A randomized, double-blinded, placebo-controlled, multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and biological activity of ATYR1940 in adult patients with facioscapulohumeral muscular dystrophy (FSHD)

FSHD, a rare, debilitating, genetic skeletal myopathy is associated with inflammation and dystrophic changes in muscle tissue. ATYR1940, a Physiocrine based protein that modulates immune responses in skeletal muscles preclinically, is identical to substantially all of human histidyl tRNA synthetase, a protein that is released from skeletal muscle. This double-blinded, phase 1b/2a study evaluated the safety, tolerability, pharmacokinetics (PK), immunogenicity, and biological activity of multiple ascending doses of intravenous ATYR1940 in adult FSHD. Exploratory pharmacodynamic (PD) measures included the individualized neuromuscular quality of life (INQoL) questionnaire, lower extremity muscle targeted MRI and circulating PD markers. Weekly doses of 0.3 (n = 4), 1.0 (n = 8), and 3.0 (n = 8) mg/kg were tested over 4, 4, and 12 weeks, respectively. Patients (n = 20) were randomized 3:1 (ATYR1940: placebo) across all dose groups and followed for 4 and 12 weeks after the last study drug dose. A dose-related improvement was detected by INQoL from baseline in all dose cohorts and at 3.0 mg/kg at 12 weeks an improvement compared to placebo of 25.5% was observed (p = 0.03). Measured circulating PD markers and MRI did not record substantial differences between placebo and ATYR1940. Manual muscle testing indicated no reportable disease progression. All reported adverse events were assessed as mild or moderate in intensity. One moderate adverse event reported in a test article treated patient (a reversible generalized infusion related reaction in the 3.0 mg/kg dose cohort) was reclassified to a serious adverse event by the sponsor. PK was consistent throughout the study course and across all dose cohorts. The potential signals of activity of ATYR1940 in the INQoL and the safety profile support advancement of ATYR1940 in FSHD and potentially other rare diseases.