Enhanced Benefit in Diabetic Macular Edema from AKB-9778 Tie2 Activation Combined with Vascular Endothelial Growth Factor Suppression

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This article reports 12-month outcomes of patients with diabetic macular edema previously treated with other antivascular endothelial growth factor agents and transitioned to fixed dosing of intravitreal aflibercept (IAI). This prospective, single-arm study enrolled patients to receive IAI 2 mg (0.05 mL) every 4 weeks until optical coherence tomography demonstrated no fluid. Patients then received fixed dosing of IAI 2 mg once every 8 weeks through 12 months. Primary outcome was mean absolute change from baseline central subfield thickness (CST) at 12 months measured by optical coherence tomography. Twenty eyes were enrolled. At baseline, best-corrected visual acuity was 70.0 letters, mean CST was 419.7 µm ± 92.0, superficial capillary perfusion density (CPD) was 46.0 ± 4.2%, and deep CPD was 50.8 ± 4.3%. At 12 months, the mean CST improved to 287.2 µm ± 80.2 (P < .001), superficial CPD decreased to 43.6 ± 4.8% (P = .04), and deep CPD decreased to 47.6 ± 4.8% (P = .05). Patients who switched to fixed dosing of IAI demonstrated significant anatomic improvements in CST at 12 months. CPD values decreased significantly both in superficial and deep layers without significant changes in vision.

The RHONE-X study (ClinicalTrials.gov identifier, NCT04432831) evaluated long-term safety and tolerability (primary end points), and efficacy (exploratory end points) of faricimab, a dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor A (VEGF-A) inhibitor, using a treat-and-extend (T&E) protocol in patients with diabetic macular edema (DME). Global phase 3, multicenter, nonrandomized, 2-year open-label extension study of the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) studies. Of 1622 patients who completed YOSEMITE and RHINE, 1474 patients (91%) were included in the RHONE-X trial. Patients transitioned from faricimab every 8 weeks (Q8W), faricimab T&E, or aflibercept 2.0 mg Q8W in YOSEMITE and RHINE to the RHONE-X study without requiring monthly initiation doses. All received faricimab T&E at up to 16-week intervals based on best-corrected visual acuity (BCVA) and central subfield thickness (CST), per YOSEMITE and RHINE criteria. Patients attended every month during the initial 4-month masked period, then only for T&E dosing visits (open-label arm). Analysis windows were defined for the RHONE-X study years 1, 1.5, and 2 to account for visit asynchronicity. The primary end point was incidence and severity of ocular and nonocular adverse events (AEs). Exploratory end points included change from baseline BCVA and CST, proportion of patients with absence of DME (CST < 325 μm), and treatment durability. Overall, 1204 patients (82%) completed the RHONE-X trial. The incidence of AEs leading to treatment discontinuation (1.5%) and rates of intraocular inflammation (1.3%) were low. Overall, faricimab T&E maintained visual and anatomic improvements achieved in YOSEMITE and RHINE. Adjusted mean BCVA improvements from YOSEMITE and RHINE baseline to the end of the RHONE-X trial were +10.1 letters (faricimab T&E), +11.4 letters (faricimab T&E [prior Q8W]), and +9.5 letters (faricimab T&E [prior aflibercept]); CST reductions were -198.3 μm, -202.5 μm, and -204.9 μm, respectively. At study end, more than 90% of patients achieved DME absence, regardless of prior treatment. Median number of injections over the RHONE-X trial (2 years) were 7 (faricimab T&E), 8 (faricimab T&E [prior Q8W]), and 8 (faricimab T&E [prior aflibercept]). By the RHONE-X trial completion, approximately 80% of patients received faricimab at ≥Q12W intervals. Faricimab, a dual Ang-2 and VEGF-A inhibitor, provided long-term safety, efficacy, and durability in patients with DME treated using a T&E regimen. Sustained visual and anatomic improvements were observed, with extended dosing intervals and reduced treatment burden. Faricimab was well tolerated, with a safety profile consistent with the YOSEMITE and RHINE trials. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

