Innovations in medical retina are rapidly evolving, and all are aimed at providing safe and optimal care to retina patients. These include advancements in imaging that allow us to see the retina with unprecedented detail, precise treatment strategies of previously untreatable sight-threatening diseases and delivering novel and familiar agents in new ways.
While reports indicate that the first intravitreal injection (of air) was administered in 1911, significant progress in the intravitreal treatment of retinal diseases didn’t really pick up steam until about 25 years ago. Case in point: The US Medicare billing code for ‘intravitreal injection of a pharmacologic agent’ was submitted approximately 2,300 times in 1993, compared to 3.4 million times in the past few years.
Keep in mind this was solely based on Medicare billing—the real number of injections is estimated to be closer to 7 or 8 million in the US alone. To keep up with the demand for treating a wide range of retinal conditions that can be managed by intravitreal injections. There are reports of some retinal specialists performing over 50 injections each day!
Keeping up with the demand
Don’t get me wrong, you won’t hear the retina community complaining. Having treatment options where none existed before is wonderful— especially for those who have been practicing both before and since the anti-vascular endothelial growth factor (VEGF) era. However, the growing number of patients – primarily those with age-related retinal disease and the increasing prevalence of diabetic-related complications – coupled with the need for frequent treatments, is squeezing retina clinics into a major capacity challenge. It’s like needing to wear roller skates to keep up!
New agents on the block
In order to meet this demand, researchers and innovators are taking their best shots to develop products that are safe, efficacious and durable.
So what are the main forms of the innovation pipeline? New agents include new molecules with new modes of action as well as some familiar agents with new formulations or dosing regimens. Although safety is the highest priority, efficacy and durability are key to reducing the number of patient visits. This all lessens the burden on patients and caregivers, and reduces the stress on retina specialists and their bursting clinics.
Dr. Arshad M. Khanani, a vitreoretinal specialist, managing partner and director of clinical research and director of fellowship at Sierra Eye Associates, as well as a clinical associate professor at the University of Nevada at Reno, has been on the frontline of many of these innovations as a principal investigator for numerous clinical trials.
Dr. Khanani has been witness to how anti-VEGF therapies have revolutionized the management of neovascular age-related macular degeneration (nAMD) and other VEGF-driven ocular diseases, significantly improving visual outcomes.
However, he also recognizes that there is still work to do. “Unfortunately, treatment burden continues to be a major concern for many patients, their caregivers and the healthcare system. For most of the current agents, some patients are still requiring eye injections as frequently as every month, and outcomes outside of clinical trials tell us that we can still improve with longer-acting and more durable therapies.”
Dr. Khanani notes that the approval of faricimab (Vabysmo; Genentech, California, USA) has provided a welcome addition to the retinal armamentarium. “It is the first bispecific drug approved for retina diseases and results in simultaneous and potent inhibition of VEGF-A and angiopoietin-2, which play an important role in vascular stability and permeability. [This] delivers the potential for sustained efficacy through extended durability, which, importantly, can help reduce treatment burden for our patients.”
Dr. Benjamin Bakall is a retina specialist at Associated Retina Consultants in Phoenix, Arizona and a clinical assistant professor at the University of Arizona College of Medicine in Phoenix. “The recent approval of intravitreal Vabysmo for both neovascular AMD and diabetic macular edema has definitely been an exciting addition to current treatment options,” he agreed. “Because it is a dual antibody with two binding sites for both VEGF-A and Ang-2, it delivers that additional benefit over the current treatments we have available.”
Clinical trials versus real-world scenarios
A challenge often arises when new agents are released into the real world. Outcomes may differ from those published in clinical trials. Patients seen in the clinic are not necessarily represented by trial participants. Some have been previously heavily treated, some have been non-responders and others switched from other agents.
Dr. Khanani was the lead author of the recently published TRUCKEE study, describing the real-world treatment and outcomes of 376 patients treated with faricimab.1
This group, with varied treatment history, demonstrated positive results in both visual and anatomical parameters, including maintenance of their visual acuity and significant improvements in their anatomy, via central subfield thickness (CST) and improvement of intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelium detachment (PED)—even after just one injection. The treatment was well-tolerated with a low incidence of intraocular inflammation.
