Phase 2 Trial Evaluating Minocycline for Geographic Atrophy in Age-Related Macular Degeneration: A Nonrandomized Controlled Trial.

Importance: Existing therapies to slow geographic atrophy (GA) enlargement in age-related macular degeneration (AMD) have relatively modest anatomic efficacy, require intravitreal administration, and increase the risk of neovascular AMD. Additional therapeutic approaches are desirable. Objective: To evaluate the safety and possible anatomic efficacy of oral minocycline, a microglial inhibitor, for the treatment of GA in AMD. Design, Setting, and Participants: This was a phase 2, prospective, single-arm, 45-month, nonrandomized controlled trial conducted from December 2016 to April 2023. Patients with GA from AMD in 1 or both eyes were recruited from the National Institutes of Health (Bethesda, Maryland) and Bristol Eye Hospital (Bristol, UK). Study data were analyzed from September 2022 to May 2023. Intervention: After a 9-month run-in phase, participants began oral minocycline, 100 mg, twice daily for 3 years. Main Outcomes and Measures: The primary outcome measure was the difference in rate of change of square root GA area on fundus autofluorescence between the 24-month treatment phase and 9-month run-in phase. Results: Of the 37 participants enrolled (mean [SD] age, 74.3 [7.6] years; 21 female [57%]), 36 initiated the treatment phase. Of these participants, 21 (58%) completed at least 33 months, whereas 15 discontinued treatment (8 by request, 6 for adverse events/illness, and 1 death). Mean (SE) square root GA enlargement rate in study eyes was 0.31 (0.03) mm per year during the run-in phase and 0.28 (0.02) mm per year during the treatment phase. The primary outcome measure of mean (SE) difference in enlargement rates between the 2 phases was -0.03 (0.03) mm per year (P = .39). Similarly, secondary outcome measures of GA enlargement rate showed no differences between the 2 phases. The secondary outcome measures of mean difference in rate of change between 2 phases were 0.2 letter score per month (95% CI, -0.4 to 0.9; P = .44) for visual acuity and 0.7 µm per month (-0.4 to 1.8; P = .20) for subfoveal retinal thickness. Of the 129 treatment-emergent adverse events among 32 participants, 49 (38%) were related to minocycline (with no severe or ocular events), including elevated thyrotropin level (15 participants) and skin hyperpigmentation/discoloration (8 participants). Conclusions and Relevance: In this phase 2 nonrandomized controlled trial, oral minocycline was not associated with a decrease in GA enlargement over 24 months, compared with the run-in phase. This observation was consistent across primary and secondary outcome measures. Oral minocycline at this dose is likely not associated with slower rate of enlargement of GA in AMD.

Oral minocycline for the treatment of retinitis pigmentosa-associated cystoid macular edema: results of a phase I/II clinical trial.

PURPOSE: The etiology of retinitis pigmentosa (RP)-associated cystoid macular edema (CME) has been related to retinal neuroinflammation and microglial activation. Minocycline, a drug FDA-approved for anti-microbial indications, also inhibits microglial activation and expression of inflammatory mediators. This study investigates the safety and efficacy of oral minocycline as primary treatment for RP-associated CME. METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with RP-associated CME. Participants had lead-in assessments prior to the initiation of oral minocycline 100 mg twice daily for 12 months. Main outcome variables included changes in best-corrected visual acuity (BCVA) and retinal central subfield thickness (CST) measured using spectral domain optical coherence tomography relative to mean of pre-treatment measurements. RESULTS: The study drug was well tolerated and not associated with any severe adverse events. No significant changes in mean BCVA from study baseline were noted in either the study eye (+ 0.7 ± 4.1 letters at 6 months, - 1.1 ± 1.7 letters at 12 months) or the qualifying fellow eye (- 0.3 ± 3.4 letters at 6 months, - 0.3 ± 4.6 letters at 12 months) (p > 0.05 for all comparisons). Mean percentage changes in CST from baseline however decreased progressively with treatment (decreases at 6 and 12 months: study eyes 3.9 and 9.8%; qualifying fellow eyes 1.4 and 7.7%). Considering all eyes (n = 10), mean percentage CST decrease at 6 and 12 months was 2.7 ± 9.5% (p = 0.39) and 8.7 ± 9.5% (p = 0.02) respectively. CONCLUSION: Oral minocycline administration over 12 months was associated with no significant changes in mean BCVA and a small but progressive decrease in mean CST. TRIAL REGISTRATION: NCT02140164 (05/2014).

