OR WAIT 15 SECS
Pandemic highlights need for longer-lasting agents to reduce treatment burden in evolving field.
This article was reviewed by Caroline R. Baumal, MD, and David Eichenbaum, MD, FAAO
The introduction of anti-VEGF therapy in the early 2000s revolutionized modern retina practice, forever altering the treatment paradigm and improving the prognosis of common blinding conditions such as wet age-related macular degeneration (AMD), the leading cause of visual impairment in Americans over age 60.1
“It is remarkable how medical retina went from being a field that was mostly sad and with poor prognoses to a field where we have relative happiness, success, and safety, albeit with some significant burdens and inconveniences related to treatment,” said David Eichenbaum, MD, FAAO, a partner with Retina Vitreous Associates of Florida in Tampa.
Substantial sight-saving strides have been made in the past 15 years, but the retina field has not fully evolved.
Anti-VEGF therapy may be effective — 95% of patients with neovascular AMD are able to stay within 3 lines of their baseline vision 2 years after beginning treatment2 — but its treatment burden is significant, requiring an often older patient population with comorbidities to travel to the clinic for frequent injections for the remainder of their lives.3
The next step in the retina revolution involves easing that burden through new agents with greater durability. In 2020, against the backdrop of a pandemic, this goal holds more weight than ever.
Retinal specialists face uncharted waters and impossible questions: How do you continue to save the sight of AMD patients with in-office injections while limiting their exposure to coronavirus disease 2019 (COVID-19)?
Caroline R. Baumal, MD, professor of ophthalmology at Tufts University School of Medicine in Boston, Massachusetts, and Eichenbaum recently discussed these issues and more.
Related: Characterizing localized retinal layer changes in AMD
Treatment strategies during a pandemic
Severe illness from COVID-19 increases with each decade of age, and patients with underlying health conditions such as obesity, heart conditions, chronic kidney disease, and chronic obstructive pulmonary disease are considered at high risk of COVID-19–related complications.4
Because of concerns about exposure, retinal specialists must be prepared for patients’ reluctance to come in for in-office treatments.
“This pandemic has led to a setback in treatment for some patients,” Baumal said.
She recommends tailoring treatments even more than usual to determine if injections could be delayed.
Baumal described her work at the height of the pandemic stay-at-home orders:
“There was a lot of chart reviewing, evaluating the patients’ prior images, and calling patients on the phone to ask if there were changes in visual acuity or on the Amsler grid to determine if treatment could be delayed a few weeks,” she said. “There are some patients I need to inject every 4 to 6 weeks or they will recur. I talked with those patients directly, asked if they felt safe to come in, and expedited the injection procedure. We extended any patient we could, for their comfort.”
If treatment cannot be delayed, Baumal and Eichenbaum recommend maximizing the efficiency of office visits through undilated and/or bilateral injections so nervous patients are not lingering.
“I would see the patient in one room, do their examination and treatment, and make the appointment for follow-up at the same time in the examination room, so they were able to leave directly without stopping at a checkout desk,” Baumal said. “I think that this level of efficiency made my patients feel much more comfortable to come in during the pandemic.”
Telemedicine has replaced in-office visits for many specialties during the pandemic, but Baumal and Eichenbaum said they do not see retinal specialists employing telehealth yet for AMD management.
“Almost all my medical retina decisions have an imaging component,” Eichenbaum said. “I do not think retina is ready for telemedicine in prime time.”
Although telemedicine in the traditional sense may not be realistic for this patient population, Baumal and Eichenbaum do see a place for home-based optical coherence tomography (OCT), in which patients use a simple digital diagnostic to send imaging to their physician between office visits. The daily scan takes about 6 minutes.
“I love the idea of home-based monitoring,” Baumal said. “I think it will help us treat our patients better with a more effective treat-and-extend protocol. Patients will need an examination of the entire retina at certain intervals so we don’t miss peripheral pathology, uveitis, or glaucoma. But we can use this type of device to help us better direct our patients.”
