Medications for Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of severe vision loss in adults over age 60. AMD occurs when there are changes to the macula, a small portion of the retina located on the inside back layer of the eye. The macula is the part of the eye that controls sharp, straight-ahead central vision. While AMD doesn’t cause complete blindness, losing central vision makes detailed tasks, such as reading, driving and recognizing faces, more difficult.

Two Types of AMD

The Centers for Disease Control and Prevention estimates that 1.8 million people have AMD and another 7.3 million are at substantial risk for vision loss from the disease. Caucasians are at higher risk for developing AMD, while women usually develop it at a younger age than men. Age-related macular degeneration usually does not have a clear-cut pattern of inheritance. However, an estimated 15 to 20% of people with AMD have a least one first-degree relative, such as a sibling or parent, with the condition.

Researchers have described two major types of AMD: dry form (atrophic) and wet form (exudative). The dry form is much more common, accounting for 85 to 90% of all cases of AMD. It is characterized by a buildup of yellowish deposits called drusen beneath the retina and vision loss that worsens slowly over time.

The most advanced stage of dry AMD is known as geographic atrophy, in which areas of the macula waste away (atrophy), resulting in severe vision loss. Dry AMD typically affects vision in both eyes, although vision loss often occurs in one eye before the other. While there is no specific treatment for dry AMD, studies have shown a potential benefit from vitamin supplements, a Mediterranean diet, protection from the sun’s ultraviolet light and smoking cessation.

In 10 to 15% of affected individuals, the dry form progresses to the wet form of age-related macular degeneration. This happens when a protein called vascular endothelial growth factor (VEGF) causes abnormal blood vessels to grow in the wrong place underneath the macula.

These fragile vessels leak blood and fluid causing scar tissue that damages the macula. The wet form of AMD is associated with severe vision loss that can worsen rapidly. Wet AMD may respond to intraocular injections of a VEGF inhibitor if detected and treated early. VEGF inhibitors reduce leakage from blood vessels, prevent the proliferation of new abnormal vessels, decrease swelling of the retina, and improve visual acuity in patients with wet AMD.

Leading AMD Medications

Currently, five medications are approved to treat wet AMD: brolucizumab (Beovu®), aflibercept (Eylea®), ranibizumab (Lucentis®), ranibizumab (Susvimo™) and faricimab-svoa (Vabysmo®). A sixth drug, bevacizumab (Avastin®), which has been approved by the FDA as a blood vessel growth inhibitor to treat colorectal and other cancers, is used off-label to treat AMD. It must be obtained through a 503B compounding pharmacy or repackaged in-house at a physician’s office. Avastin was shown to have similar efficacy and safety compared to Lucentis in a large clinical trial sponsored by the National Institutes of Health (NIH) and coordinated by the University of Pennsylvania.

All the VEGF inhibitors are effective at reducing or eliminating the excess blood and fluid in patients with wet AMD. The most notable difference is frequency of administration. Lucentis and Avastin are typically injected every four weeks. Eylea and Beovu have injection requirements every eight weeks and 12 weeks respectively. In October 2021, the FDA approved Susivmo, a port delivery system that requires a one-time surgical implantation of a port designed to hold a six-month supply of a customized formulation of ranibizumab.

Vabysmo was approved by the FDA January 2022 and is a next-generation product that also allows for extended dose intervals. In the most recent studies, over half the participants on Vabysmo went four months between treatments while maintaining improvements in vision after the initial administration of four monthly eye injections. Vabysmo also has a unique mechanism of action in that it is designed to block two disease pathways, angiopoitin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). Preclinical studies have shown that blocking both pathways may have complementary benefits versus inhibition of VEGF-A alone.

Biosimilars

Biosimilars will soon provide additional treatment options for wet AMD. In September 2021 Byooviz™ (formerly SB11) was the first ophthalmology biosimilar approved by the FDA. It is the first biosimilar for Lucentis and is expected to launch in June of this year. A second Lucentis biosimilar, Cimerli™, is scheduled to be reviewed by the FDA in August, and if approved, will likely launch shortly thereafter. Eylea biosimilars are expected in 2024. Currently there are two biosimilars for Avastin, Mvasi® and Zirabev™. These biosimilars have not been studied in wet AMD since the reference product, Avastin, does not have this indication and is used off-label.

Costs

Based on published list prices, costs of the anti-VEGF inhibitor medications for the treatment of AMD are difficult to compare due to differences in injection frequencies. In the current environment, Avastin provides the most cost-effective treatment alternative. It has an annual cost of approximately $200, assuming monthly injections. With monthly injections, Lucentis is the most expensive with an annual average wholesale price of over $25,000. The annual cost of Susvimo is approximately 30% less than the cost of Lucentis. Biosimilars usually provide a 15% discount to the reference brand.