Investigations of Renal Function and Age-Related Macular Degeneration Phenotypes.

Purpose: To investigate potential associations between renal function and age-related macular degeneration (AMD) features as assessed with multimodal retinal imaging. Methods: A subset of participants included in a dark adaptation study with varying AMD severities had estimated glomerular filtration rate (eGFR) values (mL/min/1.73 m2) obtained from renal function laboratory testing of serum creatinine and cystatin C. Multimodal imaging from visit dates associated with serum samples was graded by the Wisconsin Reading Center for AMD features. Associations of eGFR with AMD features and severity grades, age, smoker status and rod-intercept time were investigated. Simple univariate analyses, age-corrected multivariate analyses, and a feature-selecting least absolute shrinkage and selection operator regression were performed for eGFR as a continuous dependent variable. Results: A total of 110 patients (mean age, 75.1 ± 9.4 years; mean eGFR, 70.7 ± 18.2 mL/min/1.73 m2) were included. In univariate analyses age (estimate, -1.16 units/year; 95% confidence interval [CI], -1.46 to -0.87; P < 0.0001), rod-intercept time (estimate, -0.54 units/minute; 95% CI, -0.81 to -0.27; P < 0.001) and subretinal drusenoid deposits (-11.12 units for subretinal drusenoid deposit presence in either eye; 95% CI, -20.23 to -2.01; P = 0.017) were associated with decreased renal function. However, in age-corrected multivariate models, age was the only significant variable associated with renal function, confirmed by least absolute shrinkage and selection operator regression. Conclusions: Accounting for age, renal function parameters did not show an association with AMD features. Translational Relevance: Bruch's membrane of the eye and the glomerular basement membrane of the kidney share physiologic similarities such that decreased renal function may demonstrate associations with AMD phenotypes.

Assessment of Retinal Changes Following Intravitreal Aflibercept in 2 Patients With Von Hippel-Lindau Disease-Related Retinal Capillary Hemangioblastoma.

This case report of 2 patients describes peripheral Von Hippel-Lindau disease associated with a series of aflibercept injections.

Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30.

PURPOSE: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously. DESIGN: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2. PARTICIPANTS: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants). METHODS: Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale [person] and 9-step scale [eye]) and RPD presence simultaneously. MAIN OUTCOME MEASURES: Progression to late AMD, geographic atrophy (GA), and neovascular AMD. RESULTS: In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75-2.64). However, the risk associated with RPD presence differed at different severity scale levels: HR, 3.23 (95% CI, 1.60-6.51), HR, 3.81 (95% CI, 2.38-6.10), HR, 2.28 (95% CI, 1.59-3.27), and HR, 1.64 (95% CI, 1.20-2.24), at levels 0-1, 2, 3, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: HR, 2.54 (95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90-1.56); by eye, it was HR, 1.57 (95% CI, 1.31-1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD. CONCLUSIONS: Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.

Comparison of agents using higher dose anti-VEGF therapy for treatment-resistant neovascular age-related macular degeneration.

PURPOSE: To explore the comparative efficacy and safety of higher dose intravitreal bevacizumab, ranibizumab, or aflibercept for treatment-resistant neovascular age-related macular degeneration (nAMD). METHODS: Retrospective analysis of 37 eyes of 35 patients with treatment-resistant nAMD divided into 3 cohorts based on high-dose treatment received: 3 mg aflibercept, 0.75 mg or 1.0 mg ranibizumab, and 1.8 mg or 2.5 mg bevacizumab. The eyes were analyzed at standardized time points up to 48 months. Included eyes demonstrated active nAMD with persistent exudation on imaging for at least 6 months with at least 4 anti-VEGF injections during this time. Outcomes included change in visual acuity (VA), central retinal thickness (CRT), intraocular pressure (IOP), retinal morphology, adverse event occurrence, and yearly intravitreal injection (IVI) rate. RESULTS: There was no significant difference in VA or IOP change compared to the initiation of high-dose treatment for any agent or comparing between agents at any time point (p > 0.05). CRT improved at month 1, 3, 6, and 12 with all 3 agents (p < 0.05 for all) with a greater CRT reduction seen for ranibizumab than aflibercept at month 6 (p < 0.05), although baseline CRT was greater in the ranibizumab group than the aflibercept group (p < 0.05). Mean absolute CRT was similar at month 6 for all agents (p > 0.05). IVI rates pre- and post-conversion to higher-dose therapy were similar (1 injection per 5.7-6.4 weeks). Mean follow-up was 22.8 months. CONCLUSIONS: Higher dose therapy may achieve improved anatomic outcomes and maintain vision, but frequent injections are required to achieve this. There was no detected difference in efficacy or safety between agents.

