Will OTX-TKI change the treatment landscape for neovascular AMD?

Peter K. Kaiser, MD, Chief Development Officer at Ocular Therapeutix, discusses the company’s drug development pipeline and gives an update on clinical trials assessing OTX-TKI for neovascular age-related macular degeneration (nAMD).

How is Ocular Therapeutix leveraging its early trial successes with OTX-TKI (axitinib intravitreal implant) to navigate regulatory pathways and expand into broader retinal disease markets?

In 2024, Ocular Therapeutix transformed into a retina-focused company, assembling a world-class team of retina experts. Early results of trials with our sustained-delivery tyrosine kinase inhibitor (TKI) are compelling and demonstrate generally favorable safety data and durable biological activity in nAMD and diabetic retinopathy (DR). Our clinical trial strategy focuses on de-risking the regulatory pathway to provide both regulatory and commercial success.

The first of our ongoing pivotal trials is SOL-1, a superiority study being conducted under a Special Protocol Agreement with the US Food and Drug Administration (FDA) based on the adequacy of masking, acceptability of specific critical elements of the study design, and the statistical analysis plan.

Our second pivotal study is SOL-R, a non-inferiority study comparing OTX-TKI to aflibercept 2 mg dosed every 8 weeks.

In the long term, we plan to target expansive and unrealized retinal vascular disease markets that include not only nAMD but also DR, diabetic macular edema (DME), and retinal vein occlusion. Our mission is to improve vision in the real world.

Can you describe Ocular Therapeutix’s clinical program investigating OTX-TKI for the treatment of nAMD?

OTX-TKI is a single intravitreal bioresorbable implant containing the TKI axitinib in a proprietary biocompatible hydrogel polymer (ELUTYX™). OTX-TKI is a multitarget TKI that is intended to block all VEGF receptors for 6 to 12 months with a single implant. To date, 3 phase 1 studies have been completed and 2 pivotal phase 3 trials are ongoing.

In the US phase 1 study, conducted in previously treated nAMD patients, a single administration of OTX-TKI was compared to aflibercept 2 mg dosed every 8 weeks. Mean changes from baseline in best-corrected visual acuity (BCVA) and central subfield thickness (CSFT) were similar between the 2 groups at week 52; 100% of OTX-TKI eyes were rescue-free at 6 months and 80% were rescue-free at 10 months per protocol. An Australian phase 1 trial was conducted in treatment-naïve eyes and demonstrated improvements in BCVA and CSFT as a monotherapy.

Our first pivotal phase 3 study, SOL-1, was developed to ensure its adherence to the 2023 FDA guidance regarding the design of trials evaluating therapies for nAMD. This is a multicenter, double-masked, randomized, parallel-group trial in treatment-naïve eyes with nAMD. The goal of the SOL-1 study is to determine whether a single dose of OTX-TKI is superior to a single dose of aflibercept 2 mg, with a design optimized for regulatory approval and to demonstrate long-term durability.

Our second pivotal study in nAMD, SOL-R, is a repeat-dose study designed primarily for real-world use and commercial impact. The FDA has agreed in a type C written response that the design of the SOL-R repeat dosing study is appropriate as an adequate and well-controlled study in support of a potential New Drug Application and product label. The goal of SOL-R is to determine whether OTX-TKI given every 6 months is non-inferior to fixed-dose aflibercept 2 mg given every 8 weeks. This study is optimized for clinical impact by using a repeat dose and a standard-of-care comparator.

We have also initiated a clinical development program for OTX-TKI in non-proliferative DR (NPDR), which is the leading cause of vision loss and blindness in the working-age population and represents a large and unrealized market opportunity. The HELIOS study is a phase 1 safety trial of OTX-TKI in eyes with NPDR that demonstrated durable and sustained monotherapy activity. In HELIOS, participants with NPDR without center-involving DME were randomized 2:1 to receive a single OTX-TKI injection or sham; patients were followed for a year. The primary outcome was safety and tolerability, with secondary outcomes including a change in Diabetic Retinopathy Severity Score (DRSS) from baseline, the need for rescue therapy, and change in BCVA and CSFT. There were no serious ocular adverse events, and all adverse events were mild and balanced between arms with no inflammatory events. At 48 weeks, DRSS scores in the sham arm remained stable in 75% of eyes and worsened by 1 or more levels in 25%; in the OTX-TKI arm, 54% of eyes remained stable and 46% improved by 1 or more DRSS levels. The incidence of vision-threatening complications (proliferative DR or center-involved DME) was 37.5% in the sham arm and 0% in the OTX-TKI arm.

Can you talk more about the status of the SOL-1 trial? What is the status of patient enrollment?

SOL-1 was designed to assess patients with treatment-naïve choroidal neovascularization from nAMD. Following an 8-week run-in with 2 monthly injections of aflibercept 2 mg, participants who meet the final eligibility criteria are randomized to a single OTX-TKI injection or a third aflibercept 2 mg injection. The final criteria for randomization include either having a BCVA of 20/20 or a 10-letter gain in vision during the aflibercept run-in and CSFT <350 microns. The primary endpoint is the proportion of eyes with <15 letters loss by week 36. Key secondary endpoints include the proportion of eyes maintaining BCVA, the proportion maintaining BCVA with a single supplemental injection, and the change from baseline in BCVA. The target sample size is 150 per arm. Through exceptional engagement since study commencement in February 2024, we now expect SOL-1 to be fully enrolled and all patients randomized by the end of 2024, with topline data expected in the fourth quarter of 2025.

In SOL-R, all participants will have already received 2 monthly aflibercept 2 mg injections and receive an additional aflibercept 2 mg injection and 4 weeks later receive 2 additional monthly aflibercept 2 mg injections (a total of 5 loading doses of aflibercept 2 mg). The participants are then randomized to OTX-TKI every 6 months, aflibercept 2 mg every 8 weeks, or aflibercept 8 mg every 6 months. The primary endpoint of SOL-R is mean BCVA change from baseline at week 48; key secondary endpoints include the proportions of eyes needing rescue therapy and the mean CSFT change from baseline. The first patients were enrolled in SOL-R in July 2024.

How might OTX-TKI contribute to the wet AMD therapeutic landscape? 

An estimated 1.65 million Americans have nAMD, and it remains under-treated today largely due to its high treatment burden. Up to 40% of patients receiving treatment ultimately discontinue therapy due to the high treatment burden of injections every 4 to 8 weeks (on average) or because of ongoing vision loss that renders further therapy futile. The pulsatile nature of frequent injections with current therapies can lead to repeated cycles of macular thickening and thinning with successive injections that eventually may not be rescued with further treatment.

OTX-TKI is designed to deliver continuous therapy through localized, sustained delivery and is expected to better preserve macular structure and function over time. As evidenced by the results of phase 1 studies conducted to date, OTX-TKI has the potential to address the challenges of under-treatment, discontinuation, and vision decline while aiming to extend the duration of treatment effect.

DISCLAIMER

Caution: OTX-TKI is currently undergoing clinical evaluation and is limited by law to investigational use only. This product has not been approved by the FDA as safe or effective.