Improvements continued after three injections, which may indicate the need for loading doses or multiple injections to achieve maximum benefit—an important tip from realworld data.
Old friends getting an upgrade
High-dose anti-VEGF agents are looking to be the option for those pesky treatment-resistant cases, and recent clinical studies have shown promising results.
Most notably, high-dose aflibercept (8 mg, as compared to 2 mg)* has been evaluated in patients with nAMD in the PULSAR trial, with exciting results.2 At 48 weeks, both highdose treatment arms (8 mg every 12 weeks and 8 mg every 16 weeks after three initial monthly aflibercept injections) met the primary endpoint of non-inferior BCVA gains compared to aflibercept 2 mg, and additionally demonstrated superiority in improving anatomic outcomes of retinal fluid. Significantly, in relation to the treatment burden, 83% receiving high-dose aflibercept maintained ≥12 week treatment intervals.
Another old friend, bevacizumab, the off-label workhorse of the retina, may be receiving a makeover after nearly 20 years. Outlook Therapeutics (New Jersey, USA) is working to develop and launch the first FDAapproved ophthalmic formulation of bevacizumab ONS-5010 / LYTENAVA™ (bevacizumab-vikg) for use in retinal indications.
An ophthalmic-specific formulation means that it will adhere to the specific manufacturing standards and purity requirements for agents designed to be administered into the eye.
The more the merrier!
Current therapies are focused on blocking VEGF-A by binding to VEGF receptor 2. However, new therapies are looking at whether binding to other receptors, such as VEGF receptor 3 (VEGFR-3), and blocking VEGF-C and VEGF-D might enhance treatment efficacy, especially for those who are not achieving optimal response to current therapy.
OPT-302 (Opthea; Ontario, Canada) targets and sequesters VEGF-C and VEGF-D, so when paired with our trusty VEGF-A blocker, ranibizumab, the combination provided statistically significant superior gain in visual acuity compared to ranibizumab alone.3 Two phase 3 trials are currently underway.
Innovation can be most impactful when there are newly available treatments for devastating eye diseases. Until only a few months ago, people with advanced dry agerelated macular degeneration with geography atrophy had no options but to go home and go blind.
Dr. Bakall and many others in the medical retina community are now relieved to be able to offer treatment solutions to their patients with geography atrophy.
“The FDA approvals of IZERVAY™ (avacincaptad pegol intravitreal solution; Iveric Bio, New Jersey, USA), and SYFOVRE® (pegcetacoplan injection; Apellis Pharmaceuticals, Massachusetts, USA) are game changers. Both have demonstrated that they can effectively slow down the progression of geographic atrophy in order to prevent vision loss,” he explained.
TKIs to the rescue
Recently, there has been a growing interest in the role of tyrosine kinase inhibitors (TKIs) in the treatment of retinal disease. TKIs have the potential to be a maintenance treatment for patients with retinal diseases.
Dr. Khanani explained: “While anti-VEGF therapies target VEGF molecules in the extracellular space, selective TKIs can work intracellularly to stop the downstream effects of all the isoforms of VEGF as well as platelet-derived growth factor (PDGF), potentially improving therapeutic efficacy by inhibiting multiple components of angiogenesis,” he said.
“Early trial results have shown great promise in this space, and I’m excited to see the continued development of TKIs with multiple novel delivery platforms, aimed at promoting sustained delivery,” he continued.
Some TKIs to watch include Vorolinib (Eyepoint Pharmaceuticals, Massachusetts, USA), a TKI that targets all VEGFRs and PDGFRs and comes in the Durasert sustained delivery platform. In the Phase 1 DAVIO trial, 53% and 35% of wet AMD patients did not require a rescue anti-VEGF injection at six and 12 months, respectively, and there were no significant safety concerns.4 The Phase 2 study is ongoing.
TKIs are also taking the suprachoroidal route. Axitinib is a selective TKI for both VEGFR and PDGFR and is being investigated both intravitreally (OTX-TKI; Ocular Therapeutix, Massachusetts, USA) and suprachoroidally (CLS-AX; Clearside Biomedical, Massachusetts, USA) with both routes demonstrating important reductions in treatment burden in early studies.
