Safety and Efficacy of Different Doses and Regimens of Faricimab vs Ranibizumab in Neovascular Age-Related Macular Degeneration: The AVENUE Phase 2 Randomized Clinical Trial.

Importance: Faricimab, the first bispecific antibody designed for intraocular use, simultaneously and independently binds and neutralizes angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A). Objective: To assess the efficacy and safety of different doses and regimens of faricimab vs ranibizumab in patients with neovascular age-related macular degeneration (nAMD). Design, Setting, and Participants: AVENUE was a 36-week, multiple-dose-regimen, active comparator-controlled, double-masked, phase 2 randomized clinical study performed at 58 sites in the United States. Eligible participants were anti-VEGF treatment naive with choroidal neovascularization secondary to nAMD and best-corrected visual acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 73 (Snellen equivalent, 20/40) to 24 (Snellen equivalent, 20/320). Data were collected from August 11, 2015, to January 12, 2017, with the final patient visit completed September 26, 2017. Data were analyzed from August 11, 2015, to October 4, 2019. Interventions: Patients were randomized 3:2:2:2:3 to receive ranibizumab, 0.5 mg every 4 weeks (arm A [n = 68]); faricimab, 1.5 mg every 4 weeks (arm B [n = 47]); faricimab, 6.0 mg every 4 weeks (arm C [n = 42]); faricimab, 6.0 mg every 4 weeks until week 12, then faricimab, 6.0 mg every 8 weeks (arm D [n = 47]); and ranibizumab, 0.5 mg every 4 weeks until week 8, then faricimab, 6.0 mg every 4 weeks (arm E [n = 69]). Main Outcomes and Measures: Mean change in BCVA from baseline to week 36, proportion of participants gaining at least 15 letters, BCVA of 20/40 or better or 20/200 or worse, and ocular coherence tomographic outcomes in anti-VEGF treatment-naive participants (arms A, B, C, D) and from weeks 12 to 36 in those with incomplete response (participants in arms A and E with week 12 BCVA ETDRS letter score of ≤68 [Snellen equivalent, 20/50 or worse]). Results: A total of 263 participants were included in the analysis (172 [65.4%] female; 258 [98.1%] white; mean [SD] age, 78.3 [8.7] years). At week 36, adjusted mean change in BCVA vs ranibizumab was 1.6 (80% CI, -1.6 to 4.7) letters for arm B (P = .52), -1.6 (80% CI, -4.9 to 1.7) letters for arm C (P = .53), and -1.5 (80% CI, -4.6 to 1.6) letters for arm D (P = .53). For arm E, adjusted mean change from week 12 was -1.7 (80% CI, -3.8 to 0.4) letters (P = .30). Conclusions and Relevance: AVENUE did not meet its primary end point of superiority of faricimab over ranibizumab in BCVA at week 36. Although not superior to monthly ranibizumab as given in this trial, overall visual and anatomical gains noted with faricimab support pursuing phase 3 trials for a potential alternative to monthly anti-VEGF therapy. Faricimab showed no new or unexpected safety signals. Trial Registration: ClinicalTrials.gov Identifier: NCT02484690.

Retinal Vasculitis and Intraocular Inflammation after Intravitreal Injection of Brolucizumab.

