Prashanth G. Iyer, MD, MPH
Tufts Medical Center/Ophthalmic Consultants of Boston
Boston, MA
Macula 2023 started the day with the latest advancements in treating wet age-related macular degeneration (AMD). This first section was moderated by Chirag P. Shah, MD from Ophthalmic Consultants of Boston.
Philip J. Ferrone, MD from Vitreous Retina Macula Consultants of NY presented outcomes of the 48 week, phase 3 PULSAR study of high-dose aflibercept, which is 8mg injected in 0.07mL for treatment naïve neovascular AMD. The treatment groups included standard 2mg q8week intervals after 3 initial monthly loading injections (conventional dosing), 8mg q12 weeks after 3 initial monthly loading injections, and 8mg q16 weeks after 3 initial monthly loading injections. The 48 weeks results demonstrated noninferiority in visual acuity and central retina thickness between the three groups. 83% of patients in both the 8mg groups were maintained in at least 12 or more week intervals. At week 48, the mean number of injections was 6.9 injections in the 2mg at q8week group, 6.1 in the 8mg at q12 week group, and 5.2 in the 8mg q16 week group. The safety profile of aflibercept 8mg was consistent with the established safety profile of aflibercept 2mg, with no cases of intraocular inflammation, retinal vasculitis, occlusive retinitis, endophthalmitis, or systemic adverse events. There was no evidence of significant increased intraocular pressure (IOP) with aflibercept 8mg injected at 0.07mL. One of the audience questions posed was whether high dose aflibercept may be increase rate of geographic atrophy, which needs to be explored.
The next presenter was Ferhina Ali, MD MPH from New York Medical College who discussed real-world experience with faricimab. This bispecific antibody binds to VEGF-A and Ang-2, and was approved for treatment of diabetic macular edema and exudative AMD in January 2022, therefore real-world data is limited. The TRUCKEE study is an independent, physician led ongoing collaborative study looking at the safety and efficacy of faricimab in both treatment naïve and previously-treated patients with neovascular AMD. The TRUCKEE study demonstrated that faricimab is safe and well tolerated with stable visual acuity and rapid improvement in anatomic parameters (central retinal thickness and PED height) in both treatment naïve and previously treated patients with neovascular AMD. The FARETINA-AMD study provided important information on the early use, practice patterns and response to treatment in the real world using IRIS registry data. On average, patients had received 7 anti-VEGF injections approximately 5 weeks apart prior to initiating faricimab. After initiating faricimab, majority of patients were being extended to >6 week intervals after 2 injections of faricimab. Visual acuity parameters were also favorable. Both studies are ongoing and provide the most population-based information to date post recent approval of faricimab.
Jason Hsu, MD from Wills Eye Hospital reviewed the latest results of the port-delivery system (PDS) with ranibizumab for wet AMD which was FDA approved in October 2021. Advantages of the PDS include permanent and reliable ocular implant, higher concentration of ranibizumab (100mg/mL), continuous delivery and refills done in clinic (refills occur every 24 weeks). The LADDER phase 2 study demonstrated that 80% of patients in the PDS group reached month 6 without needing refills, recommending that PDS with ranibizumab be refilled at q24weeks. In phase III ARCHWAY study, the q24 week refill group had visual acuity and anatomic parameters that were noninferior to the monthly injections at week 96. Approximately 95% of PDS patients did not require supplemental ranibizumab through year 3. Ocular adverse effects were of significant concern, including endophthalmitis (1.6%v 0.6%, 3 fold increase), and implant dislocation (1.6%). The PDS procedure continues to evolve with new ways to construct the wound and conjunctival tissue. Early real world experience is comparable to clinical trials, although 24% of patients in the real world needed supplemental anti-VEGF. Dr Hsu addressed the recent voluntary recall in Oct 2022 commercially and in clinical trials due to concern of the septum dislodgement within the device, although the recall did not include refills of existing PDS or explanation.
