Retinal venous occlusions and monoclonal antibodies

Pubblicato il

Wednesday, 7 February 2024

Argomento

Retina

Promising results from phase 3 studies of the monoclonal antibody Faricimab, which according to the data already presented is effective in reducing macular oedema and allowing longer intravitreal administration intervals.

Retinal Vein Occlusions (RVO) constitute, after diabetic retinopathy, the most common retinal vascular disorder and affect more than 28 million people worldwide, with an even incidence between both sexes. RVOs are a common cause of visual loss in the elderly population, with a 10-year incidence of 1.6% in the population aged ≥ 49 years.

RVOs usually occur after the age of 60 and often result in sudden and painless loss of vision, caused by venous obstruction that restricts the normal flow of blood to the retina, causing ischaemia, haemorrhage, leakage and accumulation of fluid and thus, macular oedema.

The diagnosis and management of RVO have changed radically over the last 30 years, but early detection of macular ischaemia still remains crucial.

Classification and risk factors

There are two forms of RVO: thebranch retinal venous occlusion (BRVO)which is the occlusion of a branch of the central vein and constitutes the 70% of the RVOs, and thecentral retinal vein occlusion (CRVO), which accounts for the remaining 30% of cases. Within RVOs, a distinction must then be made between the non-ischemic form (perfused), and that ischaemic (unperfused).

The main risk factors are age (especially for BRVO), hypertension, diabetes, dyslipidaemia, cigarette smoking, cardiovascular disease, blood hyperviscosity and kidney disease. Additional risk factors of a purely ocular nature are glaucoma or ocular hypertension (especially for CRVO).

More than a century ago, in 1856, Virchow had already identified the three main factors involved in the pathogenesis of ocular thrombi (Virchow's Triad):

– mechanical factors, related to alterations in blood flow, stasis or turbulence, which may be due to vascular compression, atherosclerosis or district haemodynamic crises. At the ocular level, blood stasis may be facilitated by ocular hypertension and arterial hypotension.

– alterations to the vascular endotheliumwhich may be due to inflammatory, traumatic, dysmetabolic processes (diabetes, dyslipemias, etc.), high blood pressure or atherosclerosis.

– alterations in the coagulability of blood (blood hypercoagulability), which may be a genetic and/or acquired condition.

I inflammatory processes play a key role in all the phases that characterise the occlusive phenomenon, contributing to endothelial damage, to the maintenance and self-feeding of the processes that lead to thrombus formation and to the determination of the most obvious consequences of vascular occlusion, such as alterations of an ischaemic nature and macular oedema.

Therapeutic novelties
New imaging techniques have shed new light on the pathophysiological mechanisms of this pathology and the laser treatmentwhich once constituted the only therapeutic option, is now only one of the possible approaches, which include the intravitreal administration of anti-VEGF drugs or steroidswhich are currently the treatments of first choice in most cases.

Undoubtedly, long-term visual outcomes today are far better than they were 20 years ago, but unfortunately in some cases complications develop that impair vision and require a more aggressive, sometimes surgical, approach.

New therapeutic options are currently in development, including gene therapy, but the most interesting news coming from research concerns a monoclonal antibody, the faricimab, which administered by intravitreal injection could extend the treatment interval for macular oedema due to branch and central retinal venous occlusion by up to four months and which is currently managed with monthly or bimonthly therapies.

Monoclonal antibodies are produced in the laboratory from a single clone of a B lymphocyte (hence the adjective 'monoclonal'), which ensures that each resulting antibody recognises a single, specific portion of the antigen that had previously been injected into laboratory animals. Once an inoculated animal has started producing antibodies directed against the antigen, the B lymphocytes stored within its spleen are fused with extremely resistant cells to form what are called hybrids. This step ensures the survival and ability of lymphocytes to replicate virtually indefinitely.

Faricimab, in particular, is the first antibody bispecific approved for ocular use, designed to target and inhibit two metabolic pathways linked to retinal diseases: angiopoietin 2 (Ang-2) and vascular endothelial growth factor A (VEGF-A).

Faricimab is currently the subject of two phase 3 clinical trials, Balaton e Cominopresented on 3 February at the Angiogenesis, Exudation, and Degeneration 2024 conference, organised by the Bascom Palmer Eye Institute in Florida, USA.

Based on the data presented in the preview, faricimab has been shown to be effective in both BRVO and CRVO patients in improving BCVA (Best Corrected Visual Acuity) ) and reducing the extent of macular oedema, as measured by central retinal thickness. The results also show that 60% in BRVO patients and 48% in CRVO patients can extend treatment intervals by up to four months, with maintenance up to 72 weeks of the improvements in vision and reduction of retinal fluid achieved in the first 24 weeks.

Faricimab is currently already approved in more than 90 countries for the treatment of wet AMD and diabetic macular oedema (DME). Use in patients with RVO was authorised in October 2023 by the US Food and Drug Administration, and now new data from the Balaton and Comino trials will be submitted to other regulatory agencies, including the European EMA.