An eye disease with huge medical need
Retinal Vein Occlusion (RVO) is the blockage or closing of a vein in the eye. With a global prevalence with over 16 million cases, it is the second most common sight-threatening retinal vascular disorder. There is a significant, yet unmet, medical need for a safe and effective treatment. ANXV has the potential to fill that gap.
Blockage of a vein in the eye
RVO can be of different types, depending on where the occlusion occurs. The most common, less serious, type of RVO is Branch Retinal Vein Occlusion (BRVO). A less common but more sight-threatening form is Central Retinal Vein Occlusion (CRVO). Both BRVO and CRVO can be broadly classified as ischemic and non-ischemic. A non-ischemic subtype of RVO is more common, where the retinal perfusion (delivery of blood) is retained but at a much lower rate, resulting in reduced vision. The less common ischemic subtype of RVO is characterised by an acute loss of retinal perfusion, and potentially complete loss of vision. The severity of RVO also depends on the site of occlusion.
What are the causes?
Factors behind RVO
RVO is a disease with several risk factors, and with the pathogenesis still under debate. The ANXV target, Phosphatidylserine (PS), is involved in mechanisms of retinal vein occlusion, as the key molecule for erythrocyte adhesion.
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.
Unmet medical need
Many patients suffer from RVO
There is a significant, yet unmet, medical need for a safe and effective treatment for patients who experience an RVO event. The current standard of care focuses on complications, and there is no available treatment for the occlusion itself. ANXV has the potential to act on the occlusion, and thereby potentially treat the disease.
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
"The underlying problems causing RVO are not addressed with the currently available treatments, and subjects are often required to have multiple injections in the eye over many years. With ANXV, we expect to change that, to the benefit of both patients and society."
Mario Fsadni, Therapeutic Area Head Ophthalmology
ANXV expected to affect the occlusion
Administration of ANXV to patients with recent onset RVO may be beneficial due to several possible mechanisms of action, differentiated from the mechanisms of anti-VEGF.
The use of ANXV in RVO is expected to provide a benefit by mechanisms of action(s) non-overlapping to that of anti-VEGFs on macular oedema and angiogenesis. Given the mechanism of action of ANXV, it is hypothesised that the earlier treatment with ANXV is initiated, the better the likely outcome.
ANXV is expected to target Phosphatidylserine (PS) at the site of the occlusion, where PS is a factor in the adherence of the erythrocytes, forming the occlusion. The ANXV binding to PS would potentially lead to an earlier clearance of the occlusion and/or reducing further erythrocyte aggregation. As such, retinal perfusion would be improved by limiting the retinal area of non-perfusion, and providing other short and long term benefits for RVO patients.
The RVO market
A large and growing global market
The number of patients affected by RVO is constantly increasing, and the market is growing over time. The market is currently valued at up to 20 billion dollars, and is expected to significantly grow during the next 10 to 20 years.
The number of patients diagnosed with RVO is increasing, and will continue to do so during at least the next 10 to 20 years. Underlying factors, such as an ageing population, growing prevalence of retinal disease, and rising awareness of eye diseases, further influence this development.
Risk factors for retinal vein occlusion, such as atherosclerosis, diabetes, glaucoma and hypertension, are also increasing. As the number of patients increase, the market for RVO is expected to grow by six to eight per cent annually (CAGR). The current market value, estimated to be up to 20 billion dollars, is expected to reach up to 35 billion dollars by 2030.
CRVO constitutes the largest part of the market, with 60 to 70 per cent of the market share in 2022. The Asian market is expected to grow by nine to 10 per cent annually, a faster growth than in other parts of the world, partly due to the rise in healthcare expenditure.
Ref. Grand view research. Retinal vein occlusion treatment market, 2023-2030; Future market insights. Retinal vein occlusion treatment market; Biospace, Novaone advisor; Transparency market research, retinal vein occlusion market insight 2021-2031
ANXV ongoing clinical studies
The ANXV Phase 2a study in patients with RVO is currently ongoing, at several clinical sites in the USA. The study aims to obtain proof-of-concept that ANXV is safe to use and has an effect in patients with RVO.
The main purpose of the ANXV Phase 2a study is to measure safety and tolerability in patients with RVO, but efficacy is also evaluated as secondary endpoints. The first evaluation of data from the study shows that 2 out of 4 patients on ANXV had signals of effect during the study, and more were stable in their disease after having received a single dose of anti-VEGF treatment. Anti-VEGF was given 3-4 weeks after the ANXV treatment, with the aim to decrease some remaining macular oedema. Patients with RVO normally receive anti-VEGF treatments every 1-2 months over several years, it is therefore unexpected that these patients did not need more than one anti-VEGF treatment during at least a six-month period.
ClinicalTrials.gov ID: NCT05532735Read more