Sevasemten, an investigational fast skeletal myosin inhibitor designed to limit muscle damage from functional dystrophin deficits, is under investigation for treating muscular dystrophies. The Phase 1b ARCH trial (NCT05160415) enrolled twelve ambulatory male subjects (age 18-55 years) with DMD gene mutation and Becker muscular dystrophy (BMD) phenotype. Subjects received open-label sevasemten for up to 24 months. At baseline, mean (standard deviation) age was 32.9 (8.0) years and NSAA total score was 15.1 (8.4) units. Observed mean changes in NSAA total score from baseline to months 12, 18, and 24 were 0.8 (95% confidence interval [CI]: -0.5, 2.1), 0.9 (-1.0, 2.8), and 0.1 (-3.0, 3.2), respectively. To contextualize these changes, NSAA total score outcomes were predicted using a model trained on natural history data from Leiden University Medical Center (model development and validation reported separately by Niks et al.). The model predictions represent expected outcomes absent sevasemten, tailored to the treatment groups’ baseline profile in terms of age and motor function performance on the NSAA and on the timed 10-meter walk/run, rise from supine, and 4-stair climb. Comparing the treated group versus expected natural history, sevasemten was associated with significantly greater preservation of NSAA total scores by 2.3 (95% CI: [1.0, 3.6], p < 0.001) units at 12 months, 3.2 ([1.4, 5.1], p < 0.001) units at 18 months, and 3.1 ([0.3, 6.0], p = 0.034) units at 24 months. At their last NSAA assessments, all but one of the treated subjects had numerically greater NSAA scores than predicted. Conclusions: In this comparison to predicted external controls, meaningful levels of ambulatory motor function, as measured by the NSAA, were significantly preserved by sevasemten compared to expected rates of decline in BMD natural history over 24 months. These findings add to the evidence for sevasemten as a promising investigational therapy for BMD.