Purpose:To report efficacy of intravitreal pegcetacoplan treatment over 36 months in eyes with subfoveal geographic atrophy (GA). Patients and Methods:The GALE (NCT04770545) open-label extension trial adds 12 months of results to the 24-month Phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) trials, representing up to 36 months of continuous pegcetacoplan treatment. They included a heterogeneous population of eyes with subfoveal GA (63%). Pegcetacoplan-treated eyes enrolling in GALE continued at the same interval of pegcetacoplan monthly (PM) or every other month (PEOM). Patients' eyes in sham monthly or every-other-month arms crossed over to receive pegcetacoplan in GALE at the same interval (sham crossover). Consequently, projected sham, calculated from prior 24-month GA growth rate of sham-observed eyes in OAKS and DERBY averaged across four 6-month segments, was the comparator for the first 12 months of GALE (months 24-36). This analysis reports results of eyes with subfoveal GA at baseline. Results:In eyes with subfoveal GA, 84% had best corrected visual acuity (BCVA) ≥20/200 and 38% had BCVA ≥20/63 at OAKS and DERBY baseline. Pegcetacoplan reduced subfoveal GA growth rate by 21% (p<0.0001) with PM and 19% (p=0.0001) with PEOM over 36 months. Increasing efficacy over time was noted between months 24 and 36; 31% reduction in subfoveal GA growth rate with PM and 25% reduction with PEOM (both p<0.0001) compared with projected sham. Microperimetry demonstrated significant reduction in formation of absolute scotomas with PM at 24 months (-2.5 number of scotomas formed; 95% confidence interval [CI]: -4.5, -0.4; p=0.0205) and 36 months (-4.0 number of scotomas formed; 95% CI: -6.8, -1.2; p=0.0050), compared to sham crossover in subfoveal GA. Safety profile in GALE was consistent with OAKS and DERBY. Conclusion:Long-term efficacy of pegcetacoplan in slowing GA progression was demonstrated over 36 months in eyes with subfoveal GA.
Macular leakage (ML) is a biomarker of disease activity and, in retinal vein occlusion (RVO), is associated with poor vision outcomes. Faricimab, a dual angiopoietin-2 (Ang-2)/vascular endothelial growth factor (VEGF)-A inhibitor, has demonstrated efficacy and durability in RVO. This post hoc analysis of BALATON/COMINO examined the association between week 24 ML resolution and extended faricimab dosing intervals and vision outcomes achieved at week 68 in patients with RVO. BALATON and COMINO (NCT04740905/NCT04740931) were identically designed, phase 3, randomized trials that evaluated the efficacy and safety of faricimab in patients with branch or central/hemiretinal RVO, respectively. Patients initially received faricimab 6 mg every 4 weeks (Q4W) or aflibercept 2 mg Q4W; then from weeks 24–72, all patients received faricimab 6 mg up to Q16W according to a modified treat-and-extend regimen. This analysis included patients who remained in the study at week 68 and had a fluorescein angiography ML reading at week 24. Among 989 patients, 502 had ML resolution (≤ 1 mm2) and 143 had high ML (≥ 10 mm2) at week 24. The proportion of patients who achieved ≥ Q12W faricimab dosing at week 68 was higher among those with ML resolution at week 24 versus those with high ML at week 24 (56.1
STUDY QUESTION:Are segmental aneuploidies identified in human embryos more likely to occur within known fragile sites of the genome? SUMMARY ANSWER:Segmental breaks in the autosomes of human preimplantation embryos occur more frequently in known fragile areas of the genome. WHAT IS KNOWN ALREADY:Fragile sites represent specific loci in the genome characterized by inhibition of DNA synthesis when exposed to known inhibitors and are particularly sensitive to replication stress and instability. STUDY DESIGN, SIZE, DURATION:This was a retrospective analysis of single nucleotide polymorphism (SNP) array-based preimplantation genetic testing data from biopsies performed on 2066 human blastocysts in 98 assisted reproduction laboratories around the world from September 2019 to January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS:This multicenter study included eligible patients undergoing IVF with preimplantation genetic testing (PGT), in which at least one embryo was diagnosed with a segmental aneuploidy. The mean maternal age was 36.4 years (SD 4.1), ranging from 25 to 44 years. These samples were processed on high-density SNP arrays. Chromosome level copy number and B allele frequency (BAF) plots from these embryos were used to determine segmental aneuploidy breakpoints. Known fragile sites catalogued by the HumCFS database were used for correlation analyses. MAIN RESULTS AND THE ROLE OF CHANCE:Overall, a side-by-side pairing of observed breakpoints and known fragile sites demonstrated a strong concordance (r = 0.81, 95% CI [0.6, 0.92]). A chi-square test for independence for stratified groups showed a highly significant correlation between all observed breakpoints and known fragile sites (597 expected vs. 848 observed; P < 0.001) and for telomeric breaks alone (521 expected vs. 784 observed; P < 0.001). Observed interstitial breaks alone were not correlated to expected breakpoints (75 expected vs. 64 observed; P > 0.05). LIMITATIONS, REASONS FOR CAUTION:These findings should be interpreted with caution, as limitations in genomic resolution may bias detection and classification of smaller segmental aneuploidies. Additionally, this study touched upon the distribution of meiotic to mitotic breakpoints in human blastocysts as they relate to known fragile sites. Since meiotic aneuploidies increase with advanced maternal age and many IVF patients undergoing PGT-A testing fall in this category, a sampling bias should be considered for this specific metric. WIDER IMPLICATIONS OF THE FINDINGS:Demonstrating that segmental aneuploidies significantly correlate with known fragile sites highly susceptible to replication stress offers insight into the origin of subchromosomal imbalances and hints at the influence of stressors on reproductive success. STUDY FUNDING/COMPETING INTEREST(S):This study received no external funding and was fully supported by the participating authors and their affiliated institutions. The authors declare no conflicts of interest related to this study. TRIAL REGISTRATION NUMBER:N/A.