Drug Pipeline for AMD

Several medications in the pipeline may significantly alter the AMD treatment landscape over the next several years:

Lytenava™, if approved, will be a commercially available formulation of bevacizumab specifically for the treatment of AMD. Lytenava may replace repackaged Avastin and is estimated to be approximately half the price of Lucentis annually, but significantly more than the currently compounded form of Avastin. The manufacturer plans to file a BLA in 1Q 2022 with a potential FDA approval in early 2023.

Eylea HD (intravitreal injection) is a next-generation product in Phase 3 clinical trials. The high dose (8 mg) formulation of aflibercept provides longer treatment intervals than the current dosage strength of Eylea (2 mg). In clinical trials, patients are administered 8 mg of aflibercept at intervals of 12 or 16 weeks.

RGX-314 is a one-time investigational gene therapy utilizing a novel adeno-associated viral vector (AAV8) that contains a gene encoding for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation.

It should enable retinal cells to produce their own indefinite supply of anti-VEGF. The manufacturer is researching two separate routes of administration of RGX-314 to the eye, through a standardized subretinal delivery procedure, as well as delivery to the suprachoroidal space. Interim data from the Phase 2 multicenter, open-label, randomized, active-controlled, dose-escalation AAVIATE trial showed suprachoroidal delivery of RGX-314 to be safe and effective for AMD.

Six months after one-time treatment, patients in the study group were more likely to have stable visual acuity and retinal thickness and at least a 70% reduction in anti-VEGF treatment burden. In addition, 40% of those in the treatment group were free from anti-VEGF injections after six months. These results are similar to data from a study evaluating the therapy in subretinal delivery, which currently has two years of data.

A Phase 1/2a trial in which patients were given RGX-314 subretinal during vitrectomy found a reduction in anti-VEGF treatment burden and a potential for treatment effect out to three years. Overall, RGX-314 was reported to be well tolerated with only mild adverse events and intraocular inflammation that resolved within days to weeks on topical corticosteroids. Two Phase 3 trials are underway.

The ATMOSPHERE trial will compare two RGX-314 dose arms to Lucentis and two RGX-314 dose arms to Eylea. Both studies will evaluate the change from baseline in Best Corrected Visual Acuity (BCVA) at one year. The estimated primary completion date for the ATMOSPHERE trial is March 2023. A Biologics License Application (BLA) is expected to be submitted to the FDA in 2024 with a potential approval in 2025.

ADVM-022 is also a one-time investigational gene therapy that utilizes a proprietary vector capsid (AAV.7m8). The vector carries an aflibercept coding sequence designed to provide potentially sustained therapeutic levels of aflibercept. This should minimize the need for repeat injections. In the multicenter, open-label, dose-escalation OPTIC trial, patients were stratified into four dosing cohorts (two high dose and two low dose).

In October 2021, the manufacturer presented two-year follow-up data from the Phase 1 OPTIC study at the Retina Society’s 54th Annual Scientific Meeting. The data demonstrated a greater than 80% reduction in annualized anti-VEGF injections in the two low dose cohorts which is expected to be validated in an upcoming Phase 2 study. ADVM-022 was well tolerated and ocular inflammation was minimal and responsive to steroid eye drops. At the study participant’s latest visit, all low dose patients were inflammation-free, and none required any steroid eye drops to treat inflammation.

ADVM-022 was also being evaluated for diabetic macular edema (DME) in the INFINITY trial. However, in July 2021, the manufacturer announced that they would stop development of ADVM-022 in DME due to sudden drops in intra-ocular pressure in some patients who received the therapy. The adverse events were serious enough to require treatment, including surgery. Development for the AMD indication will continue with Phase 2 trials initiating this year. However, the approval outlook for this gene therapy is unclear due to the safety concerns that emerged from the DME trials.

Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in most patients. These therapies, however, require life-long intraocular injections, typically repeated every four to 12 weeks in frequency, to maintain efficacy. Due to the burden of treatment, patients often experience a decline in vision with reduced frequency of treatment over time.

Gene therapy has the potential to advance the treatment of several ophthalmic diseases, including AMD. Clinical trials for wet AMD have shown promising results, with gene therapy providing vision improvement without causing major safety concerns. However, questions regarding gene therapy remain, including long term durability, safety and high cost. Luxturna®, a one-time gene therapy for a rare inherited retinal disease, costs $850,000 for treatment in both eyes.

While AMD gene therapy treatments are unlikely to be quite that expensive due to a much larger patient population, they are still expected to cost significantly more than currently available anti-VEGF therapies.

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