Importance:Effective nonsteroidal therapies are needed for uveitic macular edema (UME). Objective:To assess the safety, tolerability, and effects associated with intravitreal (IVT) vamikibart in UME. Design, Setting, and Participants:This multipart, multicenter, open-label, multiple-ascending-dose nonrandomized clinical trial of vamikibart (RO7200220), a novel IVT anti-interleukin 6 monoclonal antibody, included monotherapy in participants with UME secondary to noninfectious uveitis (NIU). DOVETAIL was conducted from July 2019 to November 2023 at 18 sites in the US. Adults with UME secondary to NIU (optical coherence tomography central subfield thickness [CST] ≥325 µm) were eligible for inclusion. Data were analyzed from February 2024 to May 2024. Interventions:Participants were enrolled into 3 dose groups (0.25, 1, or 2.5 mg) and received IVT vamikibart at day 1, week 4, and week 8, followed by observation not receiving treatment until weeks 20 (2.5 mg) or 36 (0.25 or 1 mg). Main Outcomes and Measures:The primary outcomes were safety and tolerability; exploratory outcomes included best-corrected visual acuity (BCVA) and CST. Results:In this nonrandomized study, vamikibart was associated with improvements in BCVA and CST across all doses. A total of 37 participants with UME were enrolled (0.25 mg: n = 12; 1 mg: n = 12; 2.5 mg: n = 13); 22 of 37 patients (59.5%) were female, and the mean (SD) age was 63.5 (15.4) years. At week 12, mean (SD) change from baseline in BCVA letter score was +9.9 (8.9), an approximate 2-line improvement (improvements in letter scores of +11.1 [8.1], +10.3 [8.0], and +8.4 [10.8] for the 0.25-mg, 1-mg, and 2.5-mg groups, respectively), and mean (SD) CST reduction was -165.1 (147.5) µm (-125.0 [135.0] µm, -188.1 [152.4] µm, and -183.6 [159.4] µm for the 3 dose groups, respectively). Of 37 participants, 36 continued vamikibart throughout the 12 weeks. Ocular adverse events (AEs) in the study eye were reported in 19 participants (51.4%), including 1 serious AE (uveitis worsening, unrelated to study drug) and 1 treatment-related AE (VA reduced transiently). No cases of retinal vasculitis (occlusive or nonocclusive) were reported. Conclusions and Relevance:These results from the phase 1 DOVETAIL nonrandomized clinical trial provide preliminary evidence supporting safety, tolerability, and potential effects of vamikibart for UME secondary to NIU. Two phase 3 clinical trials (MEERKAT [NCT05642312] and SANDCAT [NCT05642325]) are underway to further evaluate vamikibart in UME. Trial Registration:ClinicalTrials.gov Identifier: NCT06771271.

