Jay S. Duker, MD- President and Chief Operating Officer, EyePoint Pharmaceuticals
We live in an age of medical exploration. Each day it seems a new drug, therapy, or clinical trial is underway to combat ailments of diverse complexities. From the latest over-the-counter treatments to advancements in cancer research, the new frontier of medicine is constantly expanding, bringing hope to patients and practitioners around the world and across specialties.
But just as important as the drugs being developed are the methods of delivery and their associated treatment burden. Often, the focus is on the “disease burden” – the impact a disease has on a patient which includes factors such as mortality, morbidity, and financial cost. Understanding the disease burden is undoubtedly important, and it is the patient need that stems from this burden that sparks much of the innovation we see across the therapeutic spectrum.
However, it’s critical that we acknowledge that treatment burden affects patients and caregivers. The level of treatment burden can be a key factor in a therapy’s success or failure and can dictate how patients utilize a treatment or even if they will utilize a treatment at all.
The ramifications of a high treatment burden can be observed in those suffering from serious eye disorders, such as age-related macular degeneration (AMD) – the leading cause of legal blindness in people 50 years of age and older in the United States.1 Especially in chronic conditions that afflict vulnerable portions of the population, such as the elderly, we must innovate to not only create new therapies but provide treatment options that can be more easily integrated into patients’ and their caregivers’ lives.
While ocular treatments have advanced exponentially, there is still much more to be done in the drug delivery space to reduce treatment burden and improve patient outcomes.
Today’s Standard of Care
Wet age-related macular degeneration (AMD), the most aggressive form of AMD, is characterized by new blood vessel growth and subsequent leakage of fluid and/or blood in the macula (center of the retina). Without early and frequent treatment, irreversible vision loss can occur – a debilitating outcome for patients and caregivers alike.
The current standard of care for this disease is in-office, intraocular injections with anti-vascular endothelial growth factor (VEGF) agents. These medications block the leakage from abnormal blood vessels and decrease the damage and scaring to the retina. Although there are many safe and effective anti-VEGF treatments available on the market today, the recommended administration of the medication involves intravitreal (back of the eye) injections approximately every month for the first three months, followed by intravitreal injection once every four to eight weeks. On average, in the United States, retinal specialists give anti-VEGF’s approximately every seven weeks to chronic wet AMD patients.
The frequency of treatment can be a deterrent for patients and/ or their caregivers as evidenced by the 2022 American Society of Retina Specialist’s PAT survey, which found that two-thirds of the undertreatment of wet AMD patients in the real world is due to patient non-compliance and/or provider preference for less frequent dosing.
Additional research into wet AMD treatment adherence has found that nearly one in nine patients are lost to follow up, or 11%, meaning they have not obtained treatment within twelve months of their first injection.2 This number only increases among patients older than 90 years of age.2
These statistics are particularly concerning when coupled with data indicating that a delay in care of only 5.34 weeks can result in visual loss (Figure 1).3 With just a single missed ophthalmology appointment, patients can experience decreased visual acuity.4
For anyone in the world treating older patients with chronic ocular diseases, these numbers should be troubling. Despite the many treatment options available, obstacles still exist for vulnerable patients, which can contribute to vision loss, and ultimately blindness, over time.
With an aging population and the number of people afflicted by serious eye disorders growing, it’s critical that we not only better understand current treatment limitations but address them for the sake of patients’ visual health and their ability to maintain performance in daily activities
The Evolution of Drug Delivery
Despite the limitations we still face, medicines and their delivery systems have evolved tremendously in the ocular disease space over the last few decades. Initially, eye drops served as the main treatment option for patients, and while they were simple, well tolerated among patients, and safe to use, they were only effective in treating the anterior segment of the eye.
To circumvent the eye’s formidable anatomical barrier mechanisms that hindered drug penetration, doctors began prescribing oral antibiotics and corticosteroids, which were effective but only for a limited number of conditions and with potential adverse systemic side effects.
Treatment then evolved to intravitreal delivery, which allowed for the targeted delivery of medicine into the back of the eye. In 1996, the US Food and Drug Administration (FDA) approved the Vitrasert Implant, the first sustained-release local ocular delivery system that provided targeted treatment to the retina without systemic side effects. Since then, ocular innovation has intensified with a variety of surgical implants and intravitreal extended duration and sustained release devices being brought to market.
And yet, despite the efforts of brilliant researchers that have achieved such impressive innovations in a relatively short period of time, a gap in patient care persists. For many patients suffering from wet AMD and other serious eye disorders, traveling for monthly injections is unsustainable regardless of how effective the treatments may be.
The challenge becomes, how do we maintain positive vision outcomes while reducing the logistical burden on vulnerable patients and their caregivers?
