A look at the latest developments in retinal disease, including clinical trials and advanced therapies.
It is amazing to witness the high speed of technologic advances in all aspects of life. Think about the changes in how audio and video media have been produced and consumed over the past 50 years. These advances are made in science and technology.
To write a research article in the 1980s, an author had to subscribe to the publications of their fields and use libraries to search for their subjects, which was costly and time-consuming.
Now all that information is at our disposal instantly through our computers and other digital devices. But there are setbacks with this instant access. One of these risks is the issue of credibility and authenticity of the source.
The concept of fake news, bad medicine, and false claims is nothing new.
However, the snake oil salesperson of the past has access to a limited segment of the population.
The snake oil salesperson and the fake news propagator of today have instant access to millions in an instant through the internet. How many spam calls do you receive every day?
Unsound treatment schemes can result in bad outcomes and harm to the public. Retina care is not immune to these types of misfortune.
An example is the US Food and Drug Administration’s (FDA) lawsuit against the South Florida ophthalmology clinic that was offering ineffective and harmful stem cell injections, which resulted in vision loss and blindness of patients.
All eye care providers (ECPs) must be aware of any deceitful and harmful products to provide better guidance to their patients.
This hot and not-so-hot news affects all aspects of our lives, including the optometric and ophthalmic professions.
Looking at these issues in the retina space, we can consider ideas in imaging and diagnostics as well as various pharmaceutical and surgical developments, including novel therapies, genetics, remote and home-monitoring devices, and artificial intelligence (AI).
On the disease and therapeutic front, it is not surprising that incidence of both age-related macular degeneration (AMD) and diabetes mellitus—and therefore diabetic retinopathy (DR)—have been and continue to be on the rise, with no cure for either condition in sight.
In the past 15 years, intravitreal antivascular endothelial growth factor (VEGF) agents have transformed the management of neovascular AMD (nAMD), DR, diabetic macular edema (DME), and many other conditions.
Despite this, the need for repeated and long-term maintenance with injections and office-based procedures is problematic.
Issues of adherence, access to care, and insurance coverage are among the challenges that need to be addressed. Research and recently FDA-approved treatment modalities are being explored to reduce the burden of treatment from both the patient’s and provider’s standpoint.
Ranibizumab injection via a port delivery system (Susvimo; Roche/Genentech) received approval from the FDA for treatment of nAMD, following the treatment-controlled phase 3 Archway clinical trial (NCT03677934).
It is currently under investigation for DR and DME in the PAVILION (NCT04503551) and PAGODA (NCT04108156) clinical trials, respectively.
Additionally, a recent clinical trial resulted in FDA approval of faricimab (Vabysmo; Genentech) for nAMD and DME.
As a new class of anti-VEGF, faricimab blocks VEGF-A and angiopoietin, which is another protein of the vascular growth factor family.
The dual mechanism of faricimab is supposed to give it more efficacy and durability than the other existing anti-VEGFs in the market.
KSI-301 (Kodiak Sciences Inc) is another novel anti-VEGF antibody polymer undergoing clinical trials, with promise of extended durability.2 On another front, adeno-associated virus (AAV) vectors are used to deliver genetic material to alter ocular tissue for endogenous anti-VEGF delivery.3 RGX-314 (REGENXBIO Inc) is exploring subretinal and suprachoroidal viral delivery to accomplish this.
It is without doubt that neglect and treatment gaps result in poor outcomes in nAMD.4 Therefore, more durable and/or permanent remedies may achieve some of the unmet needs and reduce unnecessary vision loss.
Despite treatment advancements for nAMD, dry AMD—particularly advanced dry AMD and geographic atrophy (GA)—remains a challenge.
GA and AMD
Based on the Beaver Dam Eye Study findings, the prevalence of GA increases from 4.4% to 22% from 85 to 90 years of age.