In 2024, the American Society of Retina Specialists (ASRS) Research and Safety in Therapeutics (ReST) Committee became aware of reports of coring of vial stoppers in relation to preparation of intravitreal injections. A literature review was performed to further understand and characterize this occurrence within the context of retina practice and the broader medical community. Relevant articles were identified through a systematic search of PubMed using predefined criteria. Coring can be observed when a needle punctures the rubber stopper of a medication vial, pushing a small piece or pieces of the stopper material into the container and introducing extrinsic particles into the drug product. Factors associated with coring include larger gauge needles, perpendicular needle entry, multiple-use vials, and thicker rubber stoppers. Rubber stopper thickness and composition also influence the likelihood of coring. To prevent patient safety issues from coring, filter needles are commonly used to draw up medications from vials because they are effective in mitigating particulate matter from entering syringes. No documented cases of clinical complications related to coring in ophthalmology have been identified. Coring represents an unreported phenomenon in the preparation of intraocular medications. Although there have been no safety implications in retina practice related to coring and intravitreal drug vials, these reports underscore the importance of careful medication preparation, inspection of vials, the use of appropriate needles, and adherence to best clinical practices.
Importance:Frequent prophylactic intravitreal anti-vascular endothelial growth factor injections can reduce risk of progression to vision-threatening complications in nonproliferative diabetic retinopathy (NPDR). A refillable drug delivery system for continuous intraocular ranibizumab release could offer less frequent treatment regimens. Objective:To evaluate the Port Delivery System (PDS) with ranibizumab, 100 mg/mL, with refill-exchange procedures every 36 weeks (PDS Q36W), vs no PDS (control) in moderately severe to severe NPDR without center-involved diabetic macular edema (CI-DME), monitoring both groups every 4 weeks. Design, Setting, and Participants:This was a randomized clinical trial at 50 US investigational sites. Participants aged 18 years or older with moderately severe or severe NPDR (Diabetic Retinopathy Severity Scale [DRSS] level 47 or 53) secondary to type 1 or 2 diabetes were eligible. Data analysis was performed from August 10, 2020, to October 3, 2022. Intervention:Participants were randomized (unmasked) 5:3 to PDS Q36W vs control. Both groups could receive intravitreal ranibizumab injections if CI-DME, proliferative diabetic retinopathy (PDR), or anterior segment neovascularization (ASNV) developed. Main Outcomes and Measures:Proportion of participants with an improvement of at least 2 levels in Early Treatment Diabetic Retinopathy Study DRSS from baseline at week 52. Results:A total of 174 participants (mean [SD] age, 53.9 [11.7] years; 74 [42.5%] female) were randomized to PDS Q36W (n = 106) or control (n = 68). At week 52, 80.1% of those receiving PDS Q36W vs 9.0% of control participants had at least a 2-step DRSS improvement from baseline (difference, 71.1% [95% CI, 61.0% to 81.2%]; P < .001). Secondary outcomes included rate of development of CI-DME, PDR, or ASNV through week 52 (PDS Q36W, 7.1%; control, 47.0%; hazard ratio, 0.12 [95% CI, 0.05 to 0.28]; P < .001) and best-corrected visual acuity (BCVA) change from baseline to week 52 (+1.4 letters [95% CI, -0.5 to 3.3 letters] for those receiving PDS Q36W vs -2.6 letters [95% CI, -5.0 to -0.1 letters] for control participants; difference, 4.0 letters [95% CI, 0.9 to 7.1 letters]; P = .01). The PDS Q36W group had a transient BCVA decrease of 7.4 letters (95% CI, -10.3 to -4.5 letters) at 4 weeks after implantation, resolving 8 weeks later. Ocular adverse events of special interest occurred in 17 of 105 participants (16.2%) receiving PDS Q36W (cataract, 7 participants [6.7%]; vitreous hemorrhage, 6 participants [5.7%]; conjunctival bleb, conjunctival retraction, and hyphema, each 2 participants [1.9%]; conjunctival erosion and retinal detachment, each 1 participant [1.0%]), with no endophthalmitis reported through week 52. Conclusions and Relevance:At 1 year, PDS Q36W resulted in substantially more participants achieving at least a 2-step DRSS improvement and a reduced risk of developing CI-DME, PDR, or ASNV compared with control participants, with safety outcomes consistent with previous reports. These findings should be balanced with the transient, postoperative decrease in BCVA 4 through 12 weeks after implantation and the need for longer-term BCVA and safety outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT04503551.
