Abstract: Axitinib (AG-013736) is a potent, second-generation tyrosine kinase inhibitor (TKI) that selectively targets vascular endothelial growth factor receptors (VEGFR-1, 2, and 3). While extensively utilized in oncology for various solid tumors, axitinib is emerging as a highly promising therapeutic candidate for neovascular age-related macular degeneration (nAMD). Unlike traditional anti-VEGF-A therapies, axitinib provides pan-VEGF inhibition, which may overcome treatment resistance and tachyphylaxis caused by the compensatory upregulation of alternative VEGF ligands. Due to its poor water solubility, axitinib has been formulated as an injectable suspension for suprachoroidal delivery. Preclinical models demonstrate that suprachoroidal administration yields sustained, targeted drug levels in the chorioretinal tissues without systemic exposure, effectively regressing choroidal neovascularization. Axitinib is currently undergoing Phase 1/2a clinical trials for nAMD, representing a novel approach to improve efficacy, safety, and treatment durability in ocular diseases.
1. Introduction
Neovascular age-related macular degeneration (nAMD) is a leading cause of vision loss, traditionally managed with intravitreal (IVT) injections of anti-vascular endothelial growth factor (anti-VEGF) agents [1]. However, real-world outcomes often fall short of clinical trial results due to a high treatment burden, leading to undertreatment [1]. Furthermore, specific VEGF-A inhibition can lead to the upregulation of alternative ligands, such as VEGF-C and VEGF-D, contributing to tachyphylaxis and refractory clinical cases [1]. Axitinib (AG-013736), an oral, potent, and selective second-generation tyrosine kinase inhibitor (TKI) originally approved for advanced renal cell carcinoma and investigated in other solid tumors like hepatocellular carcinoma [2][6], is now being repurposed for nAMD. By providing pan-VEGF inhibition and utilizing a novel suprachoroidal delivery route, axitinib aims to address significant unmet clinical needs in ophthalmology by improving efficacy, compartmentalizing therapy away from unaffected tissues, and reducing the frequency of administration [1].
2. Pharmacological Activity
Axitinib exhibits broad and potent antiangiogenic activity. In in vitro angiogenesis models, axitinib inhibits angiogenic sprouts more effectively than specific anti-VEGF-A therapies [1]. In preclinical in vivo models, it not only prevents angiogenesis but also successfully regresses established choroidal neovascularization, a feature highly relevant to clinical nAMD treatment [1]. Pharmacokinetically, axitinib is a poorly water-soluble small molecule, making it challenging for standard ocular delivery [1]. However, when administered as a stable suspension via suprachoroidal (SC) injection, it demonstrates highly favorable pharmacokinetics. In rabbit models, a single SC injection maintained efficacious and sustained levels of axitinib—above the in vitro IC50 for VEGFR-2—in the posterior ocular tissues (retinal pigment epithelium-choroid-sclera [RCS] and retina) for up to 10 weeks [1]. Notably, SC delivery resulted in RCS drug levels 11 times greater than an equivalent intravitreal dose, with no detectable axitinib in the plasma or aqueous humor, ensuring targeted local activity and minimizing systemic exposure [1].
3. Molecular Mechanism of Action
Axitinib functions by binding to the inactive conformation of the catalytic domain of VEGF receptor tyrosine kinases (RTKs) [2]. It is a highly selective inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 [2][4][8]. Additionally, it suppresses other receptors involved in angiogenesis and tumor progression, including the platelet-derived growth factor receptor (PDGFR) and cKIT [2]. In the context of vascular malformations and neovascularization, axitinib has been shown to block downstream signaling pathways, including the activation of ERK, AKT, and P70S6K [3]. It also inhibits the expression of hypoxia-inducible factor (HIF)-1α, VEGF, and other angiogenic mediators [3]. By inhibiting all VEGFR isoforms (pan-VEGF inhibition), axitinib prevents the compensatory signaling pathways that typically lead to resistance against selective VEGF-A inhibitors [1].
4. Structure-Activity Relationship (SAR)
Axitinib is an indazole derivative synthesized via chemical synthesis [2]. It is a small molecule with a molecular weight of approximately 386.47 to 387 g/mol [1][2]. Its specific chemical structure allows it to fit precisely into the inactive conformation of the RTK catalytic domain, granting it high binding affinities and potent pan-VEGF inhibitory properties [1][2]. The compound is characterized by extremely low aqueous solubility (0.2 µg/mL in neutral pH aqueous media) [1]. While this physicochemical property limits its formulation as a simple aqueous solution, it is highly advantageous for creating stable, long-acting injectable suspensions that form a durable drug depot in the suprachoroidal space [1].
5. Current Limitations
The primary limitation of axitinib in ophthalmology stems from its poor water solubility, which renders it unsuitable for many conventional forms of ocular delivery, such as topical drops or standard intravitreal solutions [1]. While suprachoroidal suspension delivery overcomes this, it requires specialized microinjector technology and training [1]. Systemically, axitinib is associated with significant adverse events, including hypertension, diarrhea, fatigue, and proteinuria [2][4][6]. Although suprachoroidal delivery compartmentalizes the drug away from the systemic circulation and unaffected anterior ocular tissues—thereby mitigating systemic toxicity and intrinsic ocular side effects—long-term localized toxicity and biocompatibility in human eyes require further validation, despite promising in vitro safety profiles with retinal pigment epithelial cells [1].
6. Future Perspectives
The future of axitinib in treating nAMD is highly promising, driven by advancements in suprachoroidal drug delivery. A Phase 1/2a clinical trial evaluating suprachoroidally-administered axitinib (CLS-AX) for the treatment of nAMD is currently underway [1]. If successful, this approach could revolutionize the treatment landscape by providing a durable, targeted therapy that relieves the heavy treatment burden associated with frequent intravitreal injections. Future research will likely focus on optimizing suspension formulations to further extend the duration of action, exploring its efficacy in other VEGF-driven ocular diseases like diabetic macular edema (DME) and diabetic retinopathy (DR), and evaluating its long-term safety profile in larger patient populations [1].
7. References
