OTX-TKI (Ocular Therapeutix) is an investigational bioresorbable, hydrogel implant incorporating axitinib, a small-molecule tyrosine kinase inhibitor (TKI) with anti-angiogenic properties. OTX-TKI is being evaluated for the treatment of wet age-related macular degeneration (wet AMD), diabetic retinopathy (DR), and other retinal diseases. Twelve-month data from the US-based phase 1 trial evaluating OTX-TKI for the treatment of wet AMD¹ were presented by Arshad Khanani, MD, MA, at the 2023 Clinical Trials at the Summit Annual Meeting. Results showed that patients on OTX-TKI had similar vision to patients on aflibercept (Eylea; Regeneron). Here Drs. Khanani, Paula Pecen, and Rabia Gurses Ozden weigh in on these results.

Arshad Khanani, MD, MA; Sierra Eye Associates

The OTX-TKI implant delivers axitinib, a multitargeted TKI of VEGF and PDGF receptors, using a proprietary, completely bioresorbable Elutyx polymer matrix that enables sustained targeted drug delivery.^2,3 OTX-TKI is easily injected in the clinic as a single implant into the vitreous and is designed to release axitinib for 9 to 12 months.

The Australian dose-escalation study provided proof-of-concept of OTX-TKI biological activity in untreated patients with wet AMD and uncontrolled fluid. At this year’s Clinical Trials at the Summit meeting, I provided an update on the prospective, multicenter, randomized, controlled, US-based clinical study designed to assess OTX-TKI as a maintenance therapy. Wet AMD patients with controlled retinal fluid previously treated with anti-VEGF therapy received either an OTX-TKI 600 μg single implant then a single aflibercept injection 1 month later, or aflibercept injections every 8 weeks.

Throughout the 12-month study period, baseline best-corrected visual acuity and central subfield thickness (CST) were maintained following a single OTX-TKI injection, which was similar to the effect observed with aflibercept dosed every 2 months. Because these patients were previously treated, stable — not improving — visual acuity and retinal thickness were expected. Similar to historic aflibercept trials, we saw fluctuations in CST with the aflibercept injections in this trial. A sustained delivery platform should be able to stabilize anatomy and minimize these fluctuations, which we observed with OTX-TKI.

Of the 15 patients treated with OTX-TKI, 73% did not receive a supplemental anti-VEGF injection up to 10 months, and 60% of OTX-TKI patients were supplemental injection–free up to 12 months. At 12 months, an additional 4 OTX-TKI subjects received supplemental injections, suggesting disease reactivation as the OTX-TKI therapeutic effect wanes. Importantly, patients in the OTX-TKI arm had a reduction of 89% in anti-VEGF treatment burden over 12 months.

There were no reports of drug-related ocular serious adverse events in either arm through 12 months. One patient in the OTX-TKI arm had acute endophthalmitis after the mandated aflibercept injection at month 1. This event was judged not related to OTX-TKI but rather related to the aflibercept injection and resolved with standard intravitreal antibiotic injection. All other adverse events were mild except 1 moderate event of worsening of cataract in the OTX-TKI arm and 1 moderate event of elevated intraocular pressure in the aflibercept arm.

Bioresorption of the OTX-TKI implant occurred on average around 8 to 9 months, which when taken together with the efficacy data suggest a potential window for redosing. The pharmacodynamic effects that were observed in this trial are encouraging and support OTX-TKI as a potential therapy for wet AMD, with durability of 9 to 12 months and a preliminary bioefficacy and tolerability profile comparable to the standard-of-care aflibercept injections dosed every 2 months (n=5). The baseline disease control provided by OTX-TKI, along with supplemental injections as needed based on individual disease activity, demonstrated flexibility and reduction in treatment burden for most wet AMD patients in this trial. These data support clinically meaningful extended durability for wet AMD therapies and highlight the possibility of OTX-TKI being widely adopted in the management of wet AMD. Given the promising results of the Australian and US clinical trials, additional efficacy, safety, and durability data from a larger number of patients would be valuable.

Paula Pecen, MD; Carolina Eye Associates

As a bioresorbable hydrogel implant able to slowly release axitinib over an extended period of time, OTX-TKI would help decompress retina clinics and prepare for the future of an aging population and a shortage of physicians. As the clinical trial progresses, it will be interesting to see if there is an OCT or serum biomarker that can identify when patients need retreatment or which patients will need earlier retreatment, because currently it appears that rescues after treatment occurred at random. If patients cannot be identified when retreatment is needed prior to rescue, over the long term this may lull physicians and patients into complacency and patients may ultimately go undertreated with slow degradation of visual acuity over time.