Intravitreous treatment of severe ocular von Hippel-Lindau disease using a combination of the VEGF inhibitor, ranibizumab and PDGF inhibitor, E10030: Results from a phase 1/2 clinical trial.

BACKGROUND: Treatment options for severe ocular von Hippel-Lindau (VHL) disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation. METHODS: This was a prospective, single-arm, open-label phase 1/2 study, comprised of three adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52. RESULTS: Three participants each received nine injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12 and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52. CONCLUSIONS: Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.

Age-Related Macular Degeneration: Epidemiology and Clinical Aspects.

Age-related macular degeneration (AMD) is a degenerative disease of the human retina affecting individuals over the age of 55 years. This heterogeneous condition arises from a complex interplay between age, genetics, and environmental factors including smoking and diet. It is the leading cause of blindness in industrialized countries. Worldwide, the number of people with AMD is predicted to increase from 196 million in 2020 to 288 million by 2040. By this time, Asia is predicted to have the largest number of people with the disease. Distinct patterns of AMD prevalence and phenotype are seen between geographical areas that are not explained fully by disparities in population structures. AMD is classified into early, intermediate, and late stages. The early and intermediate stages, when visual symptoms are typically absent or mild, are characterized by macular deposits (drusen) and pigmentary abnormalities. Through risk prediction calculators, grading these features helps predict the risk of progression to late AMD. Late AMD is divided into neovascular and atrophic forms, though these can coexist. The defining lesions are macular neovascularization and geographic atrophy, respectively. At this stage, visual symptoms are often severe and irreversible, and can comprise profoundly decreased central vision in both eyes. For these reasons, the condition has major implications for individuals and society, as affected individuals may experience substantially decreased quality of life and independence. Recent advances in retinal imaging have led to the recognition of an expanded set of AMD phenotypes, including reticular pseudodrusen, nonexudative macular neovascularization, and subtypes of atrophy. These developments may lead to refinements in current classification systems.

Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial.

This study explored systemic immune changes in 11 subjects with X-linked retinoschisis (XLRS) in a phase I/IIa adeno-associated virus 8 (AAV8)-RS1 gene therapy trial (ClinicalTrials.gov: NCT02317887). Immune cell proportions and serum analytes were compared to 12 healthy male controls. At pre-dosing baseline the mean CD4/CD8 ratio of XLRS subjects was elevated. CD11c+ myeloid dendritic cells (DCs) and the serum epidermal growth factor (EGF) level were decreased, while CD123+ plasmacytoid DCs and serum interferon (IFN)-γ and tumor necrosis factor (TNF)-α were increased, indicating that the XLRS baseline immune status differs from that of controls. XLRS samples 14 days after AAV8-RS1 administration were compared with the XLRS baseline. Frequency of CD11b+CD11c+ DCc was decreased in 8 of 11 XLRS subjects across all vector doses (1e9-3e11 vector genomes [vg]/eye). CD8+human leukocyte antigen-DR isotype (HLA-DR)+ cytotoxic T cells and CD68+CD80+ macrophages were upregulated in 10 of 11 XLRS subjects, along with increased serum granzyme B in 8 of 11 XLRS subjects and elevated IFN-γ in 9 of 11 XLRS subjects. The six XLRS subjects with ocular inflammation after vector application gave a modestly positive correlation of inflammation score to their respective baseline CD4/CD8 ratios. This exploratory study indicates that XLRS subjects may exhibit a proinflammatory, baseline immune phenotype, and that intravitreal dosing with AAV8-RS1 leads to systemic immune activation with an increase of activated lymphocytes, macrophages, and proinflammatory cytokines.

Systemic Sunitinib Malate Treatment for Advanced Juxtapapillary Retinal Hemangioblastomas Associated with von Hippel-Lindau Disease.

