AXPAXLI (axitinib intravitreal implant)

Evidence for the axitinib intravitreal implant consists of one completed phase 3 trial (SOL-1), one ongoing phase 3 trial without results (SOL-R), and two phase 1 trials that used a first-generation formulation different from the 450 µg formulation used in phase 3. SOL-1 is a multicenter, double-masked, randomized (1:1), parallel-group superiority trial conducted under an FDA Special Protocol Assessment agreement at more than 100 sites in the United States and Argentina. Treatment-naive participants with BCVA of at least 54 ETDRS letters (approximately 20/80) and CSFT of 500 μm or less received aflibercept 2 mg at Weeks -8 and -4; those who reached BCVA of 84 letters or more (approximately 20/20) or gained at least 10 letters, with CSFT of 350 μm or less, were randomized to a single 450 µg implant or a single aflibercept 2 mg injection, with no sham injections in either arm. Of 344 randomized participants (172 per arm), 2 implant-arm participants were misrandomized and did not receive study treatment, leaving 170 and 172 participants in the full analysis set. Mean baseline BCVA was 80.8 and 79.2 letters, compared with 52 to 62 letters in other nAMD registration trials, and 97.7% and 98.8% of participants were White. Rescue therapy was given for BCVA loss of 15 or more letters from baseline or a new macular hemorrhage likely to lead to irreversible vision loss. All randomized participants are redosed with their assigned treatment at Weeks 52 and 76 and remain masked through Week 104.

The primary endpoint was met: at Week 36, 74.1% of participants receiving the implant and 55.8% receiving aflibercept maintained vision, defined as loss of fewer than 15 ETDRS letters from baseline (risk difference 17.5%, 95% CI 7.7 to 27.4; p=0.0006; observed difference 18.3%). At Week 52, the proportions were 65.9% and 44.2% (risk difference 21.1%, 95% CI 10.8 to 31.4; p<0.0001; observed difference 21.7%). Maintenance of vision with one rescue injection or fewer was 72.4% versus 54.1% at Week 52 (p=0.0007) and 81.2% versus 66.9% at Week 36 (p=0.0036). These were the first three of five hierarchically tested key secondary endpoints; the fourth and fifth, BCVA change from baseline at Weeks 36 and 52, were not reported as met, and no values for them were identified. All six pre-specified sensitivity analyses of the primary endpoint were reported as statistically significant. Rescue-free rates were 80.6%, 74.7%, and 68.8% at Weeks 24, 36, and 52 with the implant versus 72.1%, 56.4%, and 47.7% with aflibercept. The proportion with CSFT of 350 μm or less was 68.8% versus 52.9% at Week 36 and 64.7% versus 43.6% at Week 52 (nominal p=0.0041 and p=0.0001). In post hoc analyses from Week 8, median time to a CSFT increase of 30 μm or more was 39 versus 16 weeks, and to an increase of 75 μm or more was 46 versus 24 weeks. In a post hoc analysis applying the SOL-R rescue criteria, 66.5% of implant-arm participants would have remained rescue-free at Week 52, and the company estimated a mean injection burden reduction of 72% excluding loading doses (1.95 versus 7.00 injections) and 56% including loading doses (3.95 versus 9.00) relative to a projected on-label aflibercept 2 mg every-8-week regimen with no rescues.

Through Week 52, ocular adverse events in the study eye occurred in 90 of 170 participants (52.9%) receiving the implant and 58 of 172 (33.7%) receiving aflibercept, and treatment-related ocular adverse events in 15 (8.8%) and 1 (0.6%). One ocular serious adverse event (0.6%), severe vision loss due to posterior subcapsular cataract, occurred in the implant arm, and no treatment-related ocular or systemic serious adverse events were reported. Non-ocular serious adverse events occurred in 19 (11.2%) and 21 (12.2%) participants, and adverse events leading to death in 2 (1.2%) and 1 (0.6%). The most frequent ocular adverse events with the implant were vitreous floaters (21, 12.4%, versus 2, 1.2%), cataract (12, 7.1%, versus 5, 2.9%), and conjunctival hemorrhage (11, 6.5%, versus 5, 2.9%); retinal hemorrhage occurred in 10 (5.9%) and 17 (9.9%). Nine intraocular inflammation events occurred in 7 implant-arm participants; 8 were treated with topical corticosteroids and resolved, and 1 resolved without treatment. No endophthalmitis, occlusive or non-occlusive retinal vasculitis, retinal detachment, or implant migration to the anterior chamber was observed in the implant arm. Any macular atrophy was present in 9.4% and 10.3% of participants at Week 52. No intraocular pressure data and no safety data after redosing have been reported; the company plans to submit SOL-1 Year 2 safety data at the 120-day safety update after NDA submission.