PurposeIntraocular vascular endothelial growth factor (VEGF) levels increases with the severity of diabetic retinopathy. Response of diabetic macular oedema (DMO) to ranibizumab is driven by VEGF suppression. We hypothesised that the initial reduction of central macular thickness by ranibizumab should be maximum in severe diabetic retinopathy until the levels of VEGF decreases to the levels observed in eyes with mild retinopathy.MethodsConsecutive patients with centre-involving DMO (central subfield thickness (CSFT)>300 μm) who had three consecutive monthly ranibizumab injections followed by as needed therapy were included. Retinopathy status was graded as mild non-proliferative diabetic retinopathy (NPDR) (G1), moderate to severe NPDR with no prior panretinal photocoagulation (G2), and treated PDR (G3).ResultsTwo hundred and thirty-nine eyes from 204 patients with a mean age of 64.9 years were included. The distribution was 31.4 G1, 32.2 G2, and 36.4% G3. Mean baseline CSFT for all eyes was 458.5±110.8 μm. Baseline CSFT for G1, G2, and G3, respectively, were 437.6±90.9, 472.3±109.8, and 464.7±124.9 μm (P=0.2155). Mean change in CSFT after three consecutive injections was 128.5±116.6 μm. The mean changes were 95.8±101.4 μm for G1, 137.2±112.9 μm for G2, and 148.9±126.9 μm for G3. The changes in CSFT between groups adjusted for baseline CSFT were statistically significant (P=0.0473). At 6 and 12 months after a mean of 4.5 and 7.7 injections, the changes between groups were no longer significant, P=0.4783 and P=0.8271, respectively.ConclusionsThe initial anatomical response of DMO with intravitreal ranibizumab injections was maximum in eyes with treated PDR, suggesting that the higher the VEGF levels, the better the response with ranibizumab.

Adding a laser-induced chorioretinal anastomosis (L-CRA) to current treatments for central retinal vein occlusion (CRVO) may improve outcomes and lessen therapy burdens. To determine the 2-year efficacy of intravitreal ranibizumab with an L-CRA vs ranibizumab alone for patients with macular edema caused by CRVO. In this randomized clinical trial conducted at a single university clinic from March 2012 to June 2015, 58 participants with macular edema caused by CRVO were randomized 1:1 to either an L-CRA or sham procedure at baseline. All participants received monthly intravitreal injections of ranibizumab, 0.5 mg. Data were analyzed from April 2017 to September 2017. Random assignment to L-CRA plus monthly injections of intravitreal ranibizumab, 0.5 mg, (combination group; n = 29) or to a sham L-CRA procedure plus monthly injections of intravitreal ranibizumab, 0.5 mg, (ranibizumab alone group; n = 29) for 6 months. From month 7 to month 24, participants were evaluated monthly and received an injection of ranibizumab if a loss of 5 or more letters of best-corrected visual acuity (BCVA) on ETDRS chart from previous highest score occurred or if there was evidence of residual macular edema on optical coherence tomography. Mean number of injections from month 7 to month 24, change in BCVA, and change in central subfield thickness (CST). Of the 58 included participants, 38 (66%) were men, and the mean (SD) age was 68.6 (11.8) years; participants had a mean (SD) BCVA of 57.09 (11.87) ETDRS letters (Snellen equivalent, 20/73) and a mean (SD) CST of 738.36 (175.54) μm. A successful L-CRA was created in 24 of 29 participants (83%) in the combination group. The mean number of injections from month 7 to month 24 was 3.2 (95% CI, 2.5-3.8) in the combination group and 7.1 (95% CI, 6.0-8.0) in the ranibizumab alone group. The ratio of the number of injections in the combination group compared with the ranibizumab alone group was 0.46 (95% CI, 0.36-0.61; P < .001). Mixed-effects regression modeling showed a difference in mean BCVA at 2 years between the combination and ranibizumab alone groups (combination, 70.3 letters [Snellen equivalent, 20/40]; ranibizumab alone, 61.6 letters [Snellen equivalent, 20/60]; difference, 8.8 letters; 95% CI, 0.2-17.3; P = .05). There was also a difference in CST at 2 years between the combination and ranibizumab alone groups (mean CST: combination, 303.6 μm; ranibizumab alone, 394.5 μm; difference, 90.9 μm; 95% CI, 24.3-157.5; P = .01). Four participants (14%) in the combination group required a vitrectomy for early macular traction or vitreous hemorrhage. For macular edema caused by CRVO, an L-CRA significantly reduced the number of ranibizumab injections required. anzctr.org.au Identifier: ACTRN12612000004864.