PURPOSE: To describe the clinical course of advanced juxtapapillary retinal capillary hemangioblastomas (RCH) associated with von Hippel-Lindau (VHL) disease treated with systemic sunitinib malate, an agent that inhibits both anti-vascular endothelial growth factor and anti-platelet-derived growth factor signaling. DESIGN: Observational case review. PARTICIPANTS: Three patients with advanced VHL-related juxtapapillary RCH treated with systemic sunitinib malate. METHODS: Patient 1 was followed routinely every 4 months while on systemic sunitinib prescribed by her oncologist for metastatic pancreatic neuroendocrine and kidney tumors. Patients 2 and 3 were part of a prospective clinical trial evaluating the use of systemic sunitinib for ocular VHL lesions during a period of 9 months. Visual acuity, size of RCH, and degree of exudation were recorded at each visit. Optical coherence tomography (OCT) and fluorescein angiography were also obtained at some visits. MAIN OUTCOME MEASURES: Visual acuity, size of RCH, and degree of exudation. RESULTS: Three patients with advanced VHL-associated juxtapapillary RCH were treated with systemic sunitinib malate. While none of the patients lost vision during therapy, treatment with sunitinib malate did not improve visual acuity or reduce the size of RCH. Improvements in RCH-associated retinal edema were observed in two patients. All patients experienced multiple adverse effects, including thyroid toxicity, thrombocytopenia, nausea, fatigue, jaundice, and muscle aches. Two of the three patients had to discontinue treatment prematurely and the third required dose reduction. CONCLUSIONS: Systemic sunitinib malate may be useful in slowing progression of ocular disease from VHL-associated RCH. However, significant systemic adverse effects limited its use in this small series, and systemic sunitinib malate may not be safe for treatment of RCH when used at the doses described in this report. Further studies are required to determine if this medication used at lower doses with different treatment strategies, other medications in the same class or drugs directed at multiple targets in the tumor, may be safer and more effective for the treatment of advanced VHL-associated RCH.

A Crossover Design for Comparative Efficacy: A 36-Week Randomized Trial of Bevacizumab and Ranibizumab for Diabetic Macular Edema.

PURPOSE: To investigate the comparative efficacy of bevacizumab (Avastin) and ranibizumab (Lucentis; both Genentech, Inc, South San Francisco, CA) for diabetic macular edema (DME) using a crossover study design. DESIGN: Randomized, double-masked, 36-week, 3-period crossover clinical trial. PARTICIPANTS: Fifty-six subjects with DME involving the center of the macula in one or both eyes. METHODS: Monthly intravitreous injections of bevacizumab (1.25 mg) or ranibizumab (0.3 mg). MAIN OUTCOME MEASURES: Comparison of mean changes in visual acuity and central retinal thickness, tested using a linear mixed-effects model. RESULTS: Based on the linear mixed-effects model, the 3-month estimated mean improvement in visual acuity was 5.3 letters for bevacizumab and 6.6 letters for ranibizumab (difference, 1.3 letters; P = 0.039). Estimated change in optical coherence tomography (OCT) central subfield mean thickness (CSMT) was -89 µm for bevacizumab and -137 µm for ranibizumab (difference, 48 µm; P < 0.001). Incorporating cumulative treatment benefit, the model yielded a predicted 36-week (9-month) average improvement in visual acuity of 7.1 letters (95% confidence interval [CI], 5.0-9.2) for bevacizumab and 8.4 letters (95% CI, 6.3-10.5) for ranibizumab, and a change in OCT CSMT of -128 µm (95% CI, -155 to -100) for bevacizumab and -176 µm (95% CI, -202 to -149) for ranibizumab. There was no significant treatment-by-period interaction (i.e., treatment difference was constant in all 3 periods), nor was there a significant differential carryover effect from one period to the next. CONCLUSIONS: This trial demonstrated a statistically significant but small relative clinical benefit of ranibizumab compared with bevacizumab for treatment of DME, using a markedly reduced sample size relative to a full comparative efficacy study. The effects on visual acuity and central retinal thickness for the 2 drugs are consistent with those reported at 1 year for the concurrent parallel-group trial by the Diabetic Retinopathy Clinical Research Network testing bevacizumab, ranibizumab, and aflibercept for DME. The 3-period crossover design allowed for meaningful and efficient comparison, suggesting that this approach may be useful for future comparative efficacy studies of anti-vascular endothelial growth factor drugs for DME.

Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study.

PURPOSE: Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME. METHODS: A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA). RESULTS: Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by -2.9%, -5.7%, -13.9, and -8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by -34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors. CONCLUSIONS: In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. (ClinicalTrials.gov number, NCT01120899.).