Purpose:To investigate the structure-function relationships between retinal layer attenuation on OCT and a range of functional assessments in patients with geographic atrophy (GA). Design:Retrospective analysis of 2 phase III clinical trials. Subjects:One thousand five hundred and nineteen subjects with GA who were enrolled in phase III studies investigating Lampalizumab: Chroma (NCT02247479) and Spectri (NCT02247531). Methods:Structural retinal features were assessed by artificial intelligence (AI)-based automated segmentation algorithms on OCT images to calculate metrics for outer retinal layer attenuations: loss for external limiting membrane (ELM), ellipsoid zone (EZ), and retinal pigment epithelium (RPE). Functional measures included best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), and reading speed collected in all patients. Microperimetry was collected in a subset of patients. Main Outcome Measures:Correlations (Pearson r) between the OCT layer loss metrics with visual function measures. Results:Cross-sectional analysis did not show any notable correlations between loss areas of each layer for the full OCT scan range and BCVA but did show correlations with LLVA (EZ loss area r = -0.39). After spatially defining regions using the ETDRS circles, notable correlations were observed between BCVA and ELM loss area within the central 1 mm diameter circle area (r = -0.46) and for LLVA with the central 3 mm diameter circle even after exclusion of the central 1 mm diameter region. Microperimetry outcomes correlated with OCT layer losses; the number of scotomatous points correlated equally well with total macular ELM and EZ losses (r = 0.67), mean macular sensitivity had the highest correlations with EZ loss areas, and perilesional sensitivity or responding sensitivity showed the highest correlation with the difference in EZ and RPE loss area (r = -0.50, r = -0.48). Conclusions:The current analyses using AI-based OCT layer losses provide new insights into the spatial dependency of the relationship between anatomical and functional changes in GA. The differential associations noted between BCVA and LLVA with central and paracentral macular pathology, respectively, suggest alternative pathways for diverse aspects of visual function and help inform the design of anatomical and functional assessments for clinical trials in GA. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To characterise morphological changes in neovascular age-related macular degeneration (nAMD) during anti-angiogenic therapy and explore relationships with best-corrected visual acuity (BCVA) and development of macular atrophy (MA). Post-hoc analysis of the phase III HARBOR trial. SD-OCT scans from 1097 treatment-naïve nAMD eyes were analysed. Volumes of intraretinal cystoid fluid (ICF), subretinal hyperreflective material (SHRM), subretinal fluid (SRF), pigment epithelial detachment (PED) and cyst-free retinal volume (CFRV) were measured by deep-learning model. Volumes were analysed by treatment regimen, macular neovascularisation (MNV) subtypes and topographic location. Associations of volumetric features with BCVA and MA development were quantified at month 12/24. Differences in feature volume changes by treatment regimens and MNV subtypes were observed. Each additional 100 nanolitre unit (AHNU) of residual ICF, SHRM and CFRV at month 1 in the fovea was associated with deficits of 10.3, 7.3 and 12.2 letters at month 12. Baseline AHNUs of ICF, CFRV and PED were associated with increased odds of MA development at month 12 by 10

QuestionWhat are the safety, tolerability, and effects associated with intravitreal vamikibart (anti-interleukin 6 antibody) in uveitic macular edema (UME)?FindingsIn this open-label, multiple-ascending-dose, phase 1, nonrandomized clinical trial, 37 patients with UME secondary to noninfectious uveitis (NIU) received intravitreal vamikibart. Across all doses (0.25 mg, 1 mg, 2.5 mg) from baseline to 12 weeks, vamikibart was tolerated and associated with improved best-corrected visual acuity and central subfield thickness.MeaningThis evidence supports short-term safety and tolerability, as well as visual acuity and macular central subfield thickness improvement, of intravitreal vamikibart in cases of UME secondary to NIU. ImportanceEffective nonsteroidal therapies are needed for uveitic macular edema (UME).ObjectiveTo assess the safety, tolerability, and effects associated with intravitreal (IVT) vamikibart in UME.Design, Setting, and ParticipantsThis multipart, multicenter, open-label, multiple-ascending-dose nonrandomized clinical trial of vamikibart (RO7200220), a novel IVT anti-interleukin 6 monoclonal antibody, included monotherapy