To evaluate intravitreal bevacizumab (IVB) combined with grid laser photocoagulation in macular edema (ME) secondary to branch retinal vein occlusion (BRVO). Eight eyes (8 patients) with ME associated with BRVO with at least 3 months of evolution since symptom onset were included. All subjects underwent measurement of best-corrected visual acuity (BCVA) and imaging with spectral domain optical coherence tomography (SD-OCT) at baseline and 1, 3, 6, and 12 months. Intravitreal bevacizumab was administered at baseline and macular grid laser photocoagulation 1 month later. During follow-up, additional IVB was administered based on physician discretion if persistent or recurrent intraretinal fluid (cysts) was observed on SD-OCT. The mean BCVA and SD-OCT central subfield thickness (CST) values were determined at each time point. Fisher exact test was performed to assess differences between baseline and post-treatment BCVA and SD-OCT measurements. The mean baseline BCVA was 0.28±0.14 (mean±SD), and the mean CST was 479±137 µm. The mean BCVAs at 1, 3, 6, and 12 months were 0.47±0.18 (p=0.031), 0.56±0.50 (p=0.031), 0.65±0.60 (p=0.008), and 0.66±0.65 (p=0.016), respectively. The mean CST values at 1, 3, 6, and 12 months were 295±60 µm (p=0.008), 333±114 µm (p=0.070), 339±80 µm (p=0.008), and 335±109 µm (p=0.008). A mean 2.13 injections were administered; the second injection was administered a mean of 2.71 months after baseline. Combined treatment with IVB and macular grid photocoagulation provided good results and may be considered as an alternative therapy for ME in BRVO. Further studies are needed to assess these preliminary results.

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This study aimed to evaluate the long-term (24-month) efficacy and safety of a modified treat-and-extend (mTAE) regimen of aflibercept for macular edema (ME) due to branch retinal vein occlusion (BRVO). This was a prospective multicenter intervention study. We evaluated 50 eyes in 50 patients with ME due to BRVO enrolled between October 2016 and September 2017. The patients received intravitreal aflibercept (IVA) injections according to a mTAE regimen for 24 months. This study reports the secondary endpoints of best-corrected visual acuity (BCVA) and central subfield thickness (CST) at 24 months and compares them with previously reported primary endpoints. Compared with baseline BCVA and CST of 0.33 (0.27) and 488 (165) µm (mean (standard deviation)), respectively, BCVA and CST were significantly improved at 12 and 24 months (12 months: 0.059 (0.19) LogMAR and 299 (112) µm; 24 months: 0.034 (0.18) LogMAR and 272 (81) µm, respectively; both p < 0.0001). Over the 24-month period, the mean number of IVA injections and clinic visits was 7.4 (3.3) and 11.1 (2.0), respectively. The mTAE regimen of IVA injections for ME due to BRVO was effective for improving BCVA and reducing CST over 24 months. This regimen shows promise for reducing the number of injections and clinic visits.

Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 μm; aflibercept, -196.5 μm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. ClinicalTrials.gov Identifier: NCT03917472.

BackgroundASP8232 is a potent and specific small molecule vascular adhesion protein-1 (VAP-1) inhibitor. This study evaluated the effect of ASP8232 on excess retinal thickness when given alone or in combination with ranibizumab in patients with center-involved diabetic macular edema (CI-DME).MethodsThis was a phase 2a, placebo and sham-injection controlled, double-masked, randomized, parallel-group clinical trial. Participants were patients with CI-DME and central subfield thickness (CST) ≥ 375 µm in the study eye as assessed by spectral domain optical coherence tomography. Eligible patients were randomized to (1) daily oral ASP8232 40 mg monotherapy; (2) combination therapy of daily oral ASP8232 40 mg and monthly intravitreal ranibizumab 0.3 mg; or (3) monthly intravitreal ranibizumab 0.3 mg monotherapy. The treatment period was 12 weeks. CST and best corrected visual acuity (BCVA) were assessed at baseline and at Weeks 2, 4, 8, 12, 16 and 24. The primary outcome was the mean percent change from baseline in excess CST at Week 12. Secondary outcomes were BCVA, safety and tolerability, and pharmacokinetic and pharmacodynamic characteristics of ASP8232.ResultsAfter 12 weeks, the mean (95% confidence interval) percent change in excess CST was 11.4% (− 15.0%, 37.8%) in the ASP8232 group, − 61.7% (− 86.1%, − 37.2%) in the ASP8232/ranibizumab group, and − 75.3% (− 94.8%, − 55.8%) in the ranibizumab group. The change from baseline in the two ranibizumab arms was statistically significant (P < 0.001) as was the difference between the ranibizumab groups and the ASP8232 group (P < 0.001). Mean (SD) increase in BCVA score from baseline was 3.1 (7.3) in the ASP8232 group, 5.2 (7.1) in the ASP8232/ranibizumab group, and 8.2 (9.5) in the ranibizumab group. The increase from baseline in BCVA score was statistically and clinically significant in the ranibizumab group compared with the ASP8232 group (P = 0.015). ASP8232 resulted in near complete inhibition of plasma VAP-1 activity whilst ranibizumab had no effect.ConclusionsNear complete inhibition of plasma VAP-1 activity with ASP8232 had no effect on CST in patients with CI-DME. Furthermore, combination therapy did not provide additional benefit to treatment with ranibizumab alone, which significantly reduced CST and improved BCVA.Trial registration clinicaltrials.gov; NCT02302079. Registered on November 26, 2014

