THU467 Pharmacokinetics And Pharmacodynamics Of Garetosmab In Patients With Fibrodysplasia Ossificans Progressiva

Disclosure: Y. Wang: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J. Nguyen: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. R.R. de Ruiter: None. J. Mendell: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. D. Srinivasan: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. J.D. Davis: Employee; Self; Regeneron Pharmaceuticals. Stock Owner; Self; Regeneron Pharmaceuticals. M.W. Eekhoff: Grant Recipient; Self; Regeneron Pharmaceuticals, Ipsen, AstraZeneca, IMI, IFOPA. Background: Fibrodysplasia ossificans progressiva (FOP) is a rare disorder characterized by progressive heterotopic ossification and flare-ups of soft tissue swellings. It is caused by mutations in the bone-morphogenetic protein (BMP) type-1 activin-A receptor. Garetosmab is an investigational fully human monoclonal antibody against activin-A that prevents formation of new heterotopic ossification lesions. Here we report pharmacokinetic (PK) and immunogenicity data of garetosmab from the LUMINA-1 study. Methods: LUMINA-1 (NCT03188666) was a phase 2 randomized double-blind placebo-controlled study that evaluated the safety and efficacy of garetosmab (10 mg/kg/every 4 weeks intravenous) vs placebo in adult patients with FOP over 28 weeks (Period 1), followed by a 28-week open-label treatment period (Period 2) and a subsequent open-label extension (Period 3). Serum samples were obtained from all patients throughout the study to assess PK, immunogenicity, and concentrations of BMP9. Comparative exposure-response analyses of efficacy and safety were performed with trough concentrations of functional garetosmab in serum (C(trough)) as exposure variables. Results: PK data were analyzed in 44 patients with FOP who received garetosmab. Plots of C(trough) over time showed that steady-state PK was reached approximately 12-16 weeks after the first dose of garetosmab. After reaching steady state, C(trough) averaged (±SD) 105 ± 30.8 mg/L. There was no meaningful difference in the PK profiles between patients who did and did not experience epistaxis. Immunogenicity assessments showed anti-garetosmab antibody formation in one patient (1/43; 2.3%) who had a persistently low titer that had no impact on garetosmab PK or clinical effects. Median concentrations of BMP9 in serum were approximately 40 pg/mL at baseline. Levels did not show treatment-related changes over time, nor were differences seen between patients who did and did not experience epistaxis. Over the exposure range achieved at this single-dose level, the comparative exposure-response analyses demonstrated no association between C(trough) and efficacy (number of new heterotopic ossification lesions relative to baseline) or safety (incidence or severity of treatment emergent adverse events of special interest, including epistaxis and composite skin and soft tissue infection). Conclusions: PK steady state was reached within approximately 16 weeks of starting garetosmab treatment, and there were no trends suggesting patients with higher serum exposures to functional garetosmab were more likely to experience adverse events. Incidence of anti-garetosmab antibodies was low and concentrations of BMP9 in serum had no apparent association with epistaxis. Garetosmab is being further evaluated in the phase 3 OPTIMA trial (NCT05394116). Presentation: Thursday, June 15, 2023