in participants with UME secondary to noninfectious uveitis (NIU). DOVETAIL was conducted from July 2019 to November 2023 at 18 sites in the US. Adults with UME secondary to NIU (optical coherence tomography central subfield thickness [CST] >= 325 & micro;m) were eligible for inclusion. Data were analyzed from February 2024 to May 2024.InterventionsParticipants were enrolled into 3 dose groups (0.25, 1, or 2.5 mg) and received IVT vamikibart at day 1, week 4, and week 8, followed by observation not receiving treatment until weeks 20 (2.5 mg) or 36 (0.25 or 1 mg).Main Outcomes and MeasuresThe primary outcomes were safety and tolerability; exploratory outcomes included best-corrected visual acuity (BCVA) and CST.ResultsIn this nonrandomized study, vamikibart was associated with improvements in BCVA and CST across all doses. A total of 37 participants with UME were enrolled (0.25 mg: n = 12; 1 mg: n = 12; 2.5 mg: n = 13); 22 of 37 patients (59.5%) were female, and the mean (SD) age was 63.5 (15.4) years. At week 12, mean (SD) change from baseline in BCVA letter score was +9.9 (8.9), an approximate 2-line improvement (improvements in letter scores of +11.1 [8.1], +10.3 [8.0], and +8.4 [10.8] for the 0.25-mg, 1-mg, and 2.5-mg groups, respectively), and mean (SD) CST reduction was -165.1 (147.5) & micro;m (-125.0 [135.0] & micro;m, -188.1 [152.4] & micro;m, and -183.6 [159.4] & micro;m for the 3 dose groups, respectively). Of 37 participants, 36 continued vamikibart throughout the 12 weeks. Ocular adverse events (AEs) in the study eye were reported in 19 participants (51.4%), including 1 serious AE (uveitis worsening, unrelated to study drug) and 1 treatment-related AE (VA reduced transiently). No cases of retinal vasculitis (occlusive or nonocclusive) were reported.Conclusions and RelevanceThese results from the phase 1 DOVETAIL nonrandomized clinical trial provide preliminary evidence supporting safety, tolerability, and potential effects of vamikibart for UME secondary to NIU. Two phase 3 clinical trials (MEERKAT [NCT05642312] and SANDCAT [NCT05642325]) are underway to further evaluate vamikibart in UME.Trial RegistrationClinicalTrials.gov Identifier: NCT06771271 The phase 1 DOVETAIL nonrandomized clinical trial assesses the safety, tolerability, and effects associated with intravitreal vamikibart in uveitic macular edema.

Purpose:To describe the phenotype of patients with age-related macular degeneration (AMD) carrying rare genetic variants in the complement factor H (CFH) and complement factor I (CFI) genes. Design:Cross-sectional study. Participants:Two hundred thirty-four patients with AMD carrying rare variants in CFH (n = 134) and CFI (n = 100) and 234 AMD noncarriers. Methods:Genetic data of patients with AMD from the European Genetic Database were filtered for rare coding and splice-site variants in CFH and CFI. For each carrier, an age-matched (±2 years) patient with AMD without rare variants in CFH and CFI (noncarrier) was selected. Phenotypic characteristics on color fundus photographs were graded according to the Rotterdam Classification and compared between carriers and noncarriers by univariate generalized estimating equations with binary logistic regression analyses, applying a Bonferroni correction for multiple comparisons. We performed subanalyses for pathogenic rare variants only, and we analyzed CFH and CFI carriers separately. Main Outcome Measures:Phenotypic characteristics on color fundus photographs. Results:Geographic atrophy and intermediate AMD, along with features such as predominant drusen type, largest drusen size, and drusen area, were associated with carriership of rare pathogenic variants in CFH (P < 0.001, P = 0.002, P < 0.001, and P < 0.001, respectively). Geographic atrophy and intermediate AMD, along with features such as drusen size, drusen area, and pigmentation, were associated with carriership of rare pathogenic variants in CFI (P = 0.01, P = 0.006, P < 0.001, and P = 0.006, respectively). Furthermore, carriers of rare pathogenic variants in CFH were younger (P < 0.001) and had a lower genetic risk score for common AMD-associated variants compared with noncarriers (mean [standard deviation] genetic risk score 0.83 [1.01] vs. 1.41 [1.21], P = 0.03). Conclusions:In this study, patients with AMD carrying rare variants in CFH and CFI had a more severe drusen phenotype, and a higher frequency of geographic atrophy at a relatively early age. Identifying this distinct phenotype could aid in pinpointing individuals who are more likely to benefit from complement-inhibiting therapies. Financial Disclosures:The authors have no proprietary or commercial interest in any materials discussed in this article.

