TKIs and the Expansion of Treatment Options for Wet AMD

Nearly 20 years since approval of the first treatment to improve vision for wet age-related macular degeneration (AMD) (1), the treatment landscape is poised to change dramatically. While anti-VEGF therapy is effective for many patients, the challenges of frequent intravitreal injections – generally required every four to eight weeks (1-4), less commonly, or up to 12 (4) or 16 (3,5) weeks with some agents – has contributed to undertreatment of patients, which has been associated with suboptimal outcomes (6). Thus, much of the pursuit of novel therapies in clinical trials for wet AMD has focused on reducing treatment burden while maintaining initial vision gains in real-world patients.

One such avenue of clinical development has centered around tyrosine kinase inhibitors (TKIs), small molecule pan-VEGF receptor inhibitors, within sustained-release delivery platforms amenable to in-office routine administration (intravitreal or suprachoroidal). Unlike currently-approved antibody-based treatments for wet AMD that target a subset of VEGF isoforms (1-5), TKIs work intracellularly, inhibiting all VEGF receptors (1-3) as well as other targets potentially involved in pathologic angiogenesis (7).

Three such approaches are in advanced clinical trials: DURAVYUTM ([vorolanib intravitreal insert]; investigational name: EYP-1901; EyePoint Pharmaceuticals),* AXPAXLITM ([axitinib intravitreal insert]; investigational name: OTX-TKI; Ocular Therapeutix), and CLS-AX ([axitinib injectable suspension]; Clearside Biomedical; suprachoroidal injection). DURAVYU and AXPAXLI have advanced to phase III clinical trials and so are discussed below.

DURAVYU (vorolanib intravitreal insert)
 

DURAVYU is composed of the TKI vorolanib embedded in Durasert-E,TM a bioerodible form of the Durasert^® insert used in several FDA-approved drug delivery platforms to date, including ILUVIEN^® and YUTIQ^® (Alimera Sciences, Inc) (8-10). DURAVYU is designed to continuously deliver vorolanib, starting within hours of insertion, and maintain a steady dose of vorolanib for at least six months; preclinical experiments demonstrated durability to nine months in rabbit models (10,11). DURAVYU is stable at ambient temperatures and does not require refrigeration.

DURAVYU has been assessed in the phase I DAVIO (Clinicaltrials.gov identifier, NCT04747197) and phase II DAVIO 2 (NCT05381948) clinical trials for patients with previously-treated wet AMD, with a total of 119 patients receiving DURAVYU for wet AMD (10,12). The global phase III clinical trial program, comprising pivotal trials LUGANO and LUCIA, is actively enrolling.

The phase I open-label, dose-escalation DAVIO trial (N=17; all receiving DURAVYU) demonstrated proof-of-concept durability and a favorable safety profile with no dose-limiting toxicity, no ocular serious adverse events (AEs), and no DURAVYU–related systemic AEs following a single injection of DURAVYU (10).

DAVIO 2, the largest clinical trial of an intravitreal TKI completed to date, evaluated 156 patients with previously-treated wet AMD – averaging two years of previous anti-VEGF therapy with an annualized mean of ~10 anti-VEGF injections per year before enrolling in the trial (12,13). Patients were randomized 1:1:1 to receive three monthly loading doses of aflibercept 2.0 mg followed by either aflibercept 2.0 mg every-8-weeks (q8w; consistent with on-label treatment) (2) or one injection of DURAVYU 2 mg or DURAVYU 3 mg at Month 2. All patients were assessed monthly for supplemental aflibercept injections based on prespecified best-corrected visual acuity (BCVA) and anatomical criteria. The primary endpoint was BCVA change from baseline at blended Weeks 28/32, with efficacy and safety evaluations continuing through the 56-week trial end.

