The development of sight-saving pharmacotherapy for neovascular age-related macular degeneration (nAMD) has arguably been the most significant ophthalmologic advance of the past 20 years. Rapid acceptance and widespread use of approved drugs that inhibit the actions of vascular endothelial growth factor (anti-VEGF) has reduced by approximately 50% the incidence of blindness in industrialized nations. New drug development continues at a breathtaking pace but limitations in their achievable outcomes are beginning to emerge. Ranibizumab, bevacizumab, and aflibercept improve best corrected visual acuity(BCVA)by 7 to 11 letters and recent phase III trials with abicipar, brolucizumab, and faricimab produced non-inferior efficacy results, but they failed to achieve superiority.
Creating a successful combination therapy regimen, in which a second drug that targets anon-VEGF cytokine pathway is added to an anti-VEGF regimen, that incrementally improves BCVA more than anti-VEGF monotherapy would be a long-awaited breakthrough. This requires successful completion of a superiority trial in which BCVA is at least 5 letters better than anti-VEGF monotherapy, or significantly more subjects improve by at least 15 letters. Fovista, a platelet derived growth factor inhibitor, and nesvacumab, an angiopoietin-2 inhibitor, failed to produce incremental improvements in BCVA in phase III and II trials, and faricimab, a bispecific antibody against VEGF and angiopoietin-2, failed to produce superior BCVA improvements when dosed monthly. OPT-302, a VEGF-C and VEGF-D inhibitor, in combination with ranibizumab produced 3 letters of incremental BCVA improvement in a phase II trial, and it will be evaluated in upcoming phase III. Small molecule tyrosine kinase inhibitors that target VEGF and other cytokines pathways are being developed but early results are mixed.
Abicipar, brolucizumab, and faricimab produced BCVA improvements at 3- and 4-month intervals that rivaled but did not exceed standard-of-care. As a result, drug developers have largely pivoted from trying to improve peak efficacy with anti-VEGF or multi-target therapy, and instead have focused on extending the duration of anti-VEGF therapy. Several extended duration strategies are being pursued by various companies, but recent failures emphasize that this strategy is not without its challenges.
Abicipar was non-inferior to ranibizumab but was associated with unacceptably high incidences of post-injection intraocular inflammation. Modifying the drug to reduce inflammation may not be possible, which makes the future of this drug unknown. The ranibizumab port delivery system (PDS) performed comparably to monthly ranibizumab injections in the phase 3 ARCHWAY trial, but post-approval dislocation of the impermeable septum led to voluntary removal of the device from the market for what is expected to be one year. KSI-301, a drug conjugate that was designed to have a long intraocular half-life, failed in the phase II trial to produce non-inferior results compared to the control.
Attempts to produce long-term therapies (duration of greater than 1 year) have thus faryielded mixed results. Neurotech’s encapsulated cell technology (producing ciliary neurotrophic factor) is in phase III trials for macular telangiectasia, but an anti-VEGF producing device failed in a phase II a trial. Some physicians refer to gene therapy as the “holy grail” of nAMD treatment and RegenXBio is building off the phase II AVIATE (suprachoroidal) trial by currently enrolling patients in the phase IIb/III ATMOSPHERE trial.
Probably the most disruptive drugs to enter the market over the next five years will be the biosimilars. Biosimilars to ranibizumab (Byooviz and Cymerli) are already approved and available, and biosimilars to aflibercept are likely to enter the market in 2024. Biosimilars are priced lower than their reference drugs – Byooviz is 59% the cost of ranibizumab and Cimerli is 70% the cost. My foundation’s purchasing department noted a significant decrease in Medicare reimbursement of ranibizumab without a concomitant decrease in purchase price, which exposes the buyer to a $300 to $500 loss per injection and will likely force physicians to shift from ranibizumab to a biosimilar or branded drugs such as faricimab or aflibercept. Similar price/reimbursement changes are likely to affect aflibercept use following approval of its biosimilars.
Three bevacizumab biosimilars have been approved for intravenous use but it’s not known if these will be compounded for intravitreal injections. A bevacizumab biosimilar has completed a phase III trial and a confirmatory (NORSE 2) trial is underway. If this drug is approved, it will cause major changes in nAMD drug use. Compounded bevacizumab costs approximately $50/dose but the approved biosimilar will undoubtedly be more expensive – rumor puts its future price at $600/dose. It is not clear that US Pharmacopeia Chapter 800 will allow compounding of bevacizumab once a US FDA approved dose becomes available. If this proves to be the case, then switching from compounded bevacizumab (the most used anti-VEGF by most physicians) to a biosimilar or branded drug will significantly increase the total cost of anti-angiogenesis therapy in the US.
The “Inflation Reduction Act” passed by US congress in 2022 has a provision that allows price negation for the most expensive (by total cost) drugs to Medicare Parts B and D. This legislation is intended to bring down the expenditure for expensive drugs but the many caveats within the legislation will significantly limit savings over the next 10 years.
Where does all of this lead us? I’m becoming increasingly convinced that breaking the +10 letter BCVA “ceiling” may not be achievable, no matter what pathways are targeted by new drugs. The rush of newly approved biosimilars will decrease our reliance on currently branded drugs and at the same time we’ll see a trickle of new, more expensive drugs that aim to decrease treatment burden. Physicians and patients will see an expanding array of therapeutic choices, and more than ever before, drug selection will be personalized according to the needs and wants of each patient.