Therapeutic strategies in the management of diabetic retinal diseases have typically employed anti–vascular endothelial growth factor A (anti–VEGF-A) therapies. While generally effective, clinical trials and real-world analyses demonstrate that a substantial proportion of patients do not show adequate response to this drug class, with retinal edema persisting in upwards of 60% of cases after one to two years of therapy, exhibiting suboptimal visual outcomes and insufficient disease control, with VEGF independent pathways remaining unaddressed. Inflammation is increasingly recognized as a pivotal pathogenic driver in diabetic eye disease, with Interleukin-6 (IL-6) identified as a central mediator of acute and chronic inflammatory responses. This review discusses the role of inflammation in diabetic retinal disease and synthesizes emerging evidence regarding the therapeutic targeting of IL-6. We highlight the differences between cis-, trans-, and cluster signaling, and describe the IL-6 buffer system. We review preclinical evidence demonstrating how IL-6 signaling disrupts the blood-retinal barrier, both directly and synergistically with VEGF. Finally, we describe the emerging clinical evidence for selective IL-6 and bispecific IL-6/VEGF monoclonal antibodies currently in drug development. These novel approaches aim to address the multiple pathogenic pathways that drive Diabetic Macular Edema (DME), with potential to show superior efficacy.

BACKGROUND:To investigate, for the first time, whether an unconjugated VEGF-A antisense oligonucleotide (ASO) can inhibit corneal neovascularisation and improve graft survival in a murine high-risk corneal transplantation model. METHODS:A suture-induced corneal neovascularisation model was established in BALB/c mice, followed by high-risk corneal transplantation using C57BL/6 donor corneas. A VEGF-A RNase H-recruiting ASO (gapmer) was delivered via subconjunctival injection, topical eye drops, or ex vivo preincubation of donor corneas. Blood vessels (BVs) and lymphatic vessels (LVs) were quantified by immunohistochemistry, and Vegfa mRNA expression was measured by qPCR. Immune cell profiles in draining lymph nodes (dLNs), focusing on regulatory T cells (Tregs) and dendritic cells (DCs), were analysed by flow cytometry. Graft survival was monitored for 8 weeks using Kaplan-Meier analysis. RESULTS:Subconjunctival and topical VEGF-A ASO administration significantly suppressed corneal hemangiogenesis and lymphangiogenesis (p < 0.05). Subconjunctival injection also induced regression of established vessels (BVs -21.76%, p = 0.0039; LVs -49.75%, p = 0.0110). Graft survival improved significantly after subconjunctival treatment (p = 0.0438) and donor cornea preincubation (p = 0.0148). Flow cytometry showed increased Treg frequency in dLNs following subconjunctival ASO administration (p = 0.0293). Preincubation of donor corneas markedly reduced Vegfa mRNA levels (p < 0.0001). CONCLUSIONS:VEGF-A-targeting ASO effectively inhibits corneal neovascularisation and improves graft survival in high-risk transplantation. Local and ex vivo VEGF-A inhibition using ASO represents a promising therapeutic strategy for controlling ocular neovascularisation and enhancing corneal transplant outcomes.