The promise of gene therapy
Also making big waves in the treatment of retinal disease is gene therapy. In the near future, perhaps not all gene therapy requires a trip to the operating room.
In addition to spending his days in the clinic treating the heavy hitters of medical retina, age-related macular degeneration and diabetic retinopathy, Dr. Bakall has a special interest in diagnosing, treating, and providing genetic counseling to patients with inherited retinal diseases.
He shared his thoughts on the most impactful innovation in the retina in the past five years. “Finally having an approved treatment for early onset retinal dystrophy caused by mutations in the RPE65 gene has been impactful for me and, importantly, my patients,” Dr. Bakall said. “Although LUXTURNA (voretigene neparvovec-rzyl; Spark Therapeutics, Pennsylvania, USA) is delivered by subretinal injection in the operating room, outside the purview of most medical retina specialists, this approval has stimulated new research and development into alternative, some even office-based, treatments for retinal diseases caused by different genetic mutations. Current clinical trials are underway investigating intravitreal or suprachoroidal delivery systems.”
Gene therapy does not just stop at the door of inherited retinal disease. This innovation utilizes a nonintegrating viral vector that carries an encoded genetic message to make a novel protein, specifically an anti-VEGF protein. This translates into sustained VEGF suppression, which is very exciting if the current studies are positive, investigating in-office intravitreal and suprachoroidal delivery of gene therapy for nAMD and diabetic retinopathy.
Dr. Khanani explained how gene therapy may be the next big game changer in nAMD and DR. “Once the cells produce their own anti-VEGF protein, this would effectively allow for a more permanent therapeutic effect compared to other long-lasting delivery platforms. Potentially being a one-time treatment for our patients, or certainly reducing the burden of frequent intravitreal injections,” he said.
So how can gene therapy change the landscape of retinal disease management? “Emerging data from intravitreal and suprachoroidal programs have highlighted the potential of a single in-office treatment to have great durability and disease control for patients with nAMD and DR. Gene therapy has the potential to be a paradigm shift for patients with retinal diseases in the next five to 10 years,” he shared.
REGENXBIO (Maryland, USA) is currently conducting Phase 2 trials of suprachoroidal gene therapy delivery of RGX-314 to treat wet AMD and diabetic retinopathy.
A clear vision for the future
Researchers and innovators, we salute you! In the not-too-distant future, we are hoping that patients will have access to treatment alternatives that are less demanding on their part, consequently taking some of the pressure off our retina clinics.
Maybe one day soon patients can use their home-based OCT and electronically send the scans to you, no matter where you are—whether you are at the clinic or enjoying some beachfront downtime. And perhaps you can let them know that it is time for them to come back for that 12-month retreatment.
References
- Khanani AM, Aziz AA, Khan H, et al. The real-world efficacy and safety of faricimab in neovascular age-related macular degeneration: the TRUCKEE study – 6-month results. Eye (Lond). 2023 May 12. [Online ahead of print]
- Regeneron. Aflibercept 8 mg positive pivotal results in diabetic macular edema and wet age-related macular degeneration presented at AAO. News release, September 30, 2022. Available at https://investor.regeneron.com/news-releases/news-release-details/aflibercept-8-mg-positive-pivotal-results-diabetic-macularedema#. Accessed on July 22, 2023.
- Jackson TL, Slakter J, Buyse M, et al; Opthea Study Group Investigators. A Randomized Controlled Trial of OPT-302, a VEGF-C/D Inhibitor for Neovascular Age-Related Macular Degeneration. Ophthalmology. 2023;130(6):588-597.
- EyePoint Pharmaceuticals. EyePoint Pharmaceuticals Announces First Patient Dosed in Phase 2 DAVIO 2 Clinical Trial of EYP-1901 for the Maintenance Treatment of Wet AMD. News Release, August 1, 2022. Available at https://investors.eyepointpharma.com/news-releases/news-release-details/eyepoint-pharmaceuticals-announces-firstpatient-dosed-phase-2. Accessed on July 22, 2023.
Editor’s Note
- Regeneron Pharmaceuticals, on 18 August 2023, announced that the US FDA has approved EYLEA HD (aflibercept) Injection 8 mg for the treatment of patients with wet AMD, DME and DR.
- A version of this article was first published in PIE Magazine Issue 27.
