Ophthalmology science · 2026
Oral Tonabersat Connexin-43 Modulator for Diabetic Macular Edema with Good Vision (DRCR Retina Network Protocol AN).
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Barkmeier Andrew J, Vu Thu P, Elman Michael, Franklin Crystal A, Friedman Scott M, Glassman Adam R, Jampol Lee M, Labriola Leanne T, Marcus Dennis M, Martin Daniel F, Papakostas Thanos, Salehi-Had Hani, Stockdale Cynthia R, Tian Wei, Sun Jennifer K, DRCR Retina Network
Аннотация
OBJECTIVE: Evaluate oral tonabersat, a connexin-43 hemichannel modulator, on central subfield thickness (CST) in eyes with center-involved diabetic macular edema (CI-DME) and good vision.
DESIGN: Phase II randomized, double-masked clinical trial.
PARTICIPANTS: One hundred twenty-nine adults with CI-DME and visual acuity (VA) 20/32 or better, from 24 US sites.
INTERVENTION: Participants randomly assigned 1:1- to 80-mg tonabersat (N = 64, [71 eyes]) or placebo (N = 65, [73 eyes]) for 6 months.
MAIN OUTCOME MEASURES: Change in OCT CST.
RESULTS: Overall, 37% of participants were female, with a mean age of 63 years. In tonabersat and placebo groups, respectively, the baseline mean CST was 359 and 362 μm; the mean (standard deviation [SD]) change in CST from baseline to 6 months was -15 (55) μm and +5 (51) μm; (adjusted mean difference: -16 [95% confidence interval (CI), -34 to 2], P = 0.08). A post hoc analysis limiting anti-VEGF effect showed adjusted mean difference: -21 [95% CI, -38 to -3], P = 0.02. Among participants with thinner eyes at baseline (CST <75 μm above threshold; tonabersat [n = 45] vs. placebo [n = 43]), adjusted mean difference was -2 μm (95% CI, -26 to 22). For thicker eyes (CST ≥75 μm above threshold; tonabersat [n = 20] vs. placebo [n = 24]), mean difference was -51 μm (95% CI, -83 to -19). The mean (SD) change in best-corrected VA from baseline to 6 months was: tonabersat 0.0 (5.7) letters versus placebo -0.4 (5.7) letters (adjusted mean difference: 0.82 [95% CI, -1.56 to 3.21], adjusted P = 0.39). Dizziness was more common with tonabersat (27% vs. 8%), headaches more common with placebo (17% vs. 6%), and drowsiness rates were 11% in both groups.
CONCLUSIONS: There was no statistically significant improvement in CST at 6 months in the tonabersat versus placebo groups. However, a post hoc analysis limiting anti-VEGF impact demonstrated significant benefit in the tonabersat group. Aside from increased dizziness, consistent tonabersat safety concerns were not identified. Given findings consistent with a potentially favorable biologic effect of tonabersat, further research into the role of the inflammasome in DME is warranted.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: Phase II randomized, double-masked clinical trial.
PARTICIPANTS: One hundred twenty-nine adults with CI-DME and visual acuity (VA) 20/32 or better, from 24 US sites.
INTERVENTION: Participants randomly assigned 1:1- to 80-mg tonabersat (N = 64, [71 eyes]) or placebo (N = 65, [73 eyes]) for 6 months.
MAIN OUTCOME MEASURES: Change in OCT CST.
RESULTS: Overall, 37% of participants were female, with a mean age of 63 years. In tonabersat and placebo groups, respectively, the baseline mean CST was 359 and 362 μm; the mean (standard deviation [SD]) change in CST from baseline to 6 months was -15 (55) μm and +5 (51) μm; (adjusted mean difference: -16 [95% confidence interval (CI), -34 to 2], P = 0.08). A post hoc analysis limiting anti-VEGF effect showed adjusted mean difference: -21 [95% CI, -38 to -3], P = 0.02. Among participants with thinner eyes at baseline (CST <75 μm above threshold; tonabersat [n = 45] vs. placebo [n = 43]), adjusted mean difference was -2 μm (95% CI, -26 to 22). For thicker eyes (CST ≥75 μm above threshold; tonabersat [n = 20] vs. placebo [n = 24]), mean difference was -51 μm (95% CI, -83 to -19). The mean (SD) change in best-corrected VA from baseline to 6 months was: tonabersat 0.0 (5.7) letters versus placebo -0.4 (5.7) letters (adjusted mean difference: 0.82 [95% CI, -1.56 to 3.21], adjusted P = 0.39). Dizziness was more common with tonabersat (27% vs. 8%), headaches more common with placebo (17% vs. 6%), and drowsiness rates were 11% in both groups.
CONCLUSIONS: There was no statistically significant improvement in CST at 6 months in the tonabersat versus placebo groups. However, a post hoc analysis limiting anti-VEGF impact demonstrated significant benefit in the tonabersat group. Aside from increased dizziness, consistent tonabersat safety concerns were not identified. Given findings consistent with a potentially favorable biologic effect of tonabersat, further research into the role of the inflammasome in DME is warranted.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.