Purpose: To report maculopathy associated with the long-term use of fondaparinux, a heparin mimetic and inhibitor of the extracellular matrix enzyme, heparanase. Observations: A 41-year-old woman receiving thrice weekly injections of fondaparinux as prophylaxis against deep vein thrombosis for 9 years noticed gray spots in her vision without metamorphopsias. On exam, there was bilateral altered macular pigmentation with speckled hyperpigmentation. Optical coherence tomography revealed irregular thickening of the retinal pigment epithelium. Blue autofluorescence photography demonstrated symmetric well-defined plaques of hyper-and hypoautofluorescence similar to those described in patients chronically treated with pentosan polysulfate (PPS). Review of 13 years of outside medical records confirmed no prior treatment with PPS. Two years before, optical coherence tomography (OCT) done as part of routine eye examination showed early pigmentary changes which were not felt to be clinically significant. Inherited retinal gene panel testing and mitochondrial DNA testing did not reveal pathogenic variants associated with pattern dystrophies. The maculopathy was attributed to fondaparinux due to a pharmacologic effect shared with PPS of heparanase inhibition. Thirteen months after stopping fondaparinux, there was a significant reduction in macular pigmentary changes and improvement in outer retinal abnormalities on OCT. Conclusions and importance: Fondaparinux is structurally and functionally related to PPS, which is also a heparin mimetic and heparanase inhibitor. Both drugs are now associated with phenotypically similar disruptions of the macular retinal pigment epitheliopathy. Although used for different clinical indications, both fondaparinux and PPS are sulfated oligosaccharides related to heparin that bind and inhibit heparanase, a critical enzyme in the extracellular matrix. This case is relevant for research into pharmacologic uses of heparanase inhibitors and monitoring for retinal disease in patients treated with them.
PURPOSE:To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS:A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS:Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION:These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.
Purpose:Sozinibercept inhibits vascular endothelial growth factors (VEGFs) C and D. This study evaluated outcomes following switching from anti-VEGF-A monotherapy to intravitreal injections of three dose levels of sozinibercept in combination with aflibercept in patients with diabetic macular edema (DME). Methods:A phase 1b, open-label, multicenter dose-escalation study with a 24-week follow-up. Patients received 3 loading doses of aflibercept (2 mg) in combination with sozinibercept (0.3, 1, or 2 mg) once every 4 weeks and were followed through week 24. The primary endpoint was safety, and secondary endpoints included mean change from baseline in best-corrected visual acuity (BCVA) and anatomic changes on imaging. Results:Nine patients received sozinibercept in combination with aflibercept after a mean (SD) of 6.3 (2.4) injections of previous anti-VEGF-A. Sozinibercept combination therapy was well tolerated with no dose-limiting toxicities. Mean change in BCVA at week 12 was +7.7 letters (95% confidence interval [CI], 2-13.3) from baseline (65 letters [SD 5.5]) with a dose response for increasing doses of sozinibercept. At week 12, central subfield thickness (CST) was decreased by -71 µm (95% CI, -117 to -26) from baseline (434 µm [SD 58]), and 6 of 9 (67%) patients had a ≥50% reduction in excess foveal thickness. Conclusions:In prior-treated patients with center-involved DME, switching to sozinibercept in combination with aflibercept was well tolerated with improved visual and anatomic outcomes. Translational Relevance:This first-in-human study builds upon basic research by providing safety and preliminary efficacy of sozinibercept (anti-VEGF-C/-D) in combination with aflibercept for DME.