Of the participants, 42% of eyes with GA were legally blind, and the average progression of GA was 6.4 mm2 in patients followed for 5 years.5-7 (Figure 1)
The clinical course of advancing AMD is multifactorial. In addition to genetic and environmental factors, the elements resulting in progression of GA include chronic metabolic and oxidative stress and inflammation.
Furthermore, accumulation of toxic biologic biproducts as extra- and intracellular debris drusen and lipofuscin are due to retinal pigment epithelium (RPE) dysfunction, activation and overactivation of complement system, and cellular death (RPE and photoreceptors).8
The key to combating GA is to block 1 or more of these components. Use of oral antioxidants, anti-inflammatory, neuroprotection, and inhibition of the complement system are facades that have been employed or are being studied in the race to find a viable solution for this enigma.
Age-Related Eye Disease Studies (AREDS [NCT00000145] and AREDS2 [NCT00345176]) have resulted in recommendations of antioxidants and vitamin supplementation to slow down progression of AMD.9
Low-dose doxycycline and minocycline may show benefit in slowing progression of GA because of their anti-inflammatory properties.10,11 The Brimonidine Drug Delivery System (Brimo DDS; Allergan), a cytoprotective and neuroprotective agent in the form of a sustained-release and biodegradable polymer implant, failed to show effectiveness or safety with a suspended clinical trial.12
Complement inhibition appears to be a promising strategy to hinder GA progression.13 The complement system is a complicated cascade and is part of the immune system, known as the innate immunity.14
There are multiple cogwheels involved in activating this system, the action of which is essential to fight off offending agents, such as bacteria and toxins.
However, the overaction of this system can be damaging to human tissue, such as the RPE.15 Attempts have been made to block this system at its different levels. Previously, lampalizumab (Genentech), a novel selective complement factor D inhibitor, failed to meet primary end point.16
There are several novel agents currently in various clinical trial phases. Pegcetacoplan (APL2-103; Apellis Pharmaceuticals, Inc) is a selective pegylated peptide that binds C3, preventing its cleavage, which is required for opsonization and formation of the membrane attack complex that leads to cell death (NCT03777332).
Complement Factor (CF) I inhibition via AAV vector administration is being studied by Gyroscope Therapeutics, which was recently acquired by Novartis. Additionally, CF5 inhibition by intravitreal treatment with avacincaptad pegol (Zimura; IVERIC Bio) is under investigation by IVERIC Bio.17
Ionis Pharmaceuticals, Inc and Genentech are investigating CF B-ASO inhibition (IONIS-FB-Lrx) (NCT03446144). Genentech is also exploring the inhibition of high-temperature requirement A1, a trimeric serine protease widely expressed by the RPE, as well as increased production, which leads to elimination of extracellular protein matrix.
In turn, this damages photoreceptors, RPE, Bruch membrane, and causes choroidal atrophy.18
Although the availability of safe and effective therapies that can eliminate or reduce GA—and the vision loss associated with it—may seem out of reach, with so much interest, there will likely be treatments available in the near future.
The next hurdles would be recognition of at-risk patients and their acceptance of monthly, bimonthly, or long-term therapies as a prevention. For the latter, patient education will play an essential role.
Patients have been educated to adhere to many ocular and systemic diseases to prevent morbidity or mortality. Examples of these include glaucoma and systemic hypertension.
As ECPs, we must formulate strategies to educate patients about GA and potential consequences.
In addition to risk factors such as aging and smoking, ECPs must be familiar with various biomarkers that are detectable by existing imaging techniques: optical coherence tomography (OCT) and fundus autofluorescence imaging.19,20 (Figures 2 and 3)
Just as in the treatment of glaucoma, the goal is to identify and treat patients before any or minimal optic neuropathy occurs. The optimal therapy for GA may turn out to be in patients with telltale precursor signs.