Peter Campochiaro, MD from Wilmer Eye Institute discussed the three routes of ocular delivery of gene therapy AVV vectors expressing anti-VEGF Fab (RGX-314) including subretinal injections, suprachoroidal injections and intravitreal injections for neovascular AMD. The subretinal RGX-314 Phase I/IIa study demonstrated long-term, durable treatment effect with stable/improved visual acuity and meaningful reductions in anti-VEGF burden. In terms of long-term safety, subretinal RGX-314 continues to be generally well-tolerated with a favorable immunogenicity profile. However, there were concerns for drug-related pigmentary changes that may represent transient RPE cell proliferation of unknown reasons. Next, Dr. Campochiaro reviewed the 6 month results for the AAVIATE phase II clinical trial of suprachoroidal RGX-314 compared to monthly injections. Treatment was well-tolerated in the preliminary data, and patients had stable visual acuity and retinal thickness similar to monthly injections but with 30-40% of patients not needing rescue injections. The intravitreal injection of gene therapy is currently being studied in vivo in mice and primates, with two agents called ADVM-022 and 4D-150. There is significant progress in the world of gene therapy with the hope of sustained expression and long-term suppression of exudation in patients with neovascular AMD.
Next, Susan B Bressler, MD from Wilmer Eye Institute started her talk by announcing that “biosimilars are here.” Biosimilars provide more affordable options for expensive biologic agents and can potentially expand access. Ranibizumab biosimilars include Byooviz (Biogen Inc.) and Cimerli (Coherus Biosciences Inc.) are currently being introduced in the US. Biosimilar agents are reverse engineered from the reference drug and the design specification is a time intensive process. However, the validation phase is less intense with minimal of 1 clinical trial demonstrating noninferior outcomes to the originator with similar safety signals. Like the original product, biosimilars have to deal with stability and immunogenicity issues, and robust post-marketing safety monitoring will be important.
Robert L. Avery, MD from California Retina Consultants discussed the role of tyrosine kinase inhibitors (TKIs) in wet AMD. Previous uses of oral and eye drop TKIs had been published with either no benefit or systemic adverse effects. Currently, intraocular TKIs are being studied. Dr. Avery first discussed sunitinib, an intravitreal TKI that blocks all three VEGF receptors. Phase 1 studies demonstrated that there was a reduction in treatment burden although no visual benefit. In addition, migration of bio-absorbable particles in to the anterior chamber was associated with mild intraocular IOP elevation. Next was vorolanib, an intravitreal sustained-delivery insert. Phase 1 studies demonstrated an improvement in treatment burden and stable visual acuity and OCT thickness, especially if pretreated with anti-VEGF agents. Currently two phase 2 studies targeting wet AMD and DME are ongoing. Intravitreal and suprachoroidal axitinib are also in early phase study, aiming to reduce treatment burden and reduce fluid in conjunction with supplemental anti-VEGF agents.
The panel discussion was led by Fernando Arevalo, MD PhD from Wilmer Eye Institute. The question was posed whether high dose aflibercept would have more inflammation and glaucoma issues in the real world. Dr Ferrone responded that post-marketing vigilance will be very important, but did not anticipate issues with inflammation based on the trials. If patients have baseline elevated pressures, we may have to be more careful but glaucoma will likely not be an issue. The panel next discussed how treat and extension of faricimab in the clinical trials may vary from real-world experience. Dr Ali made the point that it is difficult to do 4 loading doses in the real world especially in previously treated patients, and so ongoing data from real-world data will be important. The panel also discussed that in clinical trials, the majority of patients that had PDS did not need supplemental therapy but in the real-world 24% of patient did need anti-VEGF. Dr Hsu discussed that clinical trials may be more tolerant to subretinal fluid, and that the real-world data is small with previously treated patients as compared to clinical trials. Dr. Campochiaro stated that while all the gene therapy agents are promising, the subretinal delivery has been demonstrated previously with inherited retinal diseases. Long term consequences of gene therapy are still unclear, and we continue to monitor safety and efficacy of these treatments. Dr. Bressler discussed how biosimilars may be the solution to accessibility and affordability, while Dr. Avery emphasized that TKI may play a role to reduce treatment burden in conjunction with anti-VEGF.
Thank you for tuning in to another edition of RETINA Roundup!
