Long Term Efficacy of Faricimab Using a Treat and Extend Regimen for Type 3 Macular Neovascularization

Overview

Type 3 macular neovascularization (MNV) is a subtype of neovascular age-related macular degeneration accounting for 10-20% of cases, notable for high rates of bilateral involvement and risk of profound vision loss, particularly if undertreated. Early and proactive therapy is crucial to prevent progression and preserve vision. Faricimab offers potential advantages in this setting. Eyes with type 3 MNV often show thin choroid, reticular pseudodrusen, and high GA risk, reflecting compromised choroidal perfusion. While anti-vascular endothelial growth factor (VEGF) agents suppress neovascularization, prolonged VEGF blockade may impair choriocapillaris health. Ang-2 inhibition, by promoting Tie2 activation and vascular stability, may protect choriocapillaris and reduce widespread retinal edema and hemorrhages observed in type 3 MNV. Finally, while treat-and-extend is widely used in practice, existing trials (TENAYA, LUCERNE) applied broader extension intervals than typically used clinically. In type 3 MNV, where undertreatment carries severe consequences, a more stringent faricimab-based treat-and-extend regimen with 2-week interval adjustments warrants investigation.

1.1 The Nature of Type 3 macular neovascularization (MNV) and Recommended Therapeutic Approaches Type 3 MNV, also known as retinal angiomatous proliferation is a subtype of neovascular age-related macular degeneration (AMD) that is characterized by intraretinal neovascularization. The incidence of type 3 neovascularization is relatively lower than other subtypes of neovascular AMD, constituting 10 to 20% of entire neovascular AMD. However, it is a very important disorder because it often leads bilateral visual deterioration. The high risk of bilateral involvement is characteristic of type 3 neovascularization. In some cases, the visual prognosis of the initially uninvolved eye with better vision, is poorer than the initially involved eye. In addition, profound visual loss may occur during the treatment course, especially in undertreated cases. Thus, preserving vision is particularly important in type 3 neovascularization, which subsequently highlights the importance of investigating more effective treatment strategies. We previously suggested the need for proactive treatment in type 3 neovascularization to reduce the risk of abrupt visual loss. Furthermore, due to the progressive nature of type 3 MNV, there is an increased risk of visual impairment as the stages advance. Therefore, it is imperative to administer aggressive treatment during the early phase of the disorder to impede the progression of disease stages. 1.2 Why is Faricimab Particularly Advantageous for Type 3 MNV? (My own hypothesis) 1.2.1 The potential of ang-2 inhibition in preserving choriocapillaris Eyes with type 3 MNV usually exhibits very thin choroid, a high prevalence of reticular pseudodrusen, and a lack of choroidal vascular hyperpermeability. These observations collectively indicate compromised choroidal perfusion in such eyes. In fact, the occurrence of geographic atrophy (GA) is particularly elevated in type 3 MNV, and it serves as a significant contributing factor to the progressive deterioration of visual acuity over the long term in this condition. Due to these factors, maintaining adequate choroidal perfusion becomes particularly crucial in the treatment of type 3 MNV. The choriocapillaris is the most critical tissue for perfusion into the retinal pigment epithelium and retinal outer layers. While anti-vascular endothelial growth factor (VEGF) therapy is highly effective in stabilizing neovascularization, there have been concerns regarding its potential negative impact on the maintenance of retinal pigment epithelium and choriocapillaris by suppressing physiological VEGF, particularly following aflibercept therapy. In 2016, I was the first to propose the possibility that these aspects could pose a concern in the management of patients with type 3 MNV during actual clinical practice. It has been demonstrated in animal models of choroidal neovascularization that tie2 activation has the potential to induce choriocapillaris regeneration. It is not yet certain whether such phenomena occur in humans. Nonetheless, these research findings can provide support for the hypothesis that tie2 activation through ang-2 inhibition could potentially confer benefits in cases of compromised choroidal perfusion, such as in type 3 MNV. 1.2.2 The importance of promoting vascular stability in the treatment of type 3 MNV In Type 3 MNV, it is well-known that the neovascular lesion itself is often accompanied by extensive and severe retinal edema disproportionate to its size. Additionally, retinal hemorrhages unrelated to the location of the neovascular lesion can frequently occur. Dr. Richard Spaide, from Vitreous Retina Macula Consultants of New York, has proposed that the rapid elevation of VEGF levels leads to the occurrence of such phenomena, including increased vascular permeability and leakage, not only in the neovascular lesion but also in the surrounding retinal vessels. If this hypothesis is valid, it underscores the potential benefit of ang-2 inhibition in the treatment of type 3 MNV, as it suggests that enhancing overall retinal vessel stability, rather than solely focusing on neovascular lesion suppression, could be of substantial advantage. 1.3 Why is an Additional Treat-and-Extend Study Utilizing Faricimab Deemed Necessary? The treat-and-extend regimen is widely acknowledged as a highly effective and efficient treatment approach for type 3 MNV, and it is extensively utilized in industrialized countries. In the TENEYA and LUCERNE clinical trials, conducted to evaluate the introduction of faricimab, personalized treatment intervals (PTIs) were employed for treatment, and starting from the second year, a treatment approach similar to treat-and-extend was implemented. This approach offers a better reflection of treatment patterns in real-world settings compared to the fixed-dosing regimen utilized in previous clinical trials for the introduction of other anti-VEGF agents. Moreover, as suggested by Khanani et al., it may maximize the benefits of angiopoietin-2 blockade. However, it still differs slightly from the treat-and-extend approach commonly employed in actual clinical practice. Furthermore, in the case of type 3 MNV where undertreatment can have severe detrimental effects on the prognosis, the approach of extending injection intervals by 4 weeks, as utilized in the TENAYA and LUCERNE studies, may not be appropriate. It is deemed necessary to consider a more stringent injection extension approach with intervals of 2 weeks.