Safety and Tolerability of Suprachoroidal Axitinib Injectable Suspension, for Neovascular Age-related Macular Degeneration; Phase I/IIa Open-Label, Dose-Escalation Trial

Abstract

Purpose: To evaluate the safety and tolerability of a single dose of axitinib injectable suspension (CLS-AX), a pan-anti-VEGF tyrosine kinase inhibitor (TKI), administered via suprachoroidal injection in patients with neovascular age-related macular degeneration (nAMD).

Design: Phase I/IIa, open-label, sequential dose escalation.

Participants: Anti-VEGF treatment-experienced patients with active subfoveal choroidal neovascularization secondary to nAMD.

Methods: The study included 4 cohorts (0.03, 0.10, 0.50, and 1.0 mg) of approximately 5 patients each enrolled in a dose-escalating fashion. Enrolled patients received intravitreal aflibercept (2 mg) followed by a single unilateral dose of CLS-AX 1 month later. All patients were followed monthly for 3 months with the option of an additional 3 months of extended follow-up for cohorts 2 to 4. End points included systemic and ocular safety and tolerability, visual acuity, retinal thickness, and need for aflibercept therapy.

Main outcome measures: The number of patients reporting treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs), changes in ophthalmic examinations, and the number of patients qualifying for additional therapy for nAMD based on protocol-defined criteria.

Results: OASIS enrolled 27 patients with nAMD with mean age of 81 years, mean duration of nAMD diagnosis of 54 months, and between 5 and 90 prior anti-VEGF treatments. Twenty-six patients completed through 3 months, with 14 entering and completing the 3-month extension. No SAEs, drug-related TEAEs, or TEAEs leading to discontinuation were observed after CLS-AX administration; there were no adverse events related to ocular inflammation, vasculitis, intraocular pressure, or dispersion of drug into the vitreous or anterior chamber. Through 6 months, stable mean best-corrected visual acuity and stable mean central subfield thickness (CST) were observed, suggestive of TKI biologic effect. No aflibercept therapy was administered up to 3 months in 58% (15/26) of patients who completed 3 months of follow-up in OASIS. In the Extension, 57% (8/14) of patients went up to 6 months without receiving aflibercept therapy.

Conclusions: Up to 1.0 mg CLS-AX, a highly potent TKI targeted to the suprachoroidal space (SCS) via the SCS Microinjector, was well tolerated, with stable mean visual acuity and mean CST. A majority of patients followed for 6 months did not require aflibercept therapy.

Financial disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: AMD; Age-related macular degeneration; Axitinib; Suprachoroidal; Tyrosine kinase inhibitor.

Figure 1

Swim lane plot showing prior intravitreal (IVT) anti-VEGF injections, IVT aflibercept at screening, suprachoroidal CLS-AX (axitinib injectable suspension) injection at baseline, and postbaseline additional treatments for signs of neovascular age-related macular degeneration.

Figure 2

Line plots of mean ± SEM change from screening in ETDRS best-corrected visual acuity (BCVA) letter score for cohorts 3 and 4. A, All data. B, Excludes data after the administration of additional treatment per protocol-defined criteria. Mean BCVA at screening was 59.5 letters for cohort 3 and 65.5 letters for cohort 4. SEM = standard error of the mean.

Figure 3

Line plots of mean ± SEM change from screening in central subfield thickness (CST) via spectral-domain OCT for cohorts 3 and 4. A, All data. B, Excludes data after the administration of additional treatment per protocol-defined criteria. Mean CST at screening was 177.1 μm for cohort 3 and 201.5 μm for cohort 4. SEM = standard error of the mean.

Figure 4

Case study of participant 2 of cohort 3 (0.50 mg). BCVA = best-corrected visual acuity; CLS-AX = axitinib injectable suspension; CST = central subfield thickness; PED = pigment epithelial detachment.