DAVIO 2 met its primary endpoint, with DURAVYU 2 mg (N=50) and 3 mg (N=52) maintaining vision through Month 8 (6 months after DURAVYU insertion) that was statistically noninferior to the standard-of-care aflibercept q8w arm (N=54) (12-14). DURAVYU similarly maintained fluid control (measured by central subfield thickness [CST]), without the “sawtooth” pattern seen with aflibercept q8w treatment. Notably, 63 percent of DURAVYU arm patients were supplemental-injection free up to Month 8, with >80 percent of DURAVYU patients receiving 0 or 1 supplemental injection up to Month 8. This represented a substantial 89 percent and 85 percent reduction in treatment burden for patients treated with DURAVYU 2 mg and 3 mg, respectively, versus their own treatment in the year before the trial, and an 83 percent and 78 percent reduction relative to the aflibercept q8w arm. Vision and fluid were maintained through the end of the 1-year trial. DAVIO 2 demonstrated a favorable safety profile for DURAVYU, with no DURAVYU-related serious AEs.

Phase III clinical trials LUGANO and LUCIA are multicenter, double-masked, aflibercept-controlled trials evaluating noninferiority of DURAVYU 2.7 mg re-dosed every six months versus aflibercept q8w (14). The trials will each enroll a combined target population of ~400 patients with active wet AMD, including both previously-treated and treatment-naïve.

Following a traditional study design for wet AMD, patients in LUGANO and LUCIA will be randomized 1:1 to either DURAVYU 2.7 mg or aflibercept 2.0 mg q8w arms, with sham injections for masking. All patients will receive three-monthly loading doses of aflibercept 2.0 mg. At Month 2, DURAVYU-arm patients will receive a single intravitreal injection of DURAVYU 2.7 mg, followed by redosing at six-month intervals; patients in the aflibercept control arm will continue with q8w dosing, as per its label (2). This control arm is the same as in recent large phase III trials assessing efficacy and extended durability for both wet AMD and diabetic macular edema (DME): in TENAYA/LUCERNE (wet AMD) and YOSEMITE/RHINE (DME) for VABYSMO^® (faricimab-svoa 6.0 mg injection, for intravitreal use; Genentech, Inc) (5); and in PULSAR (wet AMD) and PHOTON (DME) for EYLEA^® HD (aflibercept 8.0 mg injection, for intravitreal use; Regeneron Pharmaceuticals, Inc) (3).

As in DAVIO 2, all patients in LUGANO and LUCIA will be evaluated monthly for supplemental aflibercept 2.0 mg injections per prespecified criteria to ensure all patients are receiving appropriate treatment for their disease. The primary endpoint is mean change in BCVA from Day 1 to Week 52 and 56 (blended), with safety monitoring continuing through two years.

AXPAXLI (axitinib intravitreal insert)
 

AXPAXLI incorporates the TKI axitinib in a bioresorbable hydrogel implant, utilizing ElutyxTM technology for bioresorbable, targeted, and sustained drug delivery. AXPAXLI targets release of axitinib for 9-12 months, with demonstrated durability through 5-6 months in preclinical studies in eyes of rabbits and nonhuman primates (15,16).

AXPAXLI was evaluated in two phase 1 clinical trials for wet AMD to date (Australia, NCT03630315; US, NCT04989699), with 39* previously-treated and treatment-naïve patients with wet AMD receiving AXPAXLI in total (*excludes Cohort 4 of the Australian phase 1 trial; no data on these 6 patients have been reported). The pivotal phase III trial SOL-1, and an additional trial SOL-R, began in 2024. There was no phase II trial of AXPAXLI before the initiation of the phase 3 pivotal trial.

The first phase I trial, based in Australia, was an open-label, dose-escalation feasibility trial that reported outcomes from 23 participants with treatment-naïve or previously-treated active wet AMD (17). Participants received a single intravitreal injection of AXPAXLI (at different doses) at Day 0 and were assessed monthly for supplemental aflibercept injections using prespecified vision and anatomic criteria. At month 6, 61 percent were supplemental-injection free with, on average, reduced retinal thickness and stable vision.

