An eye disease with huge medical need

Pathological process

RVO is a multifactorial disease with risk factors that include ageing, systemic hypertension, dyslipidaemia, atherosclerosis, smoking, and glaucoma. The occlusive phenomenon does not seem to be related to the classic thrombus formation, although enhanced erythrocyte aggregation and blood hyper viscosity have been observed. Compression of the vein at arteriovenous crossings might contribute, at least in part, to the aetiology of RVO. However, this theory is challenged by clinical observations.

ANXV targets externalised PS in red blood cells

In patients with RVO, aberrantly externalised phosphatidylserine (PS) on erythrocytes has been proposed as a key molecule responsible for the pathologic adherence of erythrocytes to endothelium. This increase RVO erythrocyte aggregation ability, and the shear resistance of aggregates is likely to contribute to the onset of RVO by predisposing to circulatory stasis. PS that is externalised on erythrocytes and microparticles in RVO patients has recently been identified as a possible novel pharmacological target, where Annexin A5 has been proposed as a potential therapeutic agent in RVO.

Risk for complications in RVO

An overproduction of microparticles in RVO with significantly elevated externalisation levels of PS has been linked to an increased procoagulant capacity with shortened clotting time via upregulation of Factor Xa, as well as thrombin formation, which may result in an increased risk for occlusion.

Complications of RVO develop over time when macular swelling leads to vascular endothelial growth factor (VEGF)-dependent neoangiogenesis, inflammation, and retinal damage. Long-term visual impairment and blindness are life-affecting outcomes.

References: Sperduto et al. 1998; Yasuda et al. 2010; Jannssen et al. 2005; Wautier et al. 2011; Su et al. 2018; Khayat, Williams, and Lois 2018; Fraenkl, Mozaffarieh, and Flammer 2010; Su et al. 2018; Wautier et al. 2011; Colin Aronovicz Yves 2016; Chabanel et al. 1990.

Current standard of care

The current standard of care focuses on targeting not the occlusion itself but the associated complications, such as macular oedema, inflammation, and neoangiogenesis (development of new blood vessels). Intravitreal vascular endothelial growth factor (VEGF) antagonists and steroids are essentially the only pharmaceutical treatments used for RVO. These treatments are invasive, chronic, expensive, and treat only the complications and not the occlusion itself.

Vision loss may not be cured with current treatment

The introduction of the use of anti-VEGFs to treat macular oedema secondary to RVO has improved the prognosis. However, despite their widespread use, residual vision loss is more common than a recovery to normal vision. Furthermore, it is unclear whether anti-VEGFs have any beneficial effect on the retinal area of non-perfusion (insufficient blood delivery to the retina), which is associated with some of the long-term complications of RVO, such as neovascularisation (new blood vessels in tissues where blood flow has been impaired due to disease).

Treatment needed to cure RVO

Although anti-VEGFs treat macular oedema secondary to RVO, there is currently no approved treatment for RVO, either at acute onset or chronic. There is an urgent need to improve the retinal perfusion (blood flow to the retina), especially in an acute phase and prior to the emergence of complications, which might irreversibly impact vision. Improvement of the retinal perfusion in the period soon after the occlusion, would potentially reduce local VEGF production, and hence the risk of significant visual function loss or blindness, and provide other short and long term benefits for patients with RVO.

ANXV has potential to act on the occlusion

There is a significant, yet unmet, medical need for a safe and effective treatment for patients who experience an acute RVO event, and before the emergence of complications. ANXV has the potential to be a valuable treatment in RVO, and potentially act directly on the occlusion.

References: Sivaprasad et al. 2015; Brown et al 2011; Rehak and Wiedemann 2010; Janssen et al. 2005; Pulido et al. 2016