What’s Next in Wet AMD?
“It’s important to understand where we’re going, by looking at what we currently have,” said presenter Peter Kaiser, MD. He cited access to VEGF pathway inhibitors (VEGF-A, VEGF-B, and placental growth factor) as well as approved biosimilars for ranibizumab. In clinical testing are bevacizumab biosimilars that are specifically for use in ophthalmology, as well as aflibercept biosimilars. To decrease treatment burden, one approach is to increase the dose given, and Dr. Kaiser said that in the aflibercept 8 mg dose studies, in year 2, at the last treatment interval, almost 25% to 30% of patients were at q6 month intervals. When blocking VEGF-A, VEGF-C is upregulated. OPT-302 (sozinibercept; Opthea) is in development as an inhibitor of VEGF-C and VEGF-D. Sustained release strategies with gene therapy are being looked at, such as ABBV-RGX-314 (Regenxbio).
There are also gene therapy approaches in wet AMD for inhibitors of VEGF-A, VEGF-B, and placental growth factor. Tyrosine kinase inhibitors, such as OTX-TKI (Ocular Therapeutix) and EYP-1901 (Eyepoint Pharmaceuticals), are starting to show real results in ophthalmology. Tie2 pathways are activated by blocking Ang2, but Ang1 then needs to reactivate Tie2 receptors, and a drug is in development for that as well. The talk concluded with information on senescent cells, which lead to growth factors being released, and the cells releasing cytokines, so reducing these cells could lead to better outcomes, which is also being tested.
Real-world Outcomes and Treatment Patterns With Faricimab in AMD
Sophie Bakri, MD, discussed the FARETINA study, a retrospective study that used data from the IRIS registry to look at real-world experience of patients with neovascular AMD, treated with faricimab (Vabysmo; Genentech). At the time of faricimab initiation, approximately half of the eyes had 20/40 or better vision, and of previously treated eyes, 66% had been switched from aflibercept. The real-world effectiveness outcomes showed stable vision in previously treated eyes, and vision improvement in treatment-naïve eyes. Central subfield thickness decreased over 3 to 6 months, as did injection frequency, and more than 50% of eyes extended after 1 to 2 injections of faricimab. The incidence of endophthalmitis was consistent with the overall safety profile.
Long-term Results of Anti-VEGF Therapy for Central and Branch Retinal Vein Occlusion: An Overview of Current Data
Michael Ip, MD, said that knowledge gaps exist regarding long-term results of anti-VEGF therapy for retinal vein occlusion (RVO), including: is there a reduction in visual acuity (VA) from baseline, or is there an improvement in stabilization of VA; how frequently do the anti-VEGF injections need to be given over an extended period of time; and does RVO resolve or does it act more like a chronic disease? Dr. Ip discussed a database analysis he had performed with colleagues, on long-term VA outcomes with anti-VEGF for macular edema secondary to CRVO and BRVO. The study was undertaken to evaluate VA outcomes and treatment patterns over a 5-year period, and was a retrospective observational study using the Vestrum Health Database from 2014 to 2021. There were 22,365 eyes in the branch RVO group and 18,064 in the central RVO group. The study found long-term anti-VEGF therapy for RVO results in highly improved VA outcomes compared with vision at initiation of treatment, although there is attenuation of the initial gains over time. There is also a reduction in the frequency of anti-VEGF therapy provided. Dr. Ip said the main takeaway points are that both central and branch RVO require continued monitoring for many years to minimize the attenuation of VA gains, and it should be recognized that both are not acute conditions but should be seen as chronic diseases.
The Wisconsin Silicone Oil Vitrectomy Study: Anatomical and Vision Outcomes of Complex Retinal Detachment Repair
The most common indication for use of silicone oil tamponade, according to Michael Altaweel, MD, is a primary retinal detachment repair that was performed with gas and failed. He said oil provides a long-term tamponade that keeps the retina in the correct place until you’re comfortable the oil can be removed. It can mitigate the tractional effects of proliferative vitreoretinopathy (PVR), supports the inferior retina, and may be useful for patients with monocular status, occupational consideration, or the need to travel. The University of Wisconsin Oil Study was a retrospective study of 315 consecutive silicone oil placement surgeries from 2013 to 2019, in 231 eyes, using 1000 centistoke oil. For anatomic outcome there was a mean of 26 months follow-up. Final complete attachment was achieved in 82% of eyes. 70 eyes (32%) redetached under oil, and when oil is removed there is a rate of nearly 30% redetachment, so patients often needed multiple surgeries, with the average being 2.7 per patient. At the end of the series, 45% needed to retain the oil to keep the retina attached. For vision outcome, Dr. Altaweel said the most important point they found was in those that had a prior repair with gas that failed, and then a second surgery with oil, there was a gain of 4.6 lines, and 67% achieved the benchmark of 5/200 or better.