The second phase I trial, based in the US, was a randomized, double-masked, aflibercept-controlled clinical trial comparing a single dose of AXPAXLI 600 μg with aflibercept q8w in previously-treated wet AMD (mean 18 months since diagnosis; annualized mean of ~8 anti-VEGF injections/year) (16-18). The AXPAXLI arm (N=16; n=15 analyzed) received a single dose at baseline. Both arms received aflibercept 2.0 mg at Week 4; the aflibercept arm (N=5) continued q8w dosing thereafter. Supplemental anti-VEGF was given per prespecified BCVA and anatomic criteria; rescue per investigator discretion was also permitted. Participants were assessed monthly for 12 months. Changes from baseline in BCVA and CST were comparable across AXPAXLI and aflibercept q8w arms over time; however, this phase I trial was not powered to formally assess efficacy. 11/15 (73 percent) of AXPAXLI arm patients were supplemental-injection free up to Week 28, with 9/15 (60 percent) supplemental-injection free up to Week 52. There were no reports of drug-related ocular or systemic SAEs in either arm through Week 52.

SOL-1 (NCT06223958), designed as a registrational trial assessing superiority of AXPAXLI, compares AXPAXLI 600 μg to aflibercept 2.0 mg, each administered as a single dose (19). SOL-1 aims to enroll ~150 treatment-naïve patients with wet AMD per treatment arm. Following two aflibercept 2.0 mg doses, anti-VEGF-responsive patients are randomized 1:1 to either a single intravitreal insertion of AXPAXLI or one injection of aflibercept 2.0 mg; this represents an off-label regimen for aflibercept 2.0 mg (2). Patients in each arm are evaluated for aflibercept retreatment at each study visit using a single criterion of a 15-letter loss in BCVA from baseline. The primary endpoint is the proportion of patients maintaining vision, defined as <15 ETDRS letters of BCVA loss at week 36; safety evaluations continue through Week 104.

SOL-R (NCT06495918), aiming to enroll a total of 825 patients across three arms, is designed to assess noninferiority of AXPAXLI 600 μg with 6-month redosing versus aflibercept 2mg Q8w (19). SOL-R will enroll treatment-naïve or recently-diagnosed (within three months) patients with wet AMD, starting with those who failed enrollment criteria for SOL-1 (i.e., <10-letter gain in response to anti-VEGF during screening). Following two-monthly aflibercept 2.0 mg loading doses, patients will be randomized 2:2:1 to AXPAXLI, dosed at baseline and week 24, aflibercept 2.0 mg q8w (on-label regimen) (2), or aflibercept 8.0 mg dosed at baseline and week 24 (off-label regimen) (3). Participants will not receive sham injections, and so will not be masked to their treatment regimen The primary endpoint is BCVA mean change from baseline at week 48.

Clinical trial design: implications for patients and outcomes
 

The DURAVYU and AXPAXLI phase III trial designs have notable differences that may inform their label and potential use in clinical practice if approved. Although previously-treated patients will be studied with both drugs, the AXPAXLI trial SOL-R restricts duration from diagnosis to within three months, while the registrational AXPAXLI trial SOL-1 includes only treatment-naïve patients. On the other hand, both LUGANO and LUCIA trials for DURAVYU do not restrict length of diagnosis or treatment and therefore will likely include patients with extensive prior experience with anti-VEGF therapy, a population that may particularly benefit from reduced treatment burden. SOL-1, which will inform the potential label for AXPAXLI, does not evaluate redosing of AXPAXLI, while SOL-R and the DURAVYU trials have scheduled retreatment at approximately six months. Interestingly, SOL-1 follows an off-label dosing regimen in the aflibercept 2.0 mg control arm, which might limit interpretability of efficacy. Additionally, the single criterion of a 15-letter loss for retreatment is atypical.

Conclusion
 

DURAVYU and AXPAXLI utilize TKIs in sustained-release platforms with the aim to decrease treatment burden while maintaining vision, providing extended treatment durations with the reassurance of a consistent presence of active drug for patients with wet AMD. With both therapies now in phase III trials, there is a strong potential for the expansion of treatment options for wet AMD in the coming years.

* DURAVYU has been conditionally accepted by the FDA as the proprietary name for EYP-1901.  DURAVYU is an investigational product; it has not been approved by the FDA. FDA approval and the timeline for potential approval is uncertain.