Garetosmab in Fibrodysplasia Ossificans Progressiva: Clinical Pharmacology Results from the Phase 2 LUMINA‐1 Trial

Abstract

Here, we report the clinical pharmacology data from LUMINA‐1 (NCT03188666), a Phase 2 trial that evaluated garetosmab (a monoclonal antibody against activin A) in patients with fibrodysplasia ossificans progressiva. Forty‐four patients were randomly assigned to intravenous 10 mg/kg of garetosmab or placebo every 4 weeks in a double‐blind 28‐week treatment period, followed by a 28‐week open‐label treatment period with garetosmab, and subsequent open‐label extension. Serum samples were obtained to assess pharmacokinetics (PK), immunogenicity, and bone morphogenetic protein 9 (BMP9). Comparative exposure–response analyses for efficacy and safety were performed with trough concentrations (Ctrough) of garetosmab prior to dosing. Steady‐state PK was reached 12‐16 weeks after the first dose of garetosmab, with mean (standard deviation) Ctrough of 105 ± 30.8 mg/L. Immunogenicity assessments showed anti‐garetosmab antibody formation in 1 patient (1/43; 2.3%); titers were low, and did not affect PK or clinical efficacy. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. There were no meaningful differences in PK or BMP9 concentration–time profiles between patients who did and did not experience epistaxis or death. The comparative exposure–response analyses demonstrated no association between Ctrough and efficacy or safety. PK findings were consistent with prior data in healthy volunteers and were typical for a monoclonal antibody administered at doses sufficient to saturate target‐mediated clearance. There were no trends that suggested patients with higher serum exposures to garetosmab were more likely to experience a reduction in heterotopic ossification or adverse events. Garetosmab is being further evaluated in the Phase 3 OPTIMA trial.