Trials investigating the utility of home-based OCT are under way.
The Home OCT system (Notal Vision; Manassas, VA) was granted breakthrough status by the US Food and Drug Administration (FDA) in 2018.5
Improved drug durability
Determining how to increase the durability of AMD treatments and thereby reduce the treatment burden is “the billion-dollar question” in retina today, Eichenbaum said. The average patient receives about 8 injections in the first year of treatment.
“I typically start off treating patients every 4 weeks until the lesion is dry,” Baumal said. “Then I’ll slowly start to extend the patient to 8 weeks and gradually to 3 months, depending on patient factors.”
Retinal specialists know from clinical trials such as CATT (NCT00593450), HORIZON, and SEVEN-UP (NCT01256827) that more frequent dosing leads to better visual outcomes.6-8
The challenge involves translating those outcomes into the clinic, without a clinical trial coordinator to shepherd a patient through frequent visits.
“We consistently see a correlation to decreased acuity at the time we convert patients from randomized controlled trial protocol dosing to extension trials with real-world style dosing or investigator-directed dosing,” Eichenbaum said. “More injections of our current agents are better.”
Clinical trial outcomes don’t translate to real-world scenarios, Baumal noted. “It is very hard for most people to maintain long-term 4-week dosing,” she said. “Our patients are getting older. “Their visual needs change with their coexisting health problems and other demands on their lives.”
New agents and drug-delivery platforms aim to resolve these issues.
For example, brolucizumab was recently approved by the FDA based on the strength of the phase 3 HAWK (NCT02307682) and HARRIER (NCT02434328) trials.9
Adverse events such as inflammation and vasculitis are a concern, however.
“From the phase 3 HAWK and HARRIER studies, there was about a 4% rate of inflammation in brolucizumab-treated eyes,” Baumal said. “Based on the HAWK and HARRIER [trials], most of these cases of inflammation were mild and resolved with treatment. Brolucizumab is an excellent drying agent with potential to extend the treatment interval in some individuals. However, the potential for inflammation or vasculitis would need to be discussed with patients. Further research may be able to elucidate more information about the pathogenesis of these findings.”
Eichenbaum and Baumal both see potential advancements in treatment durability through devices that can deliver a high dose of a drug over a longer period. The ranibizumab port-delivery system (PDS) could be one such tool.
This permanent, refillable drug reservoir can hold up to 100 mg/mL of ranibizumab. The port is surgically placed through a 3.5-mm scleral incision in the pars plana.
Top-line data from the phase 3 Archway trial (NCT03677934) were recently released, showing that patients who received PDS refills every 6 months had visual acuity outcomes equivalent to those of patients on monthly ranibizumab injections.10
“We’re superbly excited about the potential for a device that may significantly reduce treatment burden,” Dr Eichenbaum said. “[The PDS is] filled with concentrated ranibizumab solution, a reliable agent that we’ve had for almost 15 years.”
The PDS “holds great promise,” according to Baumal: “This will allow a surgical treatment for a medical disease. I’m excited to see the final clinical trial results and to be able to potentially treat my patients by refiling a port once or twice a year.”
Both physicians also note that gene therapies could play a role in future AMD management but that it is too soon to tell, given that data have been reported on fewer than 20 patients.11,12
“Gene therapy is exciting, but I have to balance my excitement by knowing we have only completed phase 1 trials,” Eichenbaum said. “The graveyard is full of successful phase 1 drugs, whereas the PDS now shows positivity in phase 3. We’re almost certainly going to get our hands on it in the real world and be able to bring some of these medical conditions back to the operating room—hopefully, with very good success, minimal risk, and a reduced overall burden to patients.”
Despite their optimism for the future of AMD treatment, Eichenbaum and Baumal emphasize the need for context when assessing new agents and drug-delivery methods.
