FOP is caused by gain-of-function mutations in the intracellular domain of activin receptor type 1 (ACVR1, also known as ALK2), a bone morphogenetic protein (BMP) type I receptor that is expressed in many tissues, including skeletal muscle and cartilage. In patients with FOP, mutant ACVR1 is activated by activin A resulting in heterotopic ossification. Garetosmab is a human IgG4 monoclonal antibody that specifically binds to and inhibits signaling by activin A to block the activation of FOP-mutant ACVR1 and reduce the formation and progression of new heterotopic bone lesions.
No pharmacodynamic studies have been conducted with garetosmab.
Following multiple doses of garetosmab 10 mg/kg or 3 mg/kg administered intravenously every 4 weeks in patients with FOP, the steady-state exposures were approximately dose proportional. The mean (SD) trough concentrations at steady-state following intravenous administration of garetosmab 10 mg/kg or 3 mg/kg every 4 weeks were 99 (34) mg/L or 27 (10) mg/L, respectively, in patients with FOP. Steady-state concentrations were attained by approximately 12 weeks with an accumulation ratio of approximately 1.7-fold.
The estimated mean (SD) volume of distribution is 5.1 (1.2) L.
Garetosmab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear, target-mediated clearance predominates.
After the last dose of garetosmab 10 mg/kg or 3 mg/kg administered intravenously every 4 weeks in patients with FOP, the median time to a non-detectable concentration was approximately 24 weeks or 17 weeks, respectively, based on population pharmacokinetic analysis.
Garetosmab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
No clinically meaningful differences in the exposure of garetosmab were observed in adults based on age (18 to 70 years), sex, body weight (32 to 128 kg), race (White 86%, Asian 10%, Black 1%), mild to moderate renal impairment (creatinine clearance 30 to 89 mL/min, estimated by Cockcroft-Gault equation), or mild to moderate hepatic impairment (total bilirubin >1.5 to ≤3 times upper limit of normal [ULN] and any aspartate aminotransferase [AST]) following 10 mg/kg and 3 mg/kg administered once every 4 weeks.
The effect of severe renal impairment or kidney failure (creatinine clearance <30 mL/min) and severe hepatic impairment (total bilirubin >3 times ULN and any AST) on garetosmab pharmacokinetics is unknown.
Since garetosmab is a monoclonal antibody that is not eliminated via renal pathways and is degraded by widely distributed proteolytic enzymes rather than restricted to hepatic tissue, changes in renal or hepatic function are not expected to impact the pharmacokinetics of garetosmab.
No drug-drug interaction studies have been conducted with garetosmab.
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