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Introduction Diffuse cutaneous systemic sclerosis (dcSSc) is a rare autoimmune disease with skin and internal organ fibrosis. Fipaxalparant is a lysophosphatidic acid receptor 1–selective antagonist. In a phase 2a trial, patients with dcSSc receiving fipaxalparant 300 mg BID for 8 weeks had numerical improvement in modified Rodnan skin score (mRSS) vs placebo. We report results from the prespecified interim analysis of BEACON, a phase 2b, double-blind, randomized controlled trial of fipaxalparant in patients with dcSSc ( NCT04781543).Material and Methods Eligible adults =/< 75 years met the 2013 ACR/EULAR criteria for SSc with dcSSc, had =/< 72 months since first manifestation, mRSS >/= 15, and forced vital capacity (FVC) >/= 45% predicted at screening; patients positive for anti-centromere antibodies were excluded (unless also anti-topoisomerase 1 antibody positive). Concomitant mycophenolate mofetil/mycophenolic acid/methotrexate/low-dose prednisone or equivalent glucocorticoids were permitted. Patients were randomized (stratified by mycophenolate mofetil use and interstitial lung disease) 1:1:1 to fipaxalparant 300 mg QD, fipaxalparant 300 mg BID, or placebo (52 weeks). Primary endpoint was change from baseline (CFB) to week 52 in FVC% predicted. Secondary endpoints included CFB in mRSS and Health Assessment Questionnaire Disability Index and Revised Composite Response Index in SSc response rate.Results BEACON included 301 patients (fipaxalparant QD, n = 100; fipaxalparant BID, n = 101; placebo, n = 100): primarily female (77.7%), White (79.1%), and mean (SD) age of 50.0 (12.0) years. Baseline mean (SD) FVC% predicted was 89.7 (21.4), 91.6 (23.2), and 88.4 (19.7) for fipaxalparant QD, fipaxalparant BID, and placebo.Patients receiving fipaxalparant QD or fipaxalparant BID had placebo-adjusted least squares mean (SE) FVC% predicted CFBs to week 52 of –0.05 (1.30; P = 0.969) and –0.75 (1.33; P = 0.572). Numerical improvements in mRSS occurred in both treatment groups vs placebo. Skin scores also improved over time.Treatment-emergent adverse events (TEAEs) occurred in 87.0%/82.4%/79.8% of patients receiving fipaxalparant QD/fipaxalparant BID/placebo, respectively; serious TEAEs occurred in 9.0%/7.8%/5.1%. TEAEs resulted in treatment discontinuation in 4.0%/8.8%/2.0% patients receiving fipaxalparant QD/fipaxalparant BID/placebo. Overall, 3.0% vs 2.0% of patients receiving fipaxalparant QD vs placebo had orthostatic hypotension. ALT and AST >3 x the upper limit of normal occurred in 3.0%/3.9%/3.0% and 2.0%/3.9%/0% of patients receiving fipaxalparant QD/fipaxalparant BID/placebo, respectively. No patients met Hy’s law.Conclusions Based on a prespecified futility analysis, the study was stopped at week 52 due to lack of efficacy in FVC% predicted in either treatment arm. TEAEs were infrequent and similar across groups.