It’s a question that drug manufacturers are currently exploring with a few potential solutions gaining traction.
New Approaches to Treatment
Patient unmet need is one of the greatest catalysts for innovation. With treatment non-compliance threatening patients’ visual health and the longevity of their sight, the pharmaceutical industry is responding to reduce treatment burden and to encourage improved outcomes through a variety of avenues spanning gene therapy, high dose treatment, intraocular implants, and sustained drug delivery. While wet AMD is the immediate application for these new approaches, innovation in this area is expected to extend more broadly to other forms of AMD, like geographic atrophy, where recent therapies currently in development have for the first time shown promising clinical benefits.
Gene Therapy
Gene therapy, although in its early stages as a drug delivery platform, is a potentially promising concept geared towards enabling ocular cells to create and deploy their own anti-VEGF proteins. REGENXBIO’s RGX-314, an anti-VEGF treatment with the potential to block VEGF for years or perhaps even indefinitely following a one-time procedure, is currently being investigated with promising interim data from its Phase II AAVIATE® trial.
Adverum Biotechnologies is also investigating a gene therapy option in Ixo-vec (ixoberogene soroparvovec, formerly referred to as ADVM-022), with patient enrollment and dosing in progress for its Phase II LUNA trial.
High Dose Treatment
Another approach to reducing patient burden is administering a higher dose of treatment with longer intervals between injections. Regeneron is exploring the viability of this concept with high-dose EYLEA®, having presented positive Phase II data in 2022 and Phase III data in 2023.
Implants
Refillable intraocular implants similarly hold potential for reducing treatment burden by involving a one-time surgical procedure to place an implant in the wall of the eye. This implant is then refilled through intraocular injection at a reduced frequency than the current standard of care. Roche’s first-of-its-kind device, SUSVIMO™, obtained FDA approval in October 2021 and additional research is underway across the industry.
Sustained Drug Delivery
In addition to gene therapy, higher dosing, and intraocular implants, sustained drug delivery is also an area of interest that has seen positive outcomes for ocular diseases, such as cytomegalovirus (CMV) retinitis, glaucoma, and chronic non-infectious uveitis. Now, the concept is being applied to wet AMD.
EyePoint’s EYP-1901, a novel sustained delivery intravitreal anti-VEGF treatment, is currently undergoing Phase II clinical trials following the completion of a successful Phase I clinical trial that showed positive safety and efficacy data. Over 50% of the enrolled patients were able to go up to six months with stable vision and anatomy after a single injection of EYP-1901, with no supplemental injection. One third of eyes went up to one year after a single injection. The insert-based technology is designed to offer a stable release of medication in the eye to prevent vision loss, as well as a reduction in treatment burden by enabling less frequent patient visits. Like the current approved anti-VEGF medications, EYP-1901 is delivered via a single intravitreal injection in the ophthalmologist’s office.
It’s clear that there are a variety of research initiatives underway that may help to ease the burden on patients suffering from serious eye disorders. With no patient being the same, the availability of multiple therapy options is necessary as clinicians take into account each patient’s individual needs and limitations when determining optimal treatment plans.
While there will never be a perfect solution for wet AMD, or any other disease for that matter, the proliferation of ophthalmic innovation and research will better enable us to minimize gaps in current patient care.
The Future of Patient Care
Driving new research initiatives forward in the ophthalmic space is how we can continue to provide value to patients. For decades, researchers and scientists in our field have leveraged their expertise to expand the limits of ophthalmic treatments, and it is incumbent upon us to continue making strides in patient care.
With a variety of novel delivery methods being explored, the future before us is an exciting one. By listening to patients and understanding the burdens of both disease and treatment, we will reimagine the current standard of eye care and ensure not just a better future but one that patients can see and experience for themselves.
References
- Johns Hopkins Medicine. Age-Related Macular Degeneration (AMD) information page. Available at: https://www.hopkinsmedicine.org/health/conditions-and-diseases/ agerelated-macular-degeneration-amd#:~:text=Age%2Drelated%20macular%20 degeneration%20is,ability%20to%20see%20fine%20details. Accessed February 9, 2023.
- AAO. Skipping This Sight-saving Treatment Is Costing Americans Their Vision. Available at: https://www.aao.org/newsroom/news-releases/detail/skipping-treatment-is-costing[1]americans-vision. Accessed February 9, 2023.
- Lotery et al. Eye. (2017) 31, 1697-1706.
- Ramakrishnan MS, Yu Y, VanderBeek BL. Association of Visit Adherence and Visual Acuity in Patients With Neovascular Age-Related Macular Degeneration: Secondary Analysis of the Comparison of Age-Related Macular Degeneration Treatment Trial. JAMA Ophthalmology. 2020;138(3):237–242. doi:10.1001/jamaophthalmol.2019.4577
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