New Developments in Macular Degeneration/Diabetic Eye Disease

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Visual impairment can be a major health issue for older adults, ranging from a minor inconvenience to vision loss significantly impacting quality of life.  Age-related macular degeneration (AMD) is a neurodegenerative disease of the retina and would fall into the latter category. It’s the leading cause of irreversible vision loss among the elderly. In 2016, eleven million patients with AMD were reported in the US, and 22 million patients with AMD are expected in the United States by 2050. There are two types of AMD, wet and dry. While dry AMD is the more common eye disease, it actually causes less damage to vision; wet AMD (wAMD) is less common but too often results in more serious loss of vision.  

A Little History 

Over 20 years ago, a diagnosis of wAMD meant loss of vision within a few years after diagnosis because there were no effective treatment options available. Initially, the breakthrough treatment for AMD was photodynamic therapy. After two years of photodynamic therapy, only 15% of patients maintained 20/40 vision while 40% of patients decreased to 20/200 or worse. In untreated patients, 90% experienced vision loss within two years and 75% declined to 20/200 or worse. 

This all changed in 2004 when Macugen (pegaptanib), the first vascular endothelial growth factor (VEGF)  inhibitor, was approved to treat wAMD. VEGF plays a major role in several ocular disorders. VEGF inhibitors reduce leakage from blood vessels, prevent formation of new abnormal vessels, decrease swelling in the retina, and improve visual acuity in patients with neovascular (wet) AMD, Diabetic Retinopathy, and Diabetic Macular Edema. Eventually Macugen was discontinued as more effective VEGF inhibitors were developed. This group of ground-breaking therapies revolutionized retinal vascular disease management and has become the new standard of care for wAMD. More recently, there have been further innovations as well as cost-savings opportunities in wAMD treatment. 

Not long after Macugen, another VEGF inhibitor was launched. Lucentis (Ranibizumab), manufactured by Genentech, was approved to treat wAMD in June 2006. Lucentis later gained FDA approval to treat diabetic macular edema (DME), diabetic retinopathy (DR), macular edema following retinal vein occlusion (ME after RVO), and myopic choroidal neovascularization (mCNV). The usual dosage to treat AMD, ME after RVO, and mCNV is 0.5mg injected intravitreally per affected eye once a month. Yes, an intravitreal injection is a shot of medicine directly into the eye using local anesthetics. The dose for DME and DR is 0.3mg injected intravitreally monthly.  The cost per dose of Lucentis 0.5mg is $1,950 and 0.3mg is $1,170. For wAMD, after 3 monthly injections, certain patients may be maintained on less frequent dosing regimens. A regimen averaging 4 to 5 injections every 9 months may be used without much change in visual acuity. Although not as effective, an every 3-month dosing regimen can be used may also be used for certain patients. Sales for Lucentis in 2021 totaled $2.28 Billion and accounted for one-fourth of the market share. 

Regeneron’s Eylea (aflibercept), another VEGF inhibitor, was approved in 2011 for the treatment of wAMD. Eylea later received FDA approvals for the treatment of DME, DR, and ME after RVO. Dosing for patients with wAMD, DME, and DR is 2 mg intravitreal injections every 4 weeks for the first 2–5 months, followed by 2 mg intravitreal injections every 8 weeks thereafter. Some patients may need to be maintained more frequently than every 8 weeks. Other patients may extend treatment frequency to every 12 weeks after one year of effective treatment, but it is not as effective as the every 8-week administration. The cost per dose of Eylea 2mg is $1,850. With sales hitting $5.21 Billion in 2021, Eylea competed primarily with Lucentis, which is usually dosed every 4 weeks, and quickly surpassed Lucentis as the market leader in the AMD/Diabetic Eye Disease category.  

 

The Next Wave 

For many years Lucentis, Eylea, and off-label use of Avastin (which will be discussed later) were the mainstays for anti-VEGF treatment. However, real world data shows visual acuity may deteriorate over time, despite the use of these treatments. Although reasons remain unclear, it has been suggested that undertreatment may be one of the causes for the slight loss of visual acuity in certain individuals as studies show patients receiving fewer injections per year on average. Many factors come into play for this including frequency and the difficult route of administration. It makes sense the next wave of treatment options focuses on less frequent administrations.  

Beovu (brolucizumab-dbll) was approved in October 2019 for the treatment of wAMD. Beovu is a recombinant human vascular endothelial growth factor (VEGF) inhibitor and joins a crowded class that includes several other VEGF inhibitors still currently available. Manufactured by Novartis, Beovu is differentiated from competitors based on greater fluid reduction in the eye and the potential for less frequent injections. However, it comes with safety concerns which will dampen Beovu’s market outlook. Beovu’s prescribing information was modified in June 2020 to warn of potential Retinal Vasculitis and/or Retinal Vascular Occlusion. Beovu 0.6mg is recommended to be injected intravitreally once a month for 3 months, followed by injections every 8 to 12 weeks. The cost per injection of Beovu is $1,850. Even though Novartis is marketing Beovu as a longer-lasting product, the optimal frequency for injections is still not clear. As sales reached only $159 million in 2021, it remains to be seen what proportion of Beovu patients will need injections every 8 weeks versus every 12 weeks. 