Purpose To investigate the structure-function relationships between retinal layer attenuation on optical coherence tomography (OCT) and a range of functional assessments in patients with geographic atrophy (GA). Design Retrospective analysis of two Phase 3 clinical trials.Subjects 1519 subjects with GA who were enrolled in Phase 3 studies investigating Lampalizumab Chroma (NCT02247479) and Spectri (NCT02247531). Methods Structural retinal features were assessed by artificial intelligence (AI)-based automated segmentation algorithms on OCT images to calculate metrics for outer retinal layer attenuations: loss for external limiting membrane (ELM), ellipsoid zone (EZ), and retinal pigment epithelium (RPE). Functional measures included best corrected visual acuity (BCVA), low luminance visual acuity (LLVA), and reading speed collected in all patients. Microperimetry was collected in a subset of patients. Main Outcome Measures Correlations (Pearson’s r) between the OCT layer loss metrics with visual function measures. Results Cross-sectional analysis did not show any notable correlations between loss areas of each layer for the full OCT scan range and BCVA but did show correlations with LLVA (EZ loss area r = -0.39). After spatially defining regions using the ETDRS circles, notable correlations were observed between BCVA and ELM loss area within the central 1mm diameter circle area (r = -0.46) and for LLVA with the central 3 mm diameter circle even after exclusion of the central 1mm diameter region.Microperimetry outcomes correlated with OCT layer losses; the number of scotomatous points correlated equally well with total macular ELM and EZ losses (r = 0.67), mean macular sensitivity had the highest correlations with EZ loss areas, and perilesional sensitivity or responding sensitivity showed the highest correlation with the difference in EZ and RPE loss area (r = -0.50, r= -0.48). Conclusions The current analyses using AI-based OCT layer losses provide new insights into the spatial dependency of the relationship between anatomical and functional changes in GA. The differential associations noted between BCVA and LLVA with central and paracentral macular pathology respectively suggest alternative pathways for diverse aspects of visual function and help inform the design of anatomical and functional assessments for clinical trials in GA.

Objective To evaluate efficacy and safety of sefaxersen, an investigational antisense oligonucleotide targeting complement factor B (FB), in slowing the progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Design Randomized, double-masked, placebo-controlled, adaptive Phase 2 clinical trial. Subjects A total of 332 patients with GA secondary to AMD were enrolled with 91% of treated patients completing the final study visit at 56 weeks. Methods In stage 1, 58 patients received subcutaneous injections of 40, 70 or 100 mg sefaxersen or placebo monthly. An interim analysis for FB, pharmacokinetics and safety was conducted when patients reached at least 13 weeks of treatment to select 2 doses for expansion. In stage 2, an additional 274 patients were randomized to 40 or 70 mg sefaxersen or placebo. Patients were stratified based on baseline GA size, baseline rate of GA growth and presence/history of exudative CNV in the fellow eye. GA area was assessed by fundus autofluorescence imaging. Safety assessments included ocular and systemic adverse events, laboratory parameters, and vital signs. Main Outcome Measures Primary endpoint was the rate of GA lesion growth from baseline to week 49. Prespecified endpoints included changes from baseline in BCVA, low-luminance best-corrected visual acuity (LLVA), systemic complement measures and occurrence of treatment-related adverse events. Results Sefaxersen did not significantly reduce the rate of GA growth vs placebo. Differences in adjusted mean GA rate of growth vs placebo were -0.25 mm2 (-11.5%, p = 0.171) and -0.08 mm2 (-3.8%, p = 0.647) for 40 mg and 70 mg groups respectively. At steady-state, a reduction in adjusted mean plasma FB levels (40 mg: -63% and 70mg: -69%) led also to a reduction in alternative pathway activity (adjusted mean -22% and -34%, respectively). The safety profile, both ocular and non-ocular, of sefaxersen was comparable to that of the placebo, with the most common adverse events being COVID-19, urinary tract infections, and nasopharyngitis. Conclusions Sefaxersen reduced systemic FB levels and alternative pathway activity but the effect on GA growth rate was not significant compared to placebo. The treatment was well-tolerated with a safety profile consistent with previous studies.