SOL-R is a multicenter, double-masked, randomized (2:2:1), three-arm trial comparing the implant every 24 weeks with aflibercept 2 mg every 8 weeks, with a third arm of aflibercept 8 mg dosed at Day 1 and Weeks 24, 48, and 72 to maintain masking. Participants were treatment-naive or recently diagnosed and completed a 6-month screening and loading period designed to exclude those with early persistent fluid or significant retinal fluid fluctuations. The primary endpoint is non-inferiority in mean BCVA change from baseline at Week 56 with a margin of -4.5 letters (90% power), and rescue aflibercept is given for loss of more than 5 letters combined with a CSFT increase of 75 μm or more. A 2026 amendment added a key secondary superiority comparison with aflibercept 8 mg at Week 96 and fibrosis and atrophy secondary endpoints, and extended masking through Week 96. SOL-R has reported no efficacy or safety results; an interim Week 52 safety analysis is planned for the fourth quarter of 2026 with a 0.0001 alpha penalty, SOL-R efficacy data are not part of the planned NDA, and topline results are expected in the first quarter of 2028.

In the U.S. phase 1 trial (OTX-TKI-2020-101), 21 previously treated participants were randomized 3:1 to a single 600 µg implant with aflibercept 2 mg four weeks later (16 participants) or aflibercept 2 mg every 8 weeks (5 participants). Among 15 implant participants in the efficacy analysis, 9 (60%) were rescue-free up to Week 52, or 33% when rescue injections given at the Week 52 visit are included; mean BCVA change at Week 52 was -1.0 letter with the implant and +2.0 letters with aflibercept, and the company reported an 89% reduction in treatment burden at 12 months. One acute endophthalmitis event occurred in the implant arm 6 days after the protocol-mandated aflibercept injection and was attributed to the injection procedure. In the open-label, dose-escalation Australian phase 1 trial (CLN-0046), 29 participants were dosed; in interim analyses of cohorts 1 to 3 (23 participants receiving 200 to 600 µg), mean CSFT changed by -101.3 μm and mean BCVA by +1.1 letters at Month 6, 14 of 23 participants (61%) were free of rescue injections at Month 6, and plasma axitinib was below the limit of quantification (less than 0.1 ng/mL) at all sampled timepoints.

No peer-reviewed publication and no ClinicalTrials.gov results were identified for any of these trials; all results come from company press releases, SEC filings, and company-hosted congress presentations. The sources disagree on several points. The February 2026 topline announcement describes the rescue-free and CSFT within 30 μm analyses as pre-specified exploratory endpoints, whereas the Macula Society presentation labels the same analyses post hoc with descriptive p-values. The p-value for time to a CSFT increase of 30 μm or more is 0.0028 in the April 2026 announcement and less than 0.0001 in the Investor Day presentation. The aflibercept-arm mean change in retinal fluid volume at Week 36 is reported as +54.0 in one presentation and 59 nL in two others. For SOL-R, the number of randomized participants is 631 in the annual report and in the February and June 2026 announcements and 640 in the quarterly report and the August 2026 announcement, while the registry lists an estimated enrollment of 825. The SOL-R primary endpoint timepoint is Week 56 in current company sources, Week 48 in the registry record and a 2024 presentation, and one year in an August 2024 announcement. SOL-R topline guidance moved from the first half of 2027 (November 2025) to the first quarter of 2027 (annual report) and then to the first quarter of 2028 (June and August 2026), and a May 2025 announcement described a rescue threshold of 10 or more letters from baseline rather than the later combined criterion. In the U.S. phase 1 trial, no elevated intraocular pressure was reported in the implant arm at the December 12, 2022 cutoff, whereas 2 of 16 implant participants (12.5%) had elevated intraocular pressure at the April 14, 2023 cutoff, and the serious adverse event percentage for the single endophthalmitis event is given as 12.5% in a 2023 presentation and 6.25% in a 2024 presentation. In CLN-0046, the Month 6 rescue-free rate in the 600 µg cohort was 66.6% (4 of 6) at the October 2021 cutoff and 83% (5 of 6) at the January 2022 cutoff.