Home OCT may become more popular over time if its use could keep patients out of clinic while identifying proper timing of rescue treatment. Initiation of phase 3 clinical trials for OTX-TKI may encourage insurance coverage of home OCT devices and programs that properly identify fluid and communicate with patients to come in for rescue treatment. Although in the trial, 60% of patients did not need rescue treatment up to 12 months, 40% of patients did require rescue prior to 12 months, though at uneven intervals. The ability of OTX-TKI to completely degrade by 9 to 10.5 months does not necessarily preclude its ability to last longer due to pan-VEGF inhibition for prolonged periods of time. The medication may be amenable to a treat-and-extend interval by months (as opposed to extension by weeks as with prior anti-VEGF medications), where initial treatments are given at 0 and 6 months, then treatment is extended by 1 to 2 months from that time. Treatment intervals may no longer be dependent on strength of VEGF inhibition or duration of drug release; treatment intervals may be dictated by disease activity.

Although the durability of action of OTX-TKI is promising for wet AMD, this medication and platform seem even more promising for patients with DR. Patients with DR are younger than patients with AMD, so a treatment given with an injection every 6 to 12 months for DR could have a great impact on the global economy by decreasing risk of potential blindness in a segment of the population that is still working. Results are eagerly anticipated from the phase 1 HELIOS clinical trial evaluating OTX-TKI for the treatment of DR, with 6-month interim results to be reported in the first quarter of 2024. While quite early, OTX-TKI shows great promise as a more durable therapy for both wet AMD and potentially DR.

Rabia Gurses Ozden, MD; Ocular Therapeutix

Despite the transformative role of anti-VEGF in retinal disease, practical limitations remain. Due to the rapid clearance of anti-VEGF agents from the vitreous, injections at intervals of 1 to 4 months are often necessary, putting considerable strain on both patients and medical professionals.^4,5 Additionally, the pulsatile dosing regimen with anti-VEGF injections can lead to fluctuations in retinal thickness, and long-term fluctuations are often considered predictors of poorer visual outcomes.^6,7 Moreover, some patients continue to experience suboptimal visual outcomes despite regular treatment with anti-VEGF injections,⁸ signifying an existing gap for innovative therapeutic approaches that overcome these current limitations of wet AMD standard of care.

The strategy with OTX-TKI is to deliver axitinib, a small-molecule therapeutic agent, utilizing Elutyx technology, a biodegradable hydrogel polymer platform. The hydrogel used for OTX-TKI is designed to extend drug delivery for 9 to 12 months. Ocular Therapeutix has successfully leveraged this technology by bringing Dextenza (dexamethasone ophthalmic insert) 0.4 mg to market.⁹ Unlike anti-VEGF agents that inhibit extracellular VEGF, axitinib intracellularly inhibits VEGF receptors and other receptors implicated in angiogenesis, such as PDGF receptors, thereby directly inhibiting downstream signaling.¹⁰ Axitinib stands out among other TKIs currently under investigation for retinal vascular diseases, because it demonstrates the highest binding affinity for VEGF receptors,^10-12 allowing for the incorporation of smaller drug quantities into a single implant.

The 12-month US randomized trial results have shown that OTX-TKI (n=15) exhibits anatomic and functional outcomes comparable with aflibercept (n=5) administered every 8 weeks, while reducing anti-VEGF treatment by 89%. These data are encouraging as they underscore the potential of OTX-TKI as a differentiated treatment for wet AMD patients with controlled retinal fluid by maintaining vision and improving treatment burden.

As mentioned by Dr. Pecen, home-based OCT devices in tandem with long-term therapeutics could herald a new era in the management of retinal vascular diseases. Frequent monitoring by home OCT devices could provide more comprehensive disease progression data, enabling personalized and timely treatment interventions. Combined with sustained-release treatments, this may lessen both the treatment and visit burden associated with wet AMD management and has the potential to enhance patients’ quality of life and treatment adherence.

To date, we have shared data on the safety and biological activity of OTX-TKI in 2 distinct wet AMD patient populations — treatment-naïve and previously treated patients with active retinal fluid and patients with controlled retinal fluid. Our dose escalation trial in Australia showed a reduction in CST and stable to improved vision with OTX-TKI in treatment-naïve patients.¹³ The available data to date support the advancement of OTX-TKI to pivotal phase 3 trials for wet AMD, which we are prepared to initiate as early as the third quarter of 2023. Additionally, we look forward to releasing interim data from the HELIOS trial evaluating OTX-TKI for DR and initiating a pivotal DR trial as early as the first quarter of 2024. RP

REFERENCES

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