None of the therapies mentioned above will address the unmet need of those patients who have already developed GA with significant functional vision loss. In that arena, stem cell therapy and cell transplantation are potential treatments we may see as therapeutic options.21,22
Inherited retinal disease
In the area of inherited retinal disease (IRD), over 270 genes have been identified as causing IRDs. These conditions are among the most common significant visual impairing conditions, affecting 1 in 3000 individuals in the US population.23,24
Genetic testing has also been more accessible and is offered through programs, such as ID Your IRD and My Retina Tracker Program, and are sponsored by Spark Therapeutics and Foundation Fighting Blindness through ECPs at no cost to the patient.
Voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) received FDA approval in 2017 and is the first FDA-approved gene therapy for conditions such as RPE65-associated retinitis pigmentosa and Leber congenital amaurosis. Using AAV2 vector technology has opened the possibility for other treatments.25,26
Therapies such as these are possible because of advances in gene editing, splicing, and the use of AAV vectors.
However, there are still hurdles and limitations to these therapeutic modalities. These include destruction of the vector or the gene fragment by preexisting host antibodies against the virus and/or the genetic load delivered by the vector and an inability to load the sufficient genetic material because of the limited size capacity of the viral vector.27
There are several studies for IRDs, such as various forms of retinitis pigmentosa (RP), Stargardt disease, and choroideremia, that are listed on the National Institutes of Health’s clinical trials website.
ECPs should remain informed with developments in this area for better care of patients suffering from IRDs.
Other hot topics in retina are in the headlines for an assortment of ocular and nonocular conditions. This includes a growth in remote and home-monitoring devices and the utilization of AI in detection and management of human ailments.
Home monitoring of medical biomarkers is not a contemporary concept. Thermometers, blood pressure (BP), and blood glucose (BG)-monitoring devices have all existed for decades.
Smartphones and watches are becoming more and more popular to monitor BP and heart rate. Even at-home echocardiograms are now recommended by cardiologists for better care of their patients.
Advances in BG monitoring and reporting with a feedback loop to insulin-delivery systems can improve the management of diabetes.
In retina care, the ForeseeHome monitoring device (Notal Vision) has been cleared by the FDA, with indication for patients with dry intermediate AMD.
Patients diagnosed with dry intermediate AMD have an increased risk for conversion to nAMD, and many may be unaware of subtle visual changes associated with early stages of choroidal neovascular membrane formation.
The use of preferential hyperacuity perimetry increases the likelihood of identification of patients’ changes in metamorphopsia preceding any subjective visual complaints, and thus detecting the conversion earlier and improving long-term visual outcomes of therapy.28,29
Notal Vision is developing the Notal Home OCT for patients who have converted and are under treatment for nAMD. This monitoring service will assist the treating retina specialist with decision-making for adjusting the follow-up intervals while relying on the Home OCT to alert the physician if any changes in fluid levels are detected, which would require the patient to return to the office.30
AI in eye care
AI is not a new concept; it has been around for several decades. However, it is becoming more and more ingrained in most of our day-to-day lives. If you need references, just ask your AI devices Alexa or Siri.
AI is also not a new concept in eye care, particularly in retina care. For example, the Swedish Interactive Thresholding Algorithm is an AI self-correcting, self-directing visual field operating system that has been around for several years.
On one hand, there is a disproportionate increase of patient populations affected by retinal disorders vs access to tertiary care providers31 and a push by insurance payors for a reduction in office visits and their financial obligations.
On the other hand, there have been significant advances made in the use of AI to screen and triage for specific disease. There is also the desire of many health care personnel for automation in clinical practice, which will inevitably increase the invasion of AI in retina diagnosis and management.
With FDA-approved imaging devices for detection of DR, we are bound to see AI assistance in diagnosis and management of retinal diseases.
We are living in an exciting era of rapid research and development of diagnostic technologies, patient care, and treatment modalities. As ECPs, our obligation is to keep up with these changes and stay informed to be able to deliver the best patient care at the highest level possible.