Susvimo (ranibizumab) manufactured by Genentech was approved in October 2021 to treat wAMD for patients who responded to at least 2 intravitreal injections of a VEGF inhibitor. Susvimo’s active ingredient ranibizumab is the same active ingredient in Lucentis. Instead of getting injected directly into the eye, Susvimo consists of a small port that is surgically implanted in the eye. This port releases ranibizumab continuously over the course of 6 months. The implant is a surgical procedure that must be performed in an operating room under aseptic conditions by a physician experienced in vitreoretinal surgery. Refills would also be performed under aseptic conditions by a physician experienced in ophthalmic surgery. Clinical trials showed similar efficacy with monthly injections of Lucentis. Susvimo is only approved for wAMD and does not currently have the other eye disorder indications that Lucentis has. Phase III trials in DME and DR are underway with results expected in 2022 and 2023 respectively.  Susvimo also comes with safety concerns. The label contains a black box warning that the Susvimo implant has a 3-fold higher rate of endophthalmitis than monthly intravitreal injections of Lucentis (1.7% Susvimo patients vs 0.5% in Lucentis patients). Endophthalmitis is an infection of the eyeball that causes severe inflammation which can possibly lead to blindness. The cost of Susvimo is $17,250 for the first year which includes the implant. The administration cost of the surgery for the implant and the refills are additional. The annual cost in subsequent years is $16,000 for refills not including the surgery cost. 

On January 2022, Vabysmo (faricimab-svoa) manufactured by Genentech was approved to treat wAMD DME. Vabysmo is a bispecific antibody designed to block both vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2) disease pathways which are linked to vision loss. Clinical trials demonstrated its efficacy was non-inferior to the market leader Eylea. Although Vabysmo is administered intravitreally, it differentiates itself from its competitors with a longer dose interval of up to 16 weeks for both wAMD and DME. At a cost of $2,190 per 6mg injection, Vabysmo costs more per dose than its other intravitreal anti-VEGF competitors; however, for patients who can be maintained long-term on an every-16-week dose interval, Vabysmo is the most cost-effective agent after Avastin. On the other hand, for patients who require a more frequent dosing interval, Vabysmo may be more expensive than Lucentis and Eylea. 

 

Management Opportunities 

Along with innovation comes opportunities to manage appropriate use of these costly treatments for patients and payers. We’ve only reviewed FDA-approved drugs used to treat wAMD thus far. A major cost-effective treatment involves the off-label use of Avastin to treat wAMD. Avastin (bevacizumab) is a monoclonal antibody given intravenously to treat several types of cancer. Avastin is very similar in structure to Lucentis which is used to treat eye disorders. In fact, Lucentis is actually an antibody fragment of Avastin. The cost of a dose of Avastin used to treat cancer is still relatively high, a typical 700mg dose costs $5,578. However, Avastin given intravitreally for eye disorders is just a fraction of the cost since the dose per eye is 1.25mg and costs around $50. Under aseptic conditions, a compounding pharmacy can extract and repackage multiple doses from a 100mg vial of Avastin. At a cost of $797 per vial you can see how cost-efficient this can be. This off-label use of Avastin has been in place since 2005. In 2011, the National Eye Institute’s  Comparison of AMD Treatment Trials (CATT) compared the safety and efficacy of Avastin to Lucentis and confirmed the two drugs to be equally efficacious and safe in treating wAMD to put aside any concerns about the differences in these two drugs. Although Avastin is not FDA-approved for the treatment of wAMD, it provides a solid cost-effective treatment alternative, even if injections are generally needed every 4 weeks. Retinal specialists across the country have embraced the off-label use of Avastin and many will use it first line in their patients. Different utilization management and provider reimbursement strategies can be employed based on line of business, type of eye disorder, and other patient factors.  

In September 2021, the FDA approved the first Lucentis biosimilar, Bioepis/Biogen’s Byooviz. Byooviz is approved to treat wAMD, macular edema following retinal vein occlusion, and myopic choroidal neovascularization. It differs from Lucentis in that Byooviz is not currently FDA-approved for diabetic retinopathy and diabetic macular edema. Only the 0.5mg/0.05ml formulation is approved which is the dose for the approved indications. Byooviz is expected to launch June 2022. In addition, another biosimilar for Lucentis from the Swiss company Bioeq AG has been filed with the FDA and a decision is expected in August 2022. 

 

Conclusion 

The AMD treatment landscape has significantly changed over the past 20 years. Transitioning from an untreatable disease often leading to blindness to a treatable condition. For patients and payers, there are many factors to consider. There are many more treatment options available that vary in cost. The off-label use of Avastin will continue to be a front-line option because of its low cost. It is difficult to compare the cost of the intravitreal injections because of varying injection frequencies. A closer scrutiny of medical claim submissions would be needed to analyze actual cost. Newer therapies such as Susvimo and Vabysmo provide extended dosing intervals, which may help with patient compliance, but side effects and administrative costs also need to be considered. Increased market competition will also impact treatment costs. Besides Byooviz, additional biosimilars to Lucentis are expected to be approved late 2022 and 2023. Eylea biosimilars are expected in late 2023 or early 2024. As treatment options for AMD become more complex, patients and payers will need to weigh all options when considering the best treatment option. 

 

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