Farcimab: a flicker of light in the darkness of neovascular age-related macular degeneration and Diabetes Mellitus – correspondence

Age-related macular degeneration (AMD) is ‘ an acquired degeneration of the retina due to the modi ﬁ cation of the Bruch ’ s membrane and the retinal pigment epithelium ’ [1] . AMD can be classi ﬁ ed as either atrophic (dry form), present in 80% of the patients, or exudative/neovascular (wet form), affecting up to 15% patients [1,2] . Although less prevalent, neovascular age-related macular degeneration (nAMD) accounts for 90% of subsequential vision loss, with patients affected by the dry form also eventually progressing to nAMD [1] . Diabetic macular edema (DME), is one of the main manifestations of diabetic retinopathy [3] . Both DME and nAMD are associated with over-expression of vascular endothelial growth factor-A (VEGF-A), particularly in the vitreous and retina, causing alteration in the genes responsible for angiogenesis and vascular permeability, with consequential breaking of the blood retinal barrier and accumulation of ﬂ uid in the macula [1,3,4] . With the global number of patients with AMD estimated to rise to up to 288 million by 2040 and DME expected to cause visual impairment in up to 25% of patients with diabetic retinopathy in the USA by 2030, it is safe to assume the two may easily be classi ﬁ ed as the most common contributors to ocular morbidity worldwide [1 – 3] . The current FDA-approved treatment for both nAMD and DME is intravitreal anti-VEGF injections, including A ﬂ ibercept, Ranibizumab,


Dear Editor,
Age-related macular degeneration (AMD) is 'an acquired degeneration of the retina due to the modification of the Bruch's membrane and the retinal pigment epithelium' [1] . AMD can be classified as either atrophic (dry form), present in 80% of the patients, or exudative/neovascular (wet form), affecting up to 15% patients [1,2] . Although less prevalent, neovascular agerelated macular degeneration (nAMD) accounts for 90% of subsequential vision loss, with patients affected by the dry form also eventually progressing to nAMD [1] . Diabetic macular edema (DME), is one of the main manifestations of diabetic retinopathy [3] . Both DME and nAMD are associated with overexpression of vascular endothelial growth factor-A (VEGF-A), particularly in the vitreous and retina, causing alteration in the genes responsible for angiogenesis and vascular permeability, with consequential breaking of the blood retinal barrier and accumulation of fluid in the macula [1,3,4] . With the global number of patients with AMD estimated to rise to up to 288 million by 2040 and DME expected to cause visual impairment in up to 25% of patients with diabetic retinopathy in the USA by 2030, it is safe to assume the two may easily be classified as the most common contributors to ocular morbidity worldwide [1][2][3] .
The current FDA-approved treatment for both nAMD and DME is intravitreal anti-VEGF injections, including Aflibercept, Ranibizumab, Bevacizumab, and Brolucizumab, which inhibit neovascular proliferation [4] . However, with multiple clinical trials, it has been observed that 68% of nAMD patients on anti-VEGF do not achieve the threshold for driving vision (bestcorrected visual acuity of 20/40 Snellen equivalent) despite a year of treatment; even increasing the dose frequency has not shown any increase in efficacy or durability of results [5] . Furthermore, the high-frequency treatment, requiring multiple visits and injections, along with the unsatisfactory outcome and vision loss over time, have contributed to lapses in care, especially in DME patients [4] . One possible hypothesis for these results is that multiple pathways contribute to choroidal neovascularization, one of them being the angiopoietin-Tie2 (Ang/Tie2) axis [4,5] . This pathway complements VEGF-mediated activity in retinovascular diseases by Ang-2 upregulation, resulting in vascular leakage, pericyte loss, and inflammation [4] . Since anti-VEGF therapy alone has not provided the desired outcome, combining it with Ang-Tie targeted drugs may help reduce the disease burden.
A recent study by Khanani et al. [4] suggests that Faricimab, a bi-specific intravitreal antibody that simultaneously binds and neutralizes both Ang-2 and VEGF-A could be a turning point in the treatment of both DME and nAMD. Multiple randomized controlled trials have been conducted to find the efficacy and safety of the drug, along with comparing it to the currently available treatment. Successful phase 1 and phase 2 studies, including BOULEVARD for DME and AVENUE and STAIRWAY for nAMD, have confirmed not only patient safety and tolerance for the drug but also improved best-corrected visual acuity and the diabetic retinopathy severity score [6] . Since Faricimab is still in phase 3 trials, little to no information is available regarding its adverse effects. However, concern has been raised regarding the use of anti-VEGF while breast-feeding. The presence of VEGF in breast milk is believed to aid in gastrointestinal tract maturation. Although unlikely due to its large size, small amounts of Faricimab may be present in breast milk; therefore, lactating women are advised to observe caution until more data becomes available [7] .
Since both the diseases are highly prevalent and major liabilities to healthcare worldwide, it is imperative that we take prompt action to reduce not only the disease burden but also the treatment burden. Bi-specific treatment like Faricimab will result in more efficient treatment with fewer dose requirements, reducing the number of visits and therefore decreasing the overall treatment burden on the patient and provider, both in terms of cost and time. This may promote long-term adherence to the treatment, which might eventually improve the overall visual outcomes for both nAMD and DME. Faricimab may thus be a valuable contribution to the ophthalmological community. Therefore, it is imperative that further studies be promptly conducted, as this would undoubtedly be a positive development.

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