Clearing the Vision: ASRS 2023 Data Highlight Advances in Wet AMD and DME
- In the PHOTON study, 89% of patients with diabetic macular edema (DME) in the aflibercept 8-mg group maintained ≥12-week dosing.
- Based on the negative results from the GLEAM and GLIMMER trials in DME, investigations into KSI-301 are being discontinued.
- In the PORTAL study, patients with wet age-related macular degeneration (AMD) had vision stability over 5 years with good durability in the 6-month interval, with no supplemental treatment needed before refill.
Increased treatment durability, whereby visual gains and anatomic improvements are achieved with fewer anti-vascular endothelial growth factor (anti-VEGF) injections, is an unmet need in the retinal space. Patients with retinal diseases such as wet AMD and DME face a notable treatment burden that often leads to undertreatment and contributes to suboptimal outcomes.1,2 During the American Society of Retinal Specialists (ASRS) 41st Annual Meeting, held July 28 to August 1, 2023, in Seattle, Washington, several abstracts were presented that produced promising safety and efficacy results in the AMD and DME space with fewer anti-VEGF injections. In the following interview, Arshad M. Khanani, MD, MA, FASRS, managing partner and director of clinical research at Sierra Eye Associates in Reno, Nevada, offers insights on key abstracts detailing treatment for AMD and DME and how they may translate to clinical practice.
High-dose aflibercept (8 mg) is a novel intravitreal formulation that delivers a 4-fold higher molar dose than the standard-dose aflibercept (2 mg). It is being studied in both AMD and DME through the ongoing PULSAR (ClinicalTrials.gov identifier: NCT04423718) and PHOTON (ClinicalTrials.gov identifier: NCT04429503) studies, respectively.3,4 The 2-year data from the PHOTON study were presented during ASRS. What were your major takeaways from this presentation?
Durability is a big unmet need in our space. We continue to look for new treatment options with greater durability. The 96-week results from PHOTON in DME showed comparable visual acuity between the 2-mg and 8-mg aflibercept groups but with 89% of patients in the aflibercept 8-mg group maintaining ≥12-week dosing. In addition, 44% of patients were assigned to a ≥20-week dosing interval at week 96. Looking at anatomy, there were no differences in drying in the head-to-head dosing period during the loading phase, and there were fluctuations in central retinal thickness in both the 2-mg and 8-mg groups with the greatest being in the dosing of 8 mg every 16 weeks. Intraocular inflammation rates were 1.2%, and this was similar between aflibercept 2 mg and 8 mg.4 Real-world experience will help us understand the drying ability of this drug as well as which patients are the best candidates for it.
In PULSAR, 17% of patients could not maintain 12- or 16- week treatment intervals with high-dose aflibercept.3 What do we know about the characteristics of those patients, and how this could translate to the real-world setting?
These are likely high-need patients in the PULSAR study who needed frequent treatment. The real-world neovascular AMD (nAMD) patient population is very different from clinical trials. We have a subset of patients in our clinic who need injections every 4 to 6 weeks no matter what drug they are given. High-dose aflibercept is going to be used initially for those high-need patients to see if they do better in terms of anatomy. However, we are not looking to extend every patient to 16 weeks, but rather control disease activity and keep the retina dry. Clinical trials use different retreatment criteria to extend treatment intervals, and it is important to pay attention to those.
For example, Marco Zarbin, MD, PhD, of Rutgers-New Jersey Medical School, presented data at ASRS that looked at how applying different disease activity criteria may have impacted faricimab dosing intervals in TENAYA (ClinicalTrials.gov identifier: NCT03823287) and LUCERNE (ClinicalTrials.gov identifier: NCT03823300). He and his colleagues found that if you use both central subfield thickness “and” vision criteria instead of “or” criteria that was used in the trial, you are able to extend 96% of patients to ≥12-week dosing.5 This shows us how durability in the trials is impacted by the disease activity criteria.
The Port Delivery System (PDS) with ranibizumab is a surgically implanted drug delivery system that provides a continuous customized formulation of ranibizumab. It was approved by the US Food and Drug Administration (FDA) in October 2021 with 2 refills per year for patients with wet AMD, but it was recalled a year later due to safety issues related to septum dislodgement.6,7 PORTAL (ClinicalTrials.gov identifier: NCT03683251) showed vision stability over 5 years, and there were also no cases of septum dislodgement reported.8 What do you make of these data within the context of your real-world experience and the recall?
The PORTAL data are about patients from the phase 2 LADDER study (ClinicalTrials.gov identifier: NCT02510794).9 Once they finished that study, they went into the PORTAL extension study for 5 years. The data clearly show that continuous delivery of anti-VEGF can maintain long-term vision and anatomy for patients with nAMD. This is the first time we have seen long-term data from a sustained delivery trial. This was achieved with about 95% of patients not requiring any supplemental treatment before each refill exchange at a 6-month interval over 5 years. There were no cases of septum dislodgement reported in this data set, as these were the phase 2 trial patients.
