Faricimab for treatment of diabetic macular oedema

8 PRACTICAL DIABETES Vol. 39 No. 6 Copyright © 2022 John Wiley & Sons D macular oedema (DME) is a common cause of sight impairment in people with diabetes. Twentyseven percent of people with type 1 diabetes develop DME within nine years of the disease onset.1 For people with type 2 diabetes, 25.4% of insulin dependent and 13.9% of those who do not use insulin have DME.2 Alarmingly, diabetes is estimated to increase by 56% in the United States by 2030, with DME causing visual impairment in up to 25% of patients.2 Given the current therapeutic options, there is a strong need for innovative drugs designed to reduce treatment burden by improved efficacy and durability.3–5 NICE recently approved faricimab (Vabysmo), a novel bispecific monoclonal antibody designed for the intravitreal treatment of diabetic eye disease.6 By targeting both vascular endothelial growth factor A (VEGF-A) and the angiopoietin–tyrosine kinase endothelial receptors pathway (Ang/ Tie pathway) it displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes and reducing the treatment burden.7,8 DME is the accumulation of excess fluid within the central area of the retina, called the macula. Risk factors include duration of diabetes, elevated HbA1c, hypertension, hyperlipidaemia, impaired renal function and the use of thiazolidinediones.9 DME usually causes distorted and blurred vision and creates difficulty especially with detailed tasks such as reading, watching television, driving and recognising faces. It gets diagnosed by a combination of clinical examination (dilated fundoscopy) and optical coherence tomography. The treatment of DME is systemic involving optimising control of diabetes, blood pressure and lipid profile as well as cessation of smoking. In addition, ophthalmic treatments are often indicated. Retinal laser has been conventionally used to treat macular thickening not directly involving the central vision.10 Fovea involving DME is managed by two main classes of intravitreal medication: anti-VEGF injections and steroid implants.4,9,11–13 Discovery of the VEGF pathway has facilitated treatments that are currently being used as mainstay of care in DME sufferers. Vascular endothelial growth factors (VEGFs) are a family of cytokines, that are involved in the process of angiogenesis. They function as signal proteins that bind with their respective transmembrane tyrosine kinase receptors (VEGFR) leading to proliferation of endothelial cells and growth of new blood vessels from existing vasculature. There are five main isoforms in the VEGF family: VEGF A–D and placental growth factor (PIGF). In patients with DME, VEGF levels are upregulated – in particular VEGF-A levels, a key component in pathological neoangiogenesis and vascular permeability.7,14,15 Anti-VEGF agents are engineered humanised antibodies that block the effects of VEGF on the leaking capillaries in DME, therefore ‘dry up’ the macula. Anti-VEGF ranibizumab and aflibercept have been adopted as a first line treatment of DME.14 Both agents need to be injected repeatedly every four to eight weeks in order to maintain their efficacy. The burden of such frequent injection intervals and associated cost have driven efforts to study other alternative molecular pathways as possible new treatment targets. Additionally, by exclusively targeting VEGF, there is an unmet need for anti-VEGF sub-responsive patients.16 Some can be treated with cortico-steroid implants; however, these have a higher side effects profile such as development of cataract and glaucoma. In this direction, the role of the Ang/Tie pathway has been investigated with promising results for the treatment of DME.4,9,17,18 In adulthood, the Ang/Tie pathway is responsible for regulating vascular homeostasis, modulating vascular permeability, neoangiogenesis, and inflammation. There are two isoforms, Ang-1 and Ang-2, which display a similar affinity to the Tie-2 receptor. Ang-1 acts as a strong agonist of the Tie-2 receptor with constitutive vessel-stabilising effects. Ang-2 is a context-dependent agonist/antagonist. Ang-2 is upregulated under pathological ischaemic conditions in the vascular endothelium, and thus acts as a competitive antagonist by inhibiting Tie-2 phosphorylation and therefore causing vascular destabilisation. It renders vessels more vulnerable to the effects of VEGF and other pro-inflammatory cytokines resulting in vascular leakage, pericyte loss, and inflammation. The blocking of Ang-2, in addition to VEGF-A, results in Tie-2 activation and vascular stabilisation. This results in better visual acuity gains and durability of treatment in patients with DME.19 The use of monoclonal antibodies in anti-VEGF therapy presented an opportunity for targeting two growth factors of retinal vascular disease with a single molecule. CrossMAb technology (Roche, Basel, Switzerland) allows the heterodimerisation of two different antigen-binding domains in a single antibody molecule.20 Such technology was used in the development of faricimab, a combined-mechanism medication with simultaneous and independent binding and inhibition of both angiopoietin-2 and vascular growth factor A.14