ALTITUDE: Suprachoroidal Delivery of ABBV-RGX-314 Investigational Gene Therapy for Diabetic Retinopathy
Mark Barakat, MD, presented 1-year results of the phase 2 ALTITUDE study, dose levels 1 and 2. He said the goal of a 1-time, in-office injection of gene therapy is to stabilize disease severity in diabetic retinopathy (DR) and perhaps improve it, and reduce the risk of vision-threatening complications. ABBV-RGX-314 (Regenxbio) is an AAV8 vector encoding anti-VEGF monoclonal antibody fragment, with the potential for long-term therapeutic anti-VEGF expression. The ALTITUDE phase 2 trial looked at patients with severe, moderately severe, or mild proliferative diabetic retinopathy without DME. They received the single in-office injection, and were followed for 1 year, with a primary endpoint of 2-step or greater improvement in Diabetic Retinopathy Severity Scale scores. Dose levels 1 and 2 were both well tolerated. The study found ABBV-RGX-314 demonstrated clinically meaningful improvements in disease severity and reduction of vision-threatening events in patients with nonproliferative diabetic retinopathy, and notably, for dose level 2, 100% of patients demonstrated stable to improved disease severity.
A 12-week Phase 2/3 Double-Masked, Randomized, Multicenter Study of OCS-01 Eye Drops in Diabetic Macular Edema
Hani Salehi-Had, MD, presented data on OCS-01 (Oculis), which is aiming to be the first eye drop developed for the treatment of diabetic macular edema (DME). The DIAMOND study evaluated OCS-01 in patients with DME. The primary endpoint was change in best-corrected visual acuity (BCVA) from baseline to week 6. Also evaluated were mean change in BCVA from baseline at 12 weeks, percentage of patients with a 3-line or greater gain in BCVA at 6 and 12 weeks, and mean change in central subfield thickness. Patients on OCS-01 had a significant improvement in mean BCVA of 7 letters at week 6 and 7.6 letters at week 12 vs. vehicle. In addition, 25.3% of patients on OCS-01 gained 3 lines or greater at week 6, and 27.4% at week 12. There was a significant decrease in central macular thickness after two weeks of use of OCS-01, which was maintained through the 12 weeks. OCS-01 was well tolerated. Dr. Salehi-Had summarized saying OCS-01 has the potential to address the unmet need of a non-invasive treatment for DME.
Treatment of Geographic Atrophy Secondary to AMD With Intravitreal ANX007, a Selective Classical Complement Inhibitor: Results of the ARCHER Study
According to presenter David Lally, MD, C1q is the initiating molecule of the classical complement cascade and a key driver of neurodegenerative disease. He said C1q localizes on photoreceptor cell synapses, and anchors the classical cascade activation, leading to microglial cell removal of those synapses, along with neural inflammation and photoreceptor loss. Inhibiting C1q will block all downstream components of the classical cascade to protect photoreceptor synapses. ANX007 (Annexon) is a differentiated inhibitor of C1q and classical component to treat geographic atrophy.
ARCHER is a phase 2 trial of ANX007 (monthly or every other month) vs sham. Both foveal and nonfoveal lesions were included and choroidal neovascularization in the fellow eye was permitted. The primary endpoint was mean change in GA lesion size at month 12, and secondary endpoints included best-corrected visual acuity, low-luminance visual deficit, and low-luminance visual acuity. Treatment with ANX007 in the monthly treatment arm showed a nonsignificant 6% reduction in lesion growth at month 12. However, treatment did demonstrate greater growth reductions in the second 6 months than in the first 6 months, which Dr. Lally said suggests lesion reduction may grow over time. He said what is “particularly compelling” in the ARCHER study are the findings from the prespecified visual acuity analyses, where treatment with ANX007 demonstrated a significant dose-dependent protection against vision loss, defined as 15 letters or greater at 2 consecutive visits or at month 12. In the time to event analysis, there was a 72% risk reduction with 15-letter loss in month 12 with the monthly dose, and a 48% risk reduction with every other month treatment. ANX007 was generally well tolerated.
Aflibercept 8 mg in Patients With Neovascular AMD: Phase 3 PULSAR Trial 96-Week Results
The PULSAR trial is a multicenter, randomized, double-masked study in patients with treatment-naïve wet age-related macular degeneration that compared aflibercept 2 mg (Eylea HD; Regeneron) every 8 weeks, to aflibercept 8 mg (Eylea; Regeneron) every 12 weeks or every 16 weeks. The primary endpoint was mean change in best-corrected visual acuity at week 48, and the end of the study was at week 96, which is what Jean-Francois Korobelnik, MD, presented. The study found at 96 weeks the aflibercept 8 mg groups achieved similar BCVA gains compared with the aflibercept 2 mg group.