The other thing I was looking for was endophthalmitis, and there were no cases reported.8 That gives me confidence that if you do the surgery correctly, and the patient heals well, they are at lower risk of endophthalmitis. PDS is a good treatment option for a subset of patients who are high need or cannot tolerate injections, but the risks and benefits need to be discussed in detail with the patients prior to implanting the PDS. In my experience, patient satisfaction is very high with the PDS, and that has also been shown in the trials where the vast majority of patients preferred PDS. It was recently announced that PDS will be back in clinical trials later this year, and I am looking forward to restarting the PDS trials in the near future.10
As you know, there are 2 newly approved biosimilars for ranibizumab: ranibizumab-nuna and ranibizumab-eqrn.11,12 Carl Awh, MD, of Tennessee Retina, presented a study during ASRS on the safety and efficacy of the ranibizumab biosimilars in the real world from >13,000 injections in >5000 eyes. The safety and efficacy seemed to be similar to ranibizumab, with 3 cases of endophthalmitis and stable vision.13 Many clinicians are hesitant to use biosimilars. Do these data help make a case for them?
Dr Awh presented a big real-world chart review, and the biosimilars did very well in terms of safety. The safety does seem to be similar between biosimilars, but sometimes you need larger numbers to find rare safety signals. The issue is we still do not have long-term data on biosimilars. During the session, I asked Dr Awh how he and his colleagues selected the biosimilar used — either ranibizumab-nuna or ranibizumab-eqrn — and it was based on insurance. An important question is if insurance was not a factor, would physicians use a biosimilar if we had safety and efficacy established for approved ranibizumab over the last 17 years? In addition, we have agents that dry better than ranibizumab and can extend the treatment interval longer for our patients, so it becomes difficult to use ranibizumab biosimilars unless we are restricted by payers.
Are we going to get to the point where second-generation agents like faricimab have replaced first-generation anti-VEGFs for nAMD and DME?
In my opinion, yes, if the second-generation agents continue to show efficacy and safety. I am personally using faricimab in most of my patients if I do not have any insurance restrictions. I am trying to get the best drying effect and greater durability for my patients.
Based on the negative results from GLEAM (ClinicalTrials.gov identifier: NCT04611152) and GLIMMER (ClinicalTrials.gov identifier: NCT04603937) in DME, investigations into KSI-301 are being discontinued. What were your impressions of these data?
The GLEAM and GLIMMER phase 3 trials for KSI-301 in DME failed to meet the primary endpoint of noninferiority to aflibercept in mean change in best corrected visual acuity from baseline to weeks 60 to 64. Patients gained 6.4 to 7.4 letters with KSI-301 vs 10.3 to 12.3 letters with aflibercept. There was also a high incidence of cataract with KSI-301 vs aflibercept (19.4% vs 8.7%, respectively). KSI-301 is an antibody biopolymer conjugate that is injected in the eye at 100 μL instead of 50 μL.14 At this point, it is unclear what caused the higher rate of cataract formation.
Can you tell us about your presentation of 48-week data from the phase 2 BEHOLD study (ClinicalTrials.gov identifier: NCT04857996) in DME with UBX1325 (foselutoclax)?15
UBX1325 has a novel mechanism of action. It is a B-cell lymphoma-extra large (Bcl-xL) inhibitor and it selectively eliminates senescent cells that secrete inflammatory cytokines. Preclinical studies have shown that intravitreal UBX1325 decreases both neovascular and avascular areas in oxygen-induced retinopathy mouse models.16 In the phase 2 BEHOLD study, patients with persistent DME despite anti-VEGF treatment received either UBX1325 or sham, and then they were followed monthly to evaluate the need for supplemental treatment. Patients treated with UBX1325 had improved visual acuity at 48 weeks by 6.2 letters (excluding post-rescue data) from baseline after a single injection with stable anatomy. In addition, approximately 50% of patients treated with UBX1325 achieved a rescue-free interval of at least 48 weeks. UBX1325 was well tolerated without any safety concerns, and no cases of intraocular inflammation were reported in the trial.15 The program is now moving forward into the phase 2b ASPIRE study to evaluate the potential of UBX1325 compared with aflibercept control in patients with persistent DME.17
This Q&A was edited for clarity and length.
Arshad M. Khanani, MD, MA, reported affiliations with AbbVie, Inc; Adverum Biotechnologies, Inc; Alcon Laboratories, Inc.; Applied Genetics Technologies Corporation; Aldebaran Therapeutics; Allergan, Inc; Annexon Biosciences; Apellis Pharmaceuticals; Arrowhead Pharmaceuticals; Aviceda Therapeutics; Bausch & Lomb, Inc; Broadwing Bio; Clearside Biomedical, Inc; Exgenesis; EyePoint Pharmaceuticals, Inc; F. Hoffmann-La Roche, Ltd; Frontera Therapeutics, Inc; Genentech, Inc; Gyroscope Therapeutics, Ltd; iLumen, Inc; Iveric Bio, Inc; Janssen Pharmaceuticals, Inc; Kato Pharmaceuticals; Kartos Therapeutics; Kodiak Sciences, Inc; Kriya Therapeutics; Ocular Therapeutix; Oculis Holding, AG; OcuTerra Therapeutics; Olives Bio; Opthea; Oxular Limited; Oxurion NV; Nanoscope Therapeutics, Inc; Neurotech Pharmaceuticals, Inc; NGM Biopharmaceuticals, Inc; Novartis Pharmaceuticals Corporation; Perfuse Therapeutics, Inc; PolyPhotonix Medical, Ltd; Protagonist Therapeutics, Inc; Ray Therapeutics; RecensMedical; Regeneron Pharmaceuticals, Inc; Regenxbio, Inc; RevOpsis Therapeutics; Rezolute, Inc; Stealth BioTherapeutics, Inc; Thea Pharma, Inc; Unity Biotechnology, Inc; Vanotech; Vial; 4D Molecular Therapeutics.
