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Supplements A Managed Care Review: Approaches to Mitigate Blindness Associated with Neovascular Age-Related Macular Degeneration
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Review of Neovascular Age-Related Macular Degeneration Treatment Options
Nancy M. Holekamp, MD
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Approaches to Mitigate Blindness Associated with Neovascular Age-Related Macular Degeneration

Review of Neovascular Age-Related Macular Degeneration Treatment Options

Nancy M. Holekamp, MD
Faricimab
Faricimab (formerly RG7716 or RO 6867461) is a bispecific antibody that binds both VEGF-A and Ang-2 with high affinity and specificity.76 Preliminary data from phase 2 clinical trials suggest that faricimab has the potential to extend the dosing interval to every 16 weeks during maintenance therapy. Phase 3 clinical trials in nAMD, TENAYA and LUCERNE, are currently underway.77

ONS-5010
ONS-5010 is an intravitreal bevacizumab formulation that entered phase 3 development for nAMD in late 201878 that is also being evaluated for treatment of diabetic macular edema and branch retinal vein occlusion. Although it met bioequivalency criteria compared with both US and European reference products in a phase 1 trial, ONS-5010 is not being developed as a biosimilar. Two phase 3 trials will be comparing ONS-5010 with ranibizumab. The first trial is currently enrolling patients in Australia and New Zealand, and the second 11-month trial began recruiting 180 patients in the United States in the second quarter of 2019.79

Ranibizumab Port Delivery System
An investigative approach that intends to provide sustained intraocular delivery of an anti-VEGF agent is the ranibizumab port delivery system (PDS).80,81 The PDS, which is slightly longer than a grain of rice, is implanted through a small incision in the sclera at the pars plana. Insertion occurs in a surgical procedure under local anesthesia. The procedure includes laser ablation of the choroidal vessels at the incision line to reduce the risk of vitreous hemorrhage. After implantation, the PDS continuously releases ranibizumab via passive diffusion into the vitreous cavity. Refilling the port is an office procedure that is slightly more complex than an intravitreal injection. A customized needle, which must be held perpendicular to the device, injects ranibizumab into a self-sealing septum in the center of the implant. The needle has a dual lumen to remove and replace any remaining ranibizumab from the implant.80

Published results of the phase 2 LADDER trial provide insights about this approach.80 After 9 months, patients receiving ranibizumab 100 mg/mL and monthly ranibizumab injections had similar increases in BCVA (adjusted mean change from baseline of +5.0 vs +3.9 letters) and reductions in central foveal thickness. In patients receiving the implant, rates of ocular serious AEs and postoperative vitreous hemorrhage were 8.9% and 4.5%, respectively. The ranibizumab PDS is currently being evaluated in ARCHWAY, a phase 3 clinical trial enrolling patients with recently diagnosed nAMD who have responded to anti-VEGF therapy.80

Intravitreal Anti-VEGF Biosimilars
In addition to the new molecular entities discussed here, managed care will likely need to adapt to the entry of anti-VEGF biosimilars in the market. Patent expiration dates in the United States are in July 2019 for bevacizumab,82 June 2020 for ranibizumab,83 and June 2020  for aflibercept.84 Bevacizumab-awwb (Mvasi), a biosimilar for the treatment of colorectal, lung, brain, kidney, and cervical cancers,85 received FDA approval in 2017.86 Patent litigation concerns have prevented bevacizumab-awwb from reaching the US market, but it is forecasted to launch in July 2019.87 Another bevacizumab biosimilar, SB8, is currently in phase 3 development.88 It is unclear how bevacizumab biosimilars intended for use in oncology will affect the repackaging of bevacizumab for intravitreal administration by compounding facilities. Any impact may be temporary, depending on whether the FDA grants approval to ONS-5010. Ranibizumab biosimilars in phase 3 development include FYB201, SB11, and Xlucane.84 Development of FYB201 is on track for FDA approval by the time patents for ranibizumab expire. Aflibercept biosimilars are also in development.84

Management of Neovascular AMD in Managed Care
The cost of providing care to patients with nAMD is a key issue for the Centers for Medicare & Medicaid Services (CMS), as anti-VEGF agents account for a large portion of the CMS budget.89 In August 2018, CMS released a memo that allows Medicare Advantage plans to implement step therapy for physician-administered part B drugs starting January 1, 2019.90 A previous 2012 memo had prohibited this practice for Medicare Advantage plans.91 This policy change has raised awareness among medical organizations that represent retinal specialists and other ophthalmologists that the policy could cause sight-threatening delays in accessing appropriate and necessary anti-VEGF agents, based on clinical judgment. Dialogue between payers and providers about the latest advancements in nAMD management is a key tool in helping to provide optimal and cost-effective healthcare services to patients with this disease. The impact of anti-VEGF agent cost efficacy and other cost- and quality-related issues will be discussed in detail in the second section of this supplement.

Conclusions
To serve the needs of patients with nAMD, retinal specialists need immediate access to new treatment options with longer dosing intervals due to sustained delivery or increased durability of anti-VEGF drugs. Agents with new mechanisms of action are also needed for patients who do not respond adequately to current anti-VEGF agents. Anti-VEGF agents that address these needs are expected to reach the market over the next few years. Brolucizumab and abicipar pegol are anti-VEGF agents proven to be effective with extended dosing intervals and are expected to be considered for FDA approval sooner than faricimab or ranibizumab PDS. Development of abicipar pegol may be impeded by a high rate of intraocular inflammation. The ranibizumab PDS phase 3 clinical trial (ARCHWAY) is expected to show whether continuous (as opposed to pulsatile with injections) exposure to anti-VEGF therapy can improve the treatment response. Clinical trials with faricimab, the bispecific antibody that binds both VEGF-A and Ang-2, will elucidate the role of Ang-2 in nAMD. FDA approval of ONS-5010, the first bevacizumab formulation designed for intravitreal administration, could eliminate the need for bevacizumab compounding by 503B compounding pharmacies. As clinical development of these agents progresses, optimism is building that patients with nAMD will soon have a lighter burden of injections and monitoring while still maintaining their vision.  

Author affiliations: Director of Retinal Services, Pepose Vision Institute, Chesterfield, MO; Professor of Clinical Ophthalmology, Washington University School of Medicine, St Louis, MO.
Funding source: This activity is supported by an independent medical education grant from Regeneron Pharmaceuticals, Inc.
Author disclosure: Dr Holekamp has the following relevant financial relationships with commercial interests to disclose:
BOARD MEMBERSHIP: Gemini Clinical Advisory Board; Consultancies: Allegro, BioTime, Clearside, Genentech, Katalyst, Novartis, Regeneron
GRANTS: Gemini, Gyroscope, Roche/Genentech
SPEAKERS BUREAU: Alimera Sciences, Allergan, Genentech, Regeneron, Spark
PATENTS: Katalyst
STOCK OWNERSHIP: Katalyst
Authorship information: Concept and design, critical revision of the manuscript for important intellectual content, and supervision.
Address correspondence to: nholekamp@peposevision.com.
Medical writing and editorial support: Jill E. Allen, PharmD, BCPS.
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