ocular melanocytosis. We refer to these lesions as "isolated choroidal melanocytosis." Lesions of this type may predispose affected patients to choroidal melanoma.

Topographical distribution of typical unifocal congenital hypertrophy of retinal pigment epithelium.

PURPOSE: To describe the topographical distribution of typical congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions in the ocular fundi. METHODS: Retrospective review of the clinical records of 52 patients with typical unifocal CHRPE. RESULTS: The 52 CHRPE lesions ranged from 2.5 mm to 11.5 mm in maximal basal diameter (mean=6.6 mm, SD=2.6 mm). The central point of the lesion was in the peripheral fundus in 44 eyes and in the intermediate fundus in eight eyes. The footprint of the lesion involved the peripheral fundus only in 25 eyes, both the intermediate and peripheral fundus in 22 eyes, and the intermediate fundus only in five eyes. The central point of the lesion was located in the temporal quadrant in 24 eyes, the inferior quadrant in 12 eyes, the nasal quadrant in nine eyes, and the superior quadrant in seven eyes. No lesion in this series involved the posterior fundus. CONCLUSIONS: The most common fundus location for typical unifocal CHRPE in this series was the peripheral fundus temporally. Although posterior fundus location of CHRPE has been reported occasionally, our study suggests that such a location is very uncommon.

Fibrovascular ingrowth at sclerotomy sites in vitrectomized diabetic eyes with recurrent vitreous hemorrhage: ultrasound biomicroscopy findings.

PURPOSE: To evaluate the frequency of fibrovascular ingrowth (FVIG) at sclerotomy sites in vitrectomized eyes of diabetic patients with postoperative vitreous hemorrhage referred for ultrasound biomicroscopy (UBM). DESIGN: Retrospective observational case series. PARTICIPANTS: Twenty-six eyes of 23 diabetic patients with recurrent, nonclearing postoperative vitreous hemorrhage subsequent to pars plana vitrectomy (PPV) for proliferative diabetic retinopathy (PDR). METHODS: Ultrasound biomicroscopy evaluation of all sclerotomy sites in patients referred for postoperative nonclearing or recurrent vitreous hemorrhage after PPV for PDR. Correlation with intraoperative findings was obtained in eyes undergoing revision of the vitrectomy. Eight eyes underwent repeat UBM after revision of the vitrectomy, and changes at previous sclerotomy sites were evaluated. MAIN OUTCOME MEASURES: Ultrasound biomicroscopy images at each sclerotomy site were classified into 3 categories: none (grade 0), minor (grade 1), and major (grade 2). The UBM characteristics of each category were defined by the examiner. Logistic regression analysis was performed to identify prognostic factors associated with development of FVIG in the study patients. RESULTS: Grade 1 or 2 FVIG was detected in 85% of cases, and grade 2 FVIG was identified in >/=1 sclerotomy site in 58% of cases. Grade 1 or 2 FVIG was detected in 56% of microvitrector sites, 41% of infusion sites, and 61% of light port sites. Ten patients underwent repeat vitrectomy because of recurrent nonclearing vitreous hemorrhage and UBM images showing FVIG. Inspection of the sclerotomy site confirmed the UBM findings in every case. Eight of these patients underwent follow-up UBM evaluation subsequent to the repeat vitrectomy. In 6 of the 8 patients, follow-up UBM showed no residual FVIG. CONCLUSIONS: Ultrasound biomicroscopy showed FVIG in a high proportion of eyes that experienced recurrent nonclearing vitreous hemorrhage after PPV for PDR. Ultrasound biomicroscopy is capable of detecting and characterizing FVIG at sclerotomy sites and may aid in reoperative planning.

Chorioretinal lesions in nonfatal cases of West Nile virus infection.

OBJECTIVE: West Nile virus (WNV) disease is a zoonotic infection with recent outbreaks in the United States. Recent reports have highlighted the intraocular findings associated with WNV disease. We describe the intraocular findings observed in two patients infected by the West Nile virus. DESIGN: Observational case reports. METHODS: During an outbreak of WNV disease in Southwest Ohio, two patients with an acute onset of a systemic febrile illness accompanied by myalgia, arthralgia, headache, and a maculopapular rash were referred for blurred vision. Complete ophthalmologic examination, fundus photographs, and fluorescein angiograms were obtained on both patients. Both patients underwent serologic testing for viruses and cultures for bacteria, viruses, and fungi. RESULTS: Ophthalmologic examination in each patient revealed anterior segment and vitreous inflammatory cells and multiple partially atrophic and partially pigmented chorioretinal lesions clustered in the peripheral fundus. Fundus examination in case 2 also revealed mild disc edema in both eyes. Intracranial pressure as measured by lumbar puncture was borderline elevated. The chorioretinal lesions in both patients showed a striking similarity and appeared hypofluorescent centrally and hyperfluorescent around the edges on a fluorescein angiogram. Serologic testing for the WNV was positive in both patients, and tests for all other bacteria, fungi, and viruses were negative. CONCLUSIONS: WNV usually causes mild symptoms, but it occasionally causes neurologic illness with fatal outcome or severe morbidity. We present the cases of two patients with serology-proven WNV disease who developed chorioretinal lesions with a targetlike appearance and iridocyclitis.

Photodynamic therapy with verteporfin for subretinal neovascularization secondary to bilateral idiopathic acquired juxtafoveolar telangiectasis.

The clinical course of a patient treated with multiple sessions of photodynamic therapy (PDT) with verteporfin for subretinal neovascularization secondary to bilateral idiopathic acquired juxtafoveolar telangiectasis is described. The patient presented with subfoveal subretinal neovascularization in one eye secondary to bilateral idiopathic acquired juxtafoveolar telangiectasis. The visual acuity improved from 5/40 to 20/60 and fluorescein angiography documented near-complete closure of the subretinal neovascularization within 2 weeks following the initial session of PDT. The visual acuity decreased to 20/200 and fluorescein angiography documented reperfusion of the neovascular membrane 6 weeks later. Four additional sessions of PDT were administered during the next 13 months with similar results. This case indicates that PDT for subretinal neovascularization due to bilateral idiopathic acquired juxtafoveolar telangiectasis may achieve partial short-term neovascular membrane closure and improvement in visual acuity.