The hunt for long-acting treatment of exudative AMD continues, and the American Academy of Ophthalmology annual meeting showcased some exciting new candidate drugs and drug-delivery platforms working toward this end. At the meeting, interim results of a phase 1 study of OTX-TKI by Ocular Therapeutics were presented, and they demonstrated positive findings for this tyrosine kinase inhibitor (TKI), which is delivered via an in-office bioresorbable hydrogel fiber injection. The goal of this treatment is to provide a durable treatment response for 6 months or longer. Here, Dr. Avery, Dr. Boyer, and Dr. Goldstein, the chief medical officer of Ocular Therapeutix, provide their takes on the interim data and ongoing phase 1 results.

Robert L. Avery, MD

California Retina Consultants

Preliminary results of the ongoing prospective phase 1 trial intravitreal OTX-TKI axitinib implant in subjects with neovascular AMD demonstrate the implant to be generally safe and well tolerated, with minimal movement and consistent resorption of the implant. A biological signal of clinically meaningful decrease in the retinal fluid — both subretinal and intraretinal — was seen in some patients. The durability of this therapy in these responding patients seems to be up to 4 months to 7 months. Given the safety and preliminary biological activity signal, further dose escalation is ongoing to determine the maximum tolerated dose. Also, another cohort will explore the utility of OTX-TKI in combination with an initial anti-VEGF injection. Hopefully, this agent will provide us with another way of reducing the treatment burden of AMD.

David S. Boyer, MD

Retina Vitreous Associates Medical Group and USC/Keck School of Medicine

The interim phase 1 OTX-TKI study data that were presented by Ocular Therapeutix at the recent virtual annual meeting of the American Academy of Ophthalmology were extremely exciting. Tyrosine kinase inhibitors have the ability to hinder multiple pathways, including inflammation and angiogenesis. Unlike our current anti-VEGF inhibitors, some TKIs can block the receptors VEGFR1, VEGFR2, VEGFR3, platelet-derived growth factor, placental growth factor, and fibroblast growth factor, giving them a theoretical advantage in treating neovascular AMD. The study, performed at 5 sites in Australia, evaluated 2 doses of axitinib (200 µg and 400 µg) formulated in a dissolvable hydrogel implant administered by intravitreal injection. Of patients who received the low dose, 50% did not meet retreatment criteria all 3 time points (6 months, 7.5 months, and 9 months). In the higher-dose group, 50% of patients did not require rescue at 6 months, and 42.9% of patients did not require rescue at 7.5 months. The safety was excellent and there were no severe adverse events. Because the maximum tolerated dose was not reached, a 600-µg dose and a 400-µg dose in conjunction with an anti-VEGF will continue to be tested in the phase 1 trial. This implant may allow for longer acting treatment with an in-office injection, adding to our other available treatments for neovascular AMD.

Michael Goldstein, MD, MBA

Ocular Therapeutix

Age-related macular degeneration is the leading cause of severe, irreversible vision loss. In the United States, the estimated number of people with AMD is expected to more than double from approximately 2 million to more than 5 million by 2050. Neovascular AMD results in vision loss due to abnormal new blood vessel growth and hyperpermeability and associated retinal vascular disease in the macula, which is primarily stimulated by local upregulation of VEGF. Without prompt and continuous treatment to control this exudative activity, patients develop irreversible vision loss. Current therapies for neovascular AMD are intravitreally administered anti-VEGF drugs. These therapies have transformed the treatment of patients with wet AMD and other posterior-segment diseases; however, they require repeated injections as often as every 4 to 12 weeks. This can be challenging for caregivers and very stressful for patients. To meet this unmet medical need, axitinib, a small-molecule TKI, is under development as a bioresorbable, hydrogel fiber implant intended for delivery via intravitreal injection for 6 months or longer. Axitinib is more potent than other TKIs, including sunitinib, sorafenib, and pazopanib, and it has greater tissue biocompatibility.

Our ongoing phase 1 clinical trial has assessed the clinical efficacy and tolerability of axitinib implants (OTX-TKI) 200 µg (n=6) and 400 µg (n=7) in subjects with wet AMD. Subjects were evaluated every 4 to 6 weeks for 11 months. Among subjects treated with the 400 µg and 600 µg doses, we observed a decrease in central subfoveal thickness by 2 months in many subjects. Subjects demonstrated durable results for 6 months and beyond (11 months in 1 subject). Safety assessments demonstrate that the implant is generally well tolerated, with a favorable safety profile. No changes in intraocular pressure were observed in any subject, and no subject required steroids. Pharmacokinetic analysis determined plasma concentrations of axitinib to be less than 0.1 ng/mL, which is the limit of assay quantification at all sampled timepoints in both cohorts. Minimal movement of the implant was observed and implants degraded after 9 months to 10.5 months. We are currently enrolling additional subjects to receive the 600 µg dosage and also exploring treatment of OTX-TKI with an induction anti-VEGF injection. Although this study enrolled a small number of subjects, we are excited to observe these promising preliminary data, and we are hopeful that we will eventually reach our goal of consistent drug delivery for 6 months or more for treating AMD. RP