Purpose: To compare the effect of faricimab, a dual angiopoietin-2 (Ang-2) and VEGF-A inhibitor, with aflibercept on resolution of hyperreflective foci (HRF) in patients with diabetic macular edema (DME). Design: A post hoc analysis of the randomized, double-masked, noninferiority YOSEMITE/RHINE (NCT03622580/NCT03622593) phase III trials. Participants: Adults with vision loss due to center-involving DME. Methods: A deep learning–based algorithm was used to automatically quantify HRF in spectral-domain OCT volume scans from YOSEMITE/RHINE. Study eyes were randomized to faricimab 6.0 mg every 8 weeks (Q8W; n = 519), faricimab 6.0 mg according to a personalized treat-and-extend (T&E)–based regimen (n = 524), and aflibercept 2.0 mg Q8W (n = 502). Hyperreflective foci were defined as hyperreflective objects up to 50 μm in diameter and assessed within the 1.0-mm and 3.0-mm–diameter ETDRS rings and by location within the inner and outer retina. Main Outcome Measures: Hyperreflective foci volume and count at baseline and over time through week 48 in the inner, outer, and total retina, 1-mm and 3-mm diameters; time to absence of HRF at 2 consecutive visits in the inner and outer retina, 1-mm diameter over 48 weeks. Results: Adjusted mean HRF volumes at week 48 were lower for faricimab Q8W (104.1 picoliter [pL]) and faricimab T&E (110.1 pL) compared with aflibercept (180.3 pL; nominal P < 0.001 for both) in the inner retina, 1-mm diameter. In the inner retina, 3-mm diameter adjusted mean HRF volumes at week 48 were lower for faricimab Q8W (763.9 pL) and faricimab T&E (777.2 pL) compared with aflibercept (1030.6 pL; nominal P < 0.001 for both). Similar results were obtained for volumes in the outer retina and for HRF counts. In the inner retina, 1-mm diameter, the 25th percentile for time to absence of HRF count at 2 consecutive visits was achieved 8 weeks earlier with faricimab Q8W and faricimab T&E versus aflibercept. Conclusions: Greater HRF reductions were achieved with faricimab versus aflibercept, supporting the therapeutic potential of dual Ang-2/VEGF-A inhibition to suppress disease activity in DME. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Age-related macular degeneration (AMD) is a multifactorial retinal disease with a large genetic risk contribution. Reticular pseudodrusen (RPD) is a sub-phenotype of AMD with a high risk of progression to late vision threatening AMD. In a genome-wide association study of 2165 AMD+/RPD+ and 4181 AMD+/RPD- compared to 7639 control participants, both chromosomes 1 (CFH) and 10 (ARMS2/HTRA1) major AMD risk loci are reidentified. However association is only detected for the chromosome 10 locus when comparing AMD+/RPD+ to AMD+/RPD- cases. The chromosome 1 locus is notably absent. The chromosome 10 RPD risk region contains a long non-coding RNA HTRA1-AS1 (ENSG00000285955/BX842242.1) which colocalizes with genetic markers of retinal thickness. HTRA1-AS1 has a strong retinal eQTL signal, pinpointing the parafoveal photoreceptor outer segment layer. Whole genome sequencing of phenotypically extreme RPD cases identifies even stronger enrichment for the chromosome 10 risk genotype.

PURPOSE:This study aimed to assess the similarity of tear proteins between experimental animals and humans to identify the most translational animal model for dry eye disease (DED). METHODS:Eleven species were selected for a structural and physicochemical comparison of healthy human tear fluid proteins involved in DED. Amino acid sequences were compared using BLAST. Protein primary structure, isoelectric point (pI) and grand average of hydropathicity (GRAVY) were determined using ExPASy and compared with humans. RESULTS:Among non-primate mammals, the cat (69.7 %) and pig (68.7 %) showed the highest protein sequence similarity to humans. The ruminants and cat showed amino acid content changes for the highest number of proteins (≥3/15). The pig, rabbit, dog and rodents had the closest global pI values to humans, while the cat showed the highest protein number (9/15) with pI values far from humans. GRAVY values for the pig and dog were the closest to humans. Tear-soluble factor study revealed that the pig was the only species with high similarity for all proteins (>60 %). Amino acid content was similar for most species compared to humans, except mouse for IL-6 and rodents and pig for IL-8. The pI and GRAVY values varied across species, though the pig and sheep were the only ones with similar pI to humans for four out of five factors. CONCLUSION:The pig exhibited the highest similarity to humans in tear protein analysis among non-primate mammals, suggesting that the porcine model may be the most translational for DED research.

