Results of the APEX phase 1b clinical study of KSI-101 for macular edema

Analysis of the final APEX Phase 1b clinical results obtained with KSI-101 (Kodiak Sciences Inc.) evaluated to treat macular edema secondary to inflammation (MESI) showed that at week 24 well over three-quarters of eyes remained fluid-free and that dose-dependent increases of three lines of vision were observed in a substantial number of patients, according to Sumit Sharma, MD.

He is a retina and uveitis specialist at the Cole Eye Institute and serves as Vice Chair for Clinical Outcomes and Safety, Quality, and Patient Experience at the Cleveland Clinic, Cleveland. Sharma presented the first-time, end-of-study clinical results at the Angiogenesis, Exudation, and Degeneration 2026 at the Bascom Palmer Eye Institute, Miami, on February 7.

KSI-101 targets interleukin-6 and vascular endothelial growth factor

KSI-101 is described by the company as “a novel, potent, and high-strength (100 mg/mL) antibody-based investigational therapy with a bispecific mechanism of action targeting both interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF).” The investigators evaluated the effects of 3 intravitreal injected doses of KSI-101: 2.5, 5, and 10 mg in the phase 1b clinical trial.

The end-of-trial week-24 data indicated that after treatment with KSI-101, there was some recurrence of intraretinal fluid. However, Sharma reported that 80% of eyes, even those in the 12-week off-treatment observation period, remained completely fluid-free throughout the 24-week period. In addition, the overall visual acuity data showed that the percentage of eyes that gained three lines of vision remained over 50% overall. For the 5-mg dose that percentage was 62% and for the 10-mg dose, 54%.

The result that surprised Sharma was not the 24-week result itself but the rapidity with which the fluid resolved in the vast majority of patients. At the 1-week timepoint, he recounted, after administration of one dose, 77% of the eyes were completely free of fluid; by week 12, 96% of the eyes were free of fluid.

“That is a fantastic result, in that we have not seen that level of improvement in any other clinical trial. To see that result with the safety profile that was observed in our study was very encouraging,” he commented.

Sharma credited the robustness of the results to a combination of factors. “KSI-101 is the first dual mechanism of action antibody that targets both IL-6 and VEGF.

The preclinical data showed that when both molecules are targeted, a stronger effect is achieved than when the molecules are targeted separately. The phase 1b results fit with the in vitro preclinical data and show that the improvement that we are seeing is greater than that seen with either an IL-6 inhibitor or a VEGF inhibitor alone. This ties in with the biology that both molecules are implicated in uveitic macular edema. It is very encouraging to see that the results mimic what the biology says they should,” Sharma explained.

The phase 1b results speak to the treatment’s durability, he pointed out, in that at the week 16 timepoint, which was 4 weeks after the previous injection, 96% of the eyes were fluid-free, and at week 24, 80% of those eyes were fluid-free. Slight fluid recurrences were seen in 16% of the eyes; however, in 80% of eyes during 12 weeks without treatment, there was no recurrence of fluid. “This is encouraging because it points to the significant degree of treatment durability in the majority of treated patients, who in some cases had severe disease that was difficult to treat. It is interesting to see that those patients responded so well and that there was a significant durability signal,” he pointed out.

In this MESI population, the only available on-label treatments are corticosteroids. “KSI-101 is the first non-corticosteroid local therapy that will potentially be available to treat these patients,” he said.

An anti-IL-6 drug is available, ie, vamikibart (RG6179 or RO7200220, Roche/Genentech), which completed 2 phase 3 studies, 1 of which met the primary endpoint.

Compared with the treatments on the market, KSI-101 would avoid the development of all steroid adverse effects, such as elevated intraocular pressure, cataracts, or occlusive vasculitis, the last of which can occur with any therapy injected intravitreally. If the safety profile remains constant in the phase 3 PEAK and PINNACLE studies, KSI-101 would appear similar to the intravitreal anti-VEGF injections and would be a big game changer considering that the adverse effects associated with corticosteroids would be eliminated, Sharma emphasized.

The phase 3 PEAK and PINNACLE trials, which are underway, are designed similarly to the phase 1b study. One difference in the phase 3 trials is that the patients will be treated monthly out through 20 weeks. The primary endpoint will be the mean change in the best-corrected visual acuity averaged at weeks 20 and 24. One actively treated eye of each patient will receive either the 5- or 10-mg dose; the fellow eyes will receive sham treatment.

In commenting on the overall results, Sharma said, “The phase 1b study informs us that during the 4 weeks of no treatment, there was no recurrence of edema. After 20 weeks of treatment, hopefully we will see that the few patients who had some fluid remaining will be completely dry and will have the best chance of having improved visual acuity.”

Sharma is a consultant to Kodiak Sciences Inc. and the company has provided clinical trial funding to the Cole Eye Institute.