1. Baumal CR. Wet age-related macular degeneration: treatment advances to reduce the injection burden. Am J Manag Care. 2020;26(suppl 5):S103-S111. doi:10.37765/ajmc.2020.43435
2. Kiss S, Campbell J, Almony A, et al. Management and outcomes for neovascular age-related macular degeneration: analysis of United States electronic health records. Ophthalmology. 2020;127(9):1179-1188. doi:10.1016/j.ophtha.2020.02.027
3. Patel J; PULSAR study investigators. Intravitreal aflibercept 8 mg injection in patients with neovascular age-related macular degeneration: 48-week results from the phase 3 PULSAR trial. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
4. Do D; PHOTON study investigators. Aflibercept 8mg for diabetic macular edema: 2-year results of the phase 2/3 PHOTON trial. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
5. Zarbin M; TENAYA study group & LUCERNE study group. An assessment of the impact of disease activity criteria on dosing interval assignment in clinical trial patients with nAMD: results. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
6. SusvimoTM. Prescribing information. Genentech, Inc; 2021. Accessed August 14, 2023. www.gene.com/download/pdf/susvimo_prescribing.pdf
7. Genentech. Voluntary recall of the SUSVIMO Ocular Implant. Published October 2022. Accessed August 14, 2023. https://www.gene.com/download/pdf/Susvimo_DHCP_Important_Prescribing_Information_2022-10-18.pdf
8. Massop D; Ladder Study group and Portal study group. Long-term efficacy and safety of the Port Delivery System with ranibizumab in patients with nAMD: results of the PORTAL 5-year subgroup analysis. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
9. Khanani AM, Callanan D, Dreyer R, et al. End-of-study results for the LADDER phase 2 trial of the Port Delivery System with ranibizumab for neovascular age-related macular degeneration. Ophthalmol Retina. 2021;5(8):775-787. doi:10.1016/j.oret.2020.11.004
10. Marcus, D, Graff, J, Campochiaro, P, et al; Pagoda investigators and Pavilion investigators. Port Delivery System With ranibizumab (PDS) for continuous treatment in DME and DR: additional results from the phase 3 Pagoda and Pavilion trials. Abstract presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
11. Biogen and Samsung Bioepis’ BYOOVIZTM (ranibizumab-nuna) launches in the United States. News release. Biogen, Inc. Published June 2, 2022. Accessed August 14, 2023. https://www.globenewswire.com/en/news-release/2022/06/02/2455159/0/en/Biogen-and-Samsung-Bioepis-BYOOVIZ-ranibizumab-nuna-Launches-in-the-United-States.html
12. U.S. Food and Drug Administration (FDA) approves FYB201/CIMERLITM (ranibizumab-eqrn), the first and only biosimilar interchangeable with Lucentis®. News release. Polypharma Biologics Group. Published March 8, 2022. Accessed August 14, 2023. https://polpharmabiologics.com/en/knowledge/latest-news/article/u-s-food-and-drug-administration-fda-approves-fyb201-cimerlitm-ranibizumab-eqrn-the-first-and-only-biosimilar-interchangeable-with-lucentis-r
13. Awh C. Efficacy and safety of biosimilar ranibizumab-nuna and ranibizumab-eqrn in clinical use by a consortium of retina practices. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
14. Wykoff C. Tarcocimab tedromer (KSI-301) anti-VEGF antibody biopolymer conjugate for DME: first-time efficacy, durability and safety results of the GLEAM and GLIMMER phase 3 studies. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
15. Khanani AM. 48-week end of study results from BEHOLD phase 2 study of UBX1325 in patients with DME. Paper presented at: American Society of Retinal Specialists (ASRS) 41st Annual Meeting; July 28-August 1, 2023; Seattle, WA.
16. Hassan JW, Bhatwadekar AD. Senolytics in the treatment of diabetic retinopathy. Front Pharmacol. 2022;13:896907. doi:10.3389/fphar.2022.896907
17. UNITY announces design of phase 2b ASPIRE study evaluating UBX1325 in diabetic macular edema (DME). News release. Unity Biotechnology, Inc. June 21, 2023. Accessed August 14, 2023. https://www.globenewswire.com/en/news-release/2023/06/21/2691854/0/en/UNITY-Announces-Design-of-Phase-2b-ASPIRE-Study-Evaluating-UBX1325-in-Diabetic-Macular-Edema-DME.html
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Reviewed August 2023