To date, axitinib has been used as a therapeutic agent for advanced renal cell cancer. Just like bevacizumab, which is also known from oncology, axitinib blocks angiogenesis. However, there are also some important differences to bevacizumab. Bevacizumab is a humanised monoclonal antibody that blocks angiogenesis by binding and neutralising VEGF-A. Axitinib, on the other hand, is a selective 2nd generation tyrosine kinase inhibitor (TKI) that inhibits signal transduction via the VEGFR-1, -2 and -3 receptors as a small molecule.1-3
When used suprachoroidally, axitinib demonstrated an excellent safety profile in the Phase I/IIa study. In the treatment of wet age-related macular degeneration, this was the case for all doses tested. This active substance has the potential to reduce the treatment burden for affected patients. TKIs represent a new molecular target in the treatment of wet AMD.
Previous AMD therapeutics targeted extracellular VEGF-A and -B. The disadvantage of these therapeutics is a potential upregulation of VEGF-C and -D. This may result in reduced efficacy in AMD. The use of TKIs in wet AMD therefore represents an unprecedented therapeutic option.1
The efficacy of axitinib in wet AMD was investigated in in vivo and in vitro models back in 2016. Even then, a major criticism of the anti-VEGF drugs currently in use was that only around 40% of patients were able to fully benefit from anti-VEGF therapy. The research group led by A. Giddabasappa also pointed out the risks of intravitreal application.
Unlike intravitreally administered anti-VEGF drugs, axitinib can be administered suprachoroidally. A further advantage of this small molecule multi-receptor tyrosine kinase inhibitor is the simultaneous inhibition of platelet-derived growth factor (PDGF) receptors, which also plays an important role in angiogenesis.3
Giddabasappa et al. investigated the effect of axitinib on neovascularisation in vitro (in human retinal microvascular endothelial cells (HRMVECs), in human brain vascular pericytes (HBVRs) and in a 3D co-culture vascular sprouting assay) and in vivo in a model of laser-induced choroidal neovascularisation (CNV) in rats.
Compared to the monoclonal antibodies directed against VEGF, axitinib inhibited neovascularisation more efficiently in the in vitro models. The research group attributed this to the synergistic effect of inhibiting the VEGF and PDGF signalling pathways.3
The axitinib suspension is administered into the suprachoroidal space via the patented SCS® microinjector. This provides unprecedented access to the back of the eye. The safety and tolerability of axitinib suspension in wet AMD was investigated in the Phase I/II-a study OASIS (NCT05131646) and its extension study. The study participants received 2 mg aflibercept in the study eye at the start of the study. One month later, CLS-AX was applied suprachoroidally.
The study comprised a total of four dose-escalation cohorts (0.03 mg, 0.1 mg, 0.5 mg and 1 mg). The follow-up period was 6 months. Monthly controls were carried out. The study participants received aflibercept during disease activity. The safety profile was excellent. There were no serious adverse events - nor inflammation or vasculitis.
The treatment burden was also reduced with stable visual acuity. The central retinal thickness was also stable up to the sixth month.1
On 1 June 2023, the biopharmaceutical company Clearside Biomedical initiated recruitment for the Phase 2b ODYSSEY clinical trial with CLS-AX (axitinib suspension) in wet AMD. This study was preceded by the successful results of the Phase I/IIa studies.
Clearside Biomedical has revolutionised the treatment of wet AMD with a new route of administration via the suprachoroidal space (SCS®). In the future, this could enrich the treatment spectrum for wet AMD with a new effective and less burdensome treatment option.4
The aim of the ODYSSEY study is to show that it is possible to maintain visual acuity with a reduced treatment burden using axitinib. The ODYSSEY study is a randomised, double-masked, active-controlled, multicentre, parallel, clinical phase 2b study with a total duration of 36 weeks. The CLS-AX arm will be compared with the aflibercept arm.
In addition to a diagnosis of wet AMD with disease activity, inclusion criteria include having received 2 to 4 anti-VEGF treatments in the 6 months prior to screening. The best corrected visual acuity (BCVA) at study inclusion should be between 20 and 80 letters.4
Study participants in both treatment arms will initially receive three monthly aflibercept injections (2 mg). In the aflibercept arm, aflibercept is injected in a fixed dosing schedule every 8 weeks. If disease activity is present, aflibercept injections are given every 4 weeks. In the CLS-AX arm, study participants receive 1.0 mg axitinib in the second loading dose. At the second loading dose (baseline visit), participants in the CLS-AX arm will receive one dose of axitinib.
Study participants will then receive axitinib at week 24 if they have not received a second dose since the baseline visit. In the case of disease activity, axitinib can also be administered 12 weeks after the last dose. If disease activity is seen less than 12 weeks after the last dose, aflibercept can be given as an add-on treatment.4
We are looking forward to the results of the ODYSSEY trial, which we can expect in Q3 2024.