Anatomic improvements in PULSAR for aflibercept 8 mg were maintained through week 96. At the end of the 96 weeks, 78% of patients randomized to receive aflibercept 8 mg q16 achieved every 16 weeks or greater dosing intervals and 53% achieved intervals of every 20 weeks or greater. There were some instances of intraocular inflammation but the safety profile of aflibercept 8 mg was comparable to that of aflibercept 2 mg over 96 weeks.
Aflibercept 8 mg for Diabetic Macular Edema: 96-week Results From the Phase 2/3 PHOTON Trial
Dr. Diana Do shared 96-week results of the PHOTON trial, a global, randomized clinical trial evaluating aflibercept 8 mg dosed every 12 weeks or every 16 weeks after 3 initial monthly doses, compared to aflibercept 2 mg dosed on-label. The primary endpoint was mean change in best-corrected visual acuity (noninferiority) at week 48. Dr. Do said both 8 mg aflibercept treatment groups met the primary endpoint and had similar visual acuity improvements compared to the 2 mg aflibercept group. A large majority of the aflibercept 8 mg group maintained their randomized dosing intervals through 1 year (91% of the 8 mg q12 group and 89% of the 8 mg q16 group). Both aflibercept 8 mg groups had similar achievements in improvement in visual acuity that were sustained through 2 years, and were comparable to that of aflibercept 2 mg. A large majority of aflibercept 8 mg patients (88% of the q12 group and 84% of the q16 group) maintained their dosing intervals through baseline and 96 weeks. Aflibercept 8 mg was very safe, with comparable rates of intraocular inflammation which were very low, and similar to that of aflibercept 2 mg. Dr. Do said the study showed aflibercept 8 mg, whether dosed every 12 weeks or every 16 weeks, resulted in similar visual acuity gains as 2 mg aflibercept, and patients were able to maintain their randomized dosing intervals.
48-week End of Study Results from BEHOLD Phase 2 Study of UBX1325 in Patients With DME
Veeral Sheth, MD, explained that senescent cells are stressed cells that are no longer dividing but are metabolically active cells that drive pathology, and they accumulate in areas of disease activity. They secrete inflammatory factors, and they do not form tight junctions with neighboring healthy endothelial cells. UBX1325, which is being tested in the BEHOLD study, selectively triggers the cell death of senescent endothelial cells, reducing retinal inflammation and leakage. Preclinical data have shown that this can lead to disease modification through vascular remodeling. The BEHOLD study looked at previously treated diabetic macular edema patients who had averaged 4.1 injections over the prior 6 months. They were randomized in the study to receive UBX1325 or sham. Primary endpoint was at 24 weeks, and Dr. Sheth presented here the 48-week end-of-study data. Efficacy results showed significantly improved visual acuity at 48 weeks by 6.2 letters from baseline after a single injection, compared to 0.6 letters in the sham group, and 53% of patients achieved a rescue-free interval of at least 48 weeks, which Dr. Sheth said may represent the potential for disease modification. UBX1325 demonstrated a favorable overall safety and tolerability profile, with no instances of intraocular inflammation, endophthalmitis, retinal artery occlusions, or vasculitis.
Tarcocimab Tedromer for Diabetic Retinopathy: Primary Endpoint Efficacy and Safety Outcomes of the GLOW Phase 3 Pivotal Study
KSI-301 (tarcocimab tedromer; Kodiak Sciences) is an anti-VEGF antibody biopolymer conjugate that blocks all VEGF-A isoforms. The GLOW study is a randomized, double-masked phase 3 superiority study of KSI-301 5 mg vs sham, involving 253 patients with moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The primary endpoint, at 48 weeks, was the proportion of eyes improving 2 or more steps in the Diabetic Retinopathy Severity Scale (DRSS) from baseline, with key secondary endpoints of proportion of eyes developing sight-threatening complications, and proportion of eyes improving 3 or more steps in DRSS from baseline. The data, reported at this session by Charles Wykoff, MD, PhD, showed that the primary endpoint was met, tarcocimab established superiority in 2-step or greater improvement in DRSS being achieved in 41.1% compared to 1.4% in the sham group. The secondary endpoint of 3 or more steps improvement in DRSS was also achieved with 5.6% in the treatment group and 0% in the sham group. The other key secondary endpoint was also met, as there was a superiority in reduction of development of sight-threatening complications. Tarcocimab was safe and well tolerated.