Purpose: To assess the safety and efficacy of supra choroidal triamcinolone injection (SCT) in cases of refractory diabetic macular oedema.&#x0D; Study Design: Interventional case series.&#x0D; Place and Duration of Study: Lahore General Hospital, Lahore, from July to December 2019.&#x0D; Methods: A total of 22 eyes of patients above 18 years of age, with either Type-1 or Type-2 diabetes mellitus and treatment resistant central Diabetic Macular Edema (DME) of 320 um or more (measured on Zeiss Cirrus HD-OCT) and Best Corrected Visual Acuity (BCVA) of less than or equal to 20/40 were included in the study. BCVA, Intra Ocular Pressure (IOP) and Central Subfield Thickness (CST) was recorded. After Supra-Choroidal triamcinolone (SCTA), patients were followed up at one and three months and same clinical parameters were recorded and the results were analysed.&#x0D; Results: out of 22 patients, 10 (45.45%) were males and 12 (54.54%) were females. Mean pre injection CST was 615.5 ± 200.28 um and Log MAR BCVA was 0.9 ± 0.20. Mean post injection CST at one and three months was 302.45 ± 52.45 and 301.66 ± 55.82 um. Mean post injection Log MAR BCVA at one and three months was 0.52 ± 0.3 and 0.40 ± 0.22. The results were statistically significant for pre and post injection CST at both one and three months (p-value &lt; 0.00001). Pre and post injection BCVA was also statistically significant (p-value &lt; 0.05).&#x0D; Conclusion: CST is a safe and effective means to reduce refractory diabetic macular edema and improve OCT macular thickness.&#x0D; Key Words: Diabetic macular edema, Suprachoroidal Triamcinolone, Central sub-field thickness.

Purpose: Diabetic macular edema (DME) is a sight-threatening complication of diabetes. Consequently, studying the proteome of DME may provide novel insights into underlying molecular mechanisms. Methods: In this study, aqueous humor samples from eyes with treatment-naïve clinically significant DME (n = 13) and age-matched controls (n = 11) were compared with label-free liquid chromatography–tandem mass spectrometry. Additional aqueous humor samples from eyes with treatment-naïve DME (n = 15) and controls (n = 8) were obtained for validation by enzyme-linked immunosorbent assay (ELISA). Best-corrected visual acuity (BCVA) was evaluated, and the severity of DME was measured as central subfield thickness (CST) employing optical coherence tomography. Control samples were obtained before cataract surgery. Significantly changed proteins were identified using a permutation-based calculation, with a false discovery rate of 0.05. A human donor eye with DME and a control eye were used for immunofluorescence. Results: A total of 101 proteins were differentially expressed in the DME. Regulated proteins were involved in complement activation, glycolysis, extracellular matrix interaction, and cholesterol metabolism. The highest-fold change was observed for the fibrinogen alpha chain (fold change = 17.8). Complement components C2, C5, and C8, fibronectin, and hepatocyte growth factor-like protein were increased in DME and correlated with best-corrected visual acuity (BCVA). Ceruloplasmin and complement component C8 correlated with central subfield thickness (CST). Hemopexin, plasma kallikrein, monocyte differentiation antigen CD14 (CD14), and lipopolysaccharide-binding protein (LBP) were upregulated in the DME. LBP was correlated with vascular endothelial growth factor. The increased level of LBP in DME was confirmed using ELISA. The proteins involved in desmosomal integrity, including desmocollin-1 and desmoglein-1, were downregulated in DME and correlated negatively with CST. Immunofluorescence confirmed the extravasation of fibrinogen at the retinal level in the DME. Conclusion: Elevated levels of pro-inflammatory proteins, including the complement components LBP and CD14, were observed in DME. DME was associated with the loss of basal membrane proteins, compromised desmosomal integrity, and perturbation of glycolysis.

