GOLDEN: Efficacy and Safety of Complement Factor B Antisense, Sefaxersen, in Geographic Atrophy due to Age-Related Macular Degeneration

OBJECTIVE: To evaluate the efficacy and safety of sefaxersen, an investigational antisense oligonucleotide targeting complement factor B (FB), in slowing the progression of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Randomized, double-masked, placebo-controlled, adaptive phase II clinical trial. SUBJECTS: A total of 332 patients with GA secondary to AMD were enrolled, with 91% of treated patients completing the final study visit at 56 weeks. METHODS: In stage 1, 58 patients received subcutaneous injections of 40, 70, or 100 mg sefaxersen or placebo monthly. An interim analysis for FB, pharmacokinetics, and safety was conducted when patients reached at least 13 weeks of treatment to select 2 doses for expansion. In stage 2, an additional 274 patients were randomized to 40 or 70 mg sefaxersen or placebo. Patients were stratified based on baseline GA size, baseline rate of GA growth, and presence/history of exudative choroidal neovascularization in the fellow eye. Geographic atrophy area was assessed by fundus autofluorescence imaging. Safety assessments included ocular and systemic adverse events, laboratory parameters, and vital signs. MAIN OUTCOME MEASURES: The primary endpoint was the rate of GA lesion growth from baseline to week 49. Prespecified endpoints included changes from baseline in best-corrected visual acuity, low-luminance visual acuity, systemic complement measures, and occurrence of treatment-related adverse events. RESULTS: Sefaxersen did not significantly reduce the rate of GA growth versus placebo. Differences in adjusted mean GA rate of growth versus placebo were -0.25 mm² (-11.5%, P = 0.171) and -0.08 mm² (-3.8%, P = 0.647) for 40 and 70 mg groups, respectively. At steady state, a reduction in adjusted mean plasma FB levels (40 mg: -63% and 70 mg: -69%) led also to a reduction in alternative pathway activity (adjusted mean -22% and -34%, respectively). The safety profile, both ocular and nonocular, of sefaxersen was comparable to that of the placebo, with the most common adverse events being coronavirus disease 2019, urinary tract infections, and nasopharyngitis. CONCLUSIONS: Sefaxersen reduced systemic FB levels and alternative pathway activity, but the effect on GA growth rate was not significant compared with placebo. The treatment was well tolerated with a safety profile consistent with previous studies. FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.