Objective: Nonproliferative diabetic retinopathy (NPDR) is a progressive disease that can lead to blindness. Current therapies for NPDR are invasive and not extensively used or accessible until the disease progresses, pointing to the need for an early noninvasive treatment. The objective of CANBERRA was to assess the safety, tolerability, and efficacy of oral administration of vicasinabin (RG7774) on the severity of diabetic retinopathy (DR) in participants with moderately severe to severe NPDR and good vision. Design: CANBERRA was a global, multicentric randomized, double-masked, parallel-group, placebo- controlled, phase II study. The study duration was 36 months. Participants: A total of 139 treatment-na & iuml;ve patients with type 1 or type 2 diabetes mellitus and Diabetic Retinopathy Severity Scale (DRSS) levels of 47 or 53 in >1 eye were enrolled. Intervention: Eligible patients were randomized 1:1:1 to 36 weeks of daily oral placebo, vicasinabin 30 mg, or vicasinabin 200 mg. Participants were followed for an additional 12 weeks. Main Outcome Measures: The primary safety objective was to evaluate the safety and tolerability of vicasinabin by the frequency and severity of adverse events (AEs). The primary efficacy objective was to assess the effect of vicasinabin on the severity of DR, assessing the proportion of participants with >2-step improvement in DRSS from baseline at week 36 in the study eye. Results: Results are presented in the following order: placebo, vicasinabin 30 mg, vicasinabin 200 mg; 47, 48, and 44 participants were enrolled. Baseline characteristics were balanced. Adherence to treatment was approximately 90%, and pharmacokinetic analysis showed dose-dependent plasma exposure to vicasinabin. The primary efficacy endpoint was not met: the percentage of participants who improved their DRSS by >2 steps at week 36 from baseline were 7.9, 9.5, and 5.7, without statistically significant differences. The systemic and ocular safety profiles of vicasinabin were favorable, and AEs distributed evenly across arms. Vicasinabin did not induce changes in glycemic control or any kidney function or cardiovascular parameters. Three patients in the placebo arm discontinued the study due to serious AEs not related to the drug. Conclusions: At the doses tested, vicasinabin did not improve DRSS in participants with NPDR. The role of the cannabinoid system in DR remains elusive.

Objectives To (1) evaluate a method for analysing hypertransmission alterations (HTAs) in eyes with neovascular age-related macular degeneration (nAMD) using en face optical coherence tomography (OCT) images, and (2) investigate associations between HTA phenotypes and best-corrected visual acuity (BCVA). Methods HTAs were manually annotated on en face OCT projections (images from eyes with active nAMD from cross-sectional biomarker study) and classified into 3 qualitative phenotypes based on homogeneity, reflectivity, and border delineation. HTA quantitative metrics and associations between HTA phenotypes, metrics, clinical characteristics and BCVA were assessed. Results Images from 186 eyes were evaluated. Among gradable eyes (n = 136), HTA lesions were present in 88% (119/136) and classified as homogeneous (19%), heterogeneous (25%), and indeterminate (56%). Heterogeneous HTAs had highest foveal involvement; homogeneous HTAs exhibited higher reflectivity, border delineation, and multifocality; indeterminate HTAs were more common in younger patients with shorter disease duration. Significant associations with lower BCVA (R 2 = 0.46) were found for HTA phenotype, larger square root HTA total area (− 5.1 letters/mm, 95% confidence interval [CI] − 7.9, − 2.3) and intraretinal fluid volume (− 1.3 letters/log2-transformed µm 3 ; 95% CI − 1.9, − 0.8). After adjusting for other variables, heterogeneous HTAs were associated with a reduction of 19.0 letters (95% CI 9.8, 28.2; p < 0.001) and 16.8 letters (95% CI 9.3, 24.3; p < 0.001) compared with homogeneous and indeterminate phenotypes, respectively. Conclusions HTAs are prevalent in eyes with nAMD and can be objectively classified into distinct phenotypes associated with differences in morphology, demographics, spatial distribution in the macula, and BCVA.