Aflibercept and ranibizumab are novel drugs for effectively treating wet age-associated macular degeneration (AMD). In the present study, the effect of aflibercept and ranibizumab on wet AMD was compared. A total of 80 AMD patients were intravitreously treated with aflibercept (2.0 mg/dose, 40 participants) or ranibizumab (0.3 mg/dose, 40 participants). The mean visual acuity and central subfield thickness (CTS) were determined at baseline and each follow-up visit (every 4 weeks). ELISA was used to detect the expression of transforming growth factor-β1 (TGF-β1), monocyte chemoattractant protein 1 (MCP-1) and interleukin 6 (IL-6). The primary outcome was the mean change in visual acuity letter score (VAS) and CTS at 1 year. The VAS was markedly improved by 13.1 in the aflibercept group and by 11.0 in the ranibizumab group. In a subgroup of patients with an initial VAS of <69, the mean improvement in the VAS was 17.7 in the aflibercept group and 13.2 in the ranibizumab group (P<0.01). The mean CTS was markedly decreased by 141 in the aflibercept group and by 134 in the ranibizumab group. In the subgroup of patients with an initial VAS of <69, the mean CTS was decreased by 171 in the aflibercept group and by 154 in the ranibizumab group (P<0.01). However, the change of VAS and CTS was similar between the ranibizumab and aflibercept groups when the initial VAS was ≥69. No significant differences in serious adverse events were identified between the aflibercept and ranibizumab groups. The levels of TGF-β1, IL-6 and MCP-1 were decreased by the aflibercept and ranibizumab treatments. The decrease in the levels of the inflammatory factors was more obvious in patients with an initial VAS of <69 in comparison with that in patients with an initial VAS of ≥69. Negative correlations between the levels of TGF-β1, MCP-1 and IL-6 and the mean change of VAS when patients were treated with aflibercept or ranibizumab were identified among all ages. Positive correlations between the levels of TGF-β1, MCP-1 and IL-6 and the mean change of CTS were observed when the initial VAS of the patients was <69. In conclusion, the efficacy of aflibercept in treating patients with AMD was better than that of ranibizumab when the initial VAS of the patients was <69. The inhibition of inflammatory factors may be a secondary effect of aflibercept and ranibizumab treatment. The present study provides a useful reference for the clinical treatment of wet AMD (Chinese Clinical Trial Registry no. ChiCTR1800017782).

To evaluate the role of central subfield thickness (CST), cube average thickness (CAT), and cube volume (CV) as imaging biomarkers for severity of diabetic retinopathy within the ETDRS-based grades of retinopathy using spectral domain optical coherence tomography (SD-OCT). This study aims to evaluate the role of macular CST, CAT, and CV on SD-OCT as imaging biomarkers for severity of DR. One hundred ninety-four consecutive cases of type 2 diabetes mellitus were divided according to ETDRS classification: diabetes mellitus without retinopathy (No DR; n = 65), nonproliferative diabetic retinopathy (NPDR; n = 66), and proliferative diabetic retinopathy (PDR; n = 63). Sixty-three healthy controls were included. CST, CAT, and CV were analyzed using SD-OCT. Data were analyzed statistically. Analysis of variance revealed a significant increase in levels of CST, CAT, CV, and LogMAR visual acuity with the increase in severity of DR. Independent t-test revealed significant difference in CST, CAT, and CV between cases with DME and cases without DME. On multivariate linear regression analysis, increase in CST, CAT, and CV were found to indicate the increase in severity of DR. SD-OCT-based imaging biomarkers CST, CAT, and CV are effective tools for documenting the severity of diabetic retinopathy. These imaging biomarkers serve as significant indicators of severity of disease.

Association of Retinal Sensitivity and Morphology during Antiangiogenic Treatment of Retinal Vein Occlusion over One Year