Long-term Efficacy and Safety of Pegcetacoplan Over 36 Months: Results From 12 Months of the GALE Open-label Extension Study
GALE is a 3-year open-label extension study following the 2-year OAKS and DERBY studies of pegcetacoplan (Syfovre; Apellis Pharmaceuticals) for treatment of geographic atrophy (GA). Jeffrey Heier, MD, said 83% of patients who completed OAKS and DERBY continued on to GALE, resulting in almost 800 patients in the extension study. Patients in the sham arms crossed over to active treatment either monthly or every other month, based on their original regimen. Patient retention in the first year of GALE was 92%. The results showed pegcetacoplan, both monthly and every other month, had increasing effects over time, with reductions in GA growth of 35% and 24%, respectively, between months 24 and 36. Functional benefits that were observed on microperimetry in OAKS correlated with best-corrected visual acuity outcomes. Safety in GALE has been similar to what was observed in OAKS and DERBY.
GATHER2: 2-year Data
Avacincaptad pegol (ACP) (Izervay; Iveric Bio/Astellas) is a small synthetic pegylated RNA aptamer that is designed to be a specific inhibitor of complement C5 protein. Arshad Khanani, MD, said in this presentation that inhibition of C5 slows inflammation and cell death associated with development and progression of GA. He also said ACP is the only treatment that has achieved the 12-month prespecified primary objective in 2 pivotal phase 3 studies. GATHER2 is a 2-year phase 3, international, multicenter, prospective, randomized, double-masked sham-controlled study, with patients receiving monthly ACP or monthly sham. In the second year, ACP-treated patients were re-randomized to receive ACP monthly or every other month, and patients who were treated with sham continued. The primary objective of the 2-year data was to evaluate long-term efficacy and safety of the re-randomized population of ACP recipients through 2 years. The results showed both monthly and every-other-month ACP 2 mg reduced GA growth vs sham. The treatment effect more than doubled over 2 years compared to 1 year for both ACP-treated groups vs sham. ACP was well tolerated over 2 years. In year 2 the incidence of choroidal neovascularization (CNV) was similar for sham vs ACP every other month, and over the 2 years there was only a slight increased incidence of CNV for ACP 2 mg vs sham.
Intravitreal Sustained-release Dexamethasone Implant for DME and RVO: 6-month Results From the First-in-Human Phase 2 RIPPLE-1 Trial
Sumit Sharma, MD, discussed the potential of IBE-814 intravitreal technology to offer several advantages over traditional polymer-based delivery systems. The polymer-based systems can only have a drug load of 20% to 60%, whereas the IBE-814 implant can have a drug load of 80% and allows for a smoother release curve. The IBE-814 allows for injection with a 30-gauge needle of a 6 mm implant that gives a 70-µg dose vs the 700-µg dose delivered with the 22-gauge commercially available dexamethasone implant. Because there is no polymer involved, there are no proinflammatory degradation products. The RIPPLE-1 study is a first-in-human study designed to evaluate the safety and efficacy of the IBE-814 intravitreal implant in patients with either treatment-naïve, or previously treated diabetic macular edema (DME) or retinal vein occlusion (RVO). Patients were randomized to receive the low dose (single 70-µg implant) or the high dose (2 70-µg implants) at baseline, and followed weekly, then monthly. Dr. Sharma presented 6-month results for both DME and RVO. The study showed that the IBE-814 implant enables sustained dexamethasone delivery to the retina. At 6 months there was reduced central subfield thickness in all cohorts and improved or stable best-corrected visual acuity in all cohorts. There was a significant reduction in treatment burden compared to pre-study, and the safety profile was comparable to that of other intravitreal steroids with no unexpected adverse events.
MCO-010 Optogenetic Therapy for Vision Loss in Stargardt Disease: Topline Data From the Phase 2 STARLIGHT Trial
Stephen Tsang, MD, explained that the idea of this therapy is to use a light-capturing multicharacteristic opsin (MCO-010) to replace lost photoreceptors in patients with Stargardt disease. The STARLIGHT trial looked at a small number of patients (n=6) with a primary endpoint of safety and tolerability at week 24, and secondary endpoints of efficacy at 48 weeks (BCVA, visual field perimetry, multiluminance Y-mobility test). The study results showed MCO-010 was well tolerated with no serious adverse events maintained through 48 weeks. Patients with predominantly macular disease experienced clinically meaningful improvements in BCVA. Mean improvement in BCVA was 5.5 ETDRS letters and 13 ETDRS letters with a wearable magnifier at 48 weeks, and there was a 2.63 dB improvement in mean defect measured by visual field perimetry. Dr. Tsang said the results warrant further investigation in a larger study.