PURPOSE: To evaluate features and outcomes of eyes with retinal vasculitis and intraocular inflammation (IOI) after intravitreal injection (IVI) of brolucizumab 6 mg/0.05 ml for treatment of neovascular age-related macular degeneration. DESIGN: Retrospective case series. PARTICIPANTS: Fifteen eyes from 12 patients identified from 10 United States centers. METHODS: Review of patient demographics, ophthalmologic examination results, and retinal imaging findings. MAIN OUTCOME MEASURES: Baseline and follow-up visual acuity (VA), prior anti-vascular endothelial growth factor (VEGF) injections, clinical presentation, retinal findings, fluorescein angiography results, and treatment strategies. RESULTS: The number of previous anti-VEGF IVIs ranged between 2 and 80 in the affected eye before switching to brolucizumab. Retinal vasculitis and IOI were diagnosed at a mean of 30 days after brolucizumab IVI. Mean VA before brolucizumab IVI was 0.426 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, 20/53) and VA at diagnosis of retinal vasculitis was 0.981 logMAR (Snellen equivalent, 20/191; range, 20/25-20/1600; P = 0.008). All affected eyes showed IOI with variable combinations of focal or elongated segmental sheathing and discontinuity of small and large retinal arteries, sclerotic arteries, regions of vascular nonperfusion, cotton-wool spots, Kyrieleis plaques, irregular venous caliber with dilated and sclerotic segments, perivenular hemorrhages, and foci of phlebitis. Fluorescein angiography revealed delayed retinal arterial filling, retinal vascular nonperfusion, and variable dye leakage from affected vessels and the optic nerve. Systemic evaluation for embolic causes was unrevealing in 2 patients, and 3 patients showed negative laboratory assessment for uveitis. Treatment consisted of various combinations of corticosteroids (systemic, intravitreal, and topical), and 2 eyes underwent vitrectomy without improvement in vision. After a mean follow-up of 25 days, mean VA was 0.833 logMAR (Snellen equivalent, 20/136), which was reduced compared with baseline (P = 0.033). CONCLUSIONS: Retinal vasculitis and IOI after brolucizumab IVI are characterized by variable occlusion of large or small retinal arteries, or both, and perivenular abnormalities. It may span from peripheral vasculitis to occlusion of large retinal arteries around the optic nerve or macula with severe vision loss. A high index of suspicion is required because vitreous cells may obscure visualization of retinal details.

Phase I Trial of Anti-Vascular Endothelial Growth Factor/Anti-angiopoietin 2 Bispecific Antibody RG7716 for Neovascular Age-Related Macular Degeneration.

PURPOSE: RG7716 is a novel bispecific antibody that simultaneously binds vascular endothelial growth factor (VEGF) and another key angiogenic factor, angiopoietin 2. A phase I study of intravitreal RG7716 was conducted to evaluate single-dose and multiple-dose safety in patients with neovascular age-related macular degeneration (AMD). DESIGN: Open-label, single and multiple ascending-dose study. PARTICIPANTS: Twenty-four patients diagnosed with neovascular AMD with best-corrected visual acuity (BCVA) of 20/40 to 20/400 (Snellen equivalent) and refractory subfoveal choroidal neovascularization defined as leakage on fluorescein angiography or fluid on spectral-domain optical coherence tomography despite 3 or more intravitreal anti-VEGF treatments in the preceding 6 months. METHODS: Single intravitreal doses of 0.5 mg, 1.5 mg, 3 mg, and 6 mg RG7716 were administered in stepwise dose-escalation groups, each with 3 patients. In the multiple-dose phase, 6 patients were enrolled and received 3 treatments each of 3 mg and 6 mg RG7716. MAIN OUTCOME MEASURES: Safety and tolerability, changes in baseline BCVA, and central subfield thickness (CST). RESULTS: There were no dose-limiting toxicities in either the single-dose or multiple-dose group. Treatment-emergent ocular adverse events were mild. There was a single withdrawal and 1 serious adverse event, both deemed to be unrelated to the study drug by principal investigators. In the combined single-dose groups and in the 6-mg multiple-dose group, BCVA increased from baseline to 28 days after the last dose administration by a median of 7 letters (range, 0-18 letters; n = 11) and 7.5 letters (range, 3-18 letters; n = 6), respectively. The corresponding median reduction from baseline in CST were 42 µm (range, -101 to 10 µm; n = 11) and -117 µm (range, -252 to -7 µm; n = 6), respectively. After multiple 3-mg RG7716 doses, no changes were observed in either BCVA (median, -0.5 letters; range, -9 to 8 letters; n = 6) or CST (median, -9 µm; range, -188 to -1 µm; n = 6). CONCLUSIONS: RG7716 was well tolerated and exhibited an overall favorable safety profile, with evidence of improvements in BCVA and anatomic parameters. These data support further evaluation of RG7716 in phase II trials.