“It is very important not to throw the baby out with the bathwater as we see new agents come to market,” Eichenbaum concluded. “We have 9 years of data in the real world on aflibercept, almost 15 years of data on ranibizumab, and over 15 years of data on repackaged bevacizumab. We’re going to see new things, some of which will have new problems, and we’re going to have to figure out how to mitigate new issues and where we can use new products best if we want to move forward.”
Read more by Michelle Dalton
Caroline R. Baumal, MD
Baumal is a professor of ophthalmology at Tufts University School of Medicine in Boston, Massachusetts.
David Eichenbaum, MD, FAAO
Eichenbaum is a partner with Retina Vitreous Associates of Florida in Tampa. He is a fellow of the American Academy of Ophthalmology and has been a clinical assistant professor of ophthalmology at the University of South Florida since 2007.
1. O’Shea JG. Age-related macular degeneration: a leading cause of blindness. Med J Aust. 1996;165(10):561-564.
2.Ho AC, Albini TA, Brown DM, Boyer DS, Regillo CD, Heier JS. The potential importance of detection of neovascular age-related macular degeneration when visual acuity is relatively good. JAMA Ophthalmol. 2017;135(3):268-273. doi:10.1001/jamaophthalmol.2016.5314
3. Zlateva GP, Javitt JC, Shah SN, Zhou Z, Murphy JG. Comparison of comorbid conditions between neovascular age-related macular degeneration patients and a control cohort in the Medicare population. Retina. 2007;27(9):1292-1299. doi:10.1097/01.iae.0000300915.81866.b8
4. Get the facts about coronavirus. Centers for Disease Control and Prevention. Accessed TK. https://www.cdc.gov/coronavirus/2019-ncov/index.html
5. Notal Vision announces FDA grants breakthrough device designation for pioneering patient-operated home optical coherence tomography (OCT) system. News release. Notal Vision, Ltd. December 3, 2018. https://www.prnewswire.com/news-releases/notal-vision-announces-fda-grants-breakthrough-device-designation-for-pioneering-patient-operated-home-optical-coherence-tomography-oct-system-300758956.html
6. Maguire MG, Martin DF et al; Comparison of Age-related Macular Degeneration Treatments Trials Research Group. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123(8):1751-1761. doi:10.1016/j.ophtha.2016.03.045
7. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology. 2013;120(11):2292-2299. doi:10.1016/j.ophtha.2013.03.046
8. Singer MA, Awh CC, Sadda S, et al. HORIZON: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175-1183. doi:10.1016/j.ophtha.2011.12.016
9. Dugel PU, Koh A, Ogura Y, et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127:72-84. doi:10.1016/j.ophtha.2019.04.017
10. Roche’s port delivery system with ranibizumab shows positive phase III results in neovascular age-related macular degeneration. News release. Roche. May 27, 2020. Accessed June 30, 2020. https://www.roche.com/media/releases/med-cor-2020-05-27.htm
11. Regenxbio announces additional positive interim phase I/IIa trial update for RGX-314 for the treatment of wet AMD at the American Academy of Ophthalmology 2019 Annual Meeting. News release. Regenxbio Inc. October 11, 2019. Accessed June 30, 2020. https://www.prnewswire.com/news-releases/regenxbio-announces-additional-positive-interim-phase-iiia-trial-update-for-rgx-314-for-the-treatment-of-wet-amd-at-the-american-academy-of-ophthalmology-2019-annual-meeting-300937385.html
12. Adverum Biotechnologies reports additional clinical data from first cohort of OPTIC phase 1 trial of ADVM-022 intravitreal gene therapy for wet AMD at the American Academy of Ophthalmology 2019 Annual Meeting. News release. Adverum Biotechnologies, Inc. News release. October 11, 2109. Accessed June 30, 2020. https://www.globenewswire.com/news-release/2019/10/11/1928842/0/en/Adverum-Biotechnologies-Reports-Additional-Clinical-Data-from-First-Cohort-of-OPTIC-Phase-1-Trial-of-ADVM-022-Intravitreal-Gene-Therapy-for-Wet-AMD-at-the-American-Academy-of-Ophth.html?print=1