Source: FDA, National Drug Code (US) Revision Year: 2026
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-grts 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-grts.
Following multiple doses of garetosmab-grts 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-grts 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-grts 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-grts 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-grts 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-grts 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-grts pharmacokinetics is unknown.
Since garetosmab-grts 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-grts.
No drug-drug interaction studies have been conducted with garetosmab-grts.
Carcinogenicity studies have not been conducted with garetosmab-grts. The mutagenic potential of garetosmab-grts has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
Dedicated fertility studies have not been conducted with garetosmab-grts. Reproductive organs and fertility-related parameters were assessed in sexually mature cynomolgus monkeys in a 26-week study in which garetosmab-grts was administered intravenously once weekly at doses up to 50 mg/kg (approximately 14 times or 49 times the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, based on AUC). Minimal to moderate seminiferous tubule degeneration was observed in male monkeys, which was reversible after a treatment-free recovery period. Changes in sperm concentration, sperm motility, or testosterone levels were not observed.
In 5-week toxicology studies in male rats, intravenous administration of garetosmab-grts resulted in adverse effects including inflammation, granulomas, and epithelial degeneration in the male reproductive tract (testes, epididymis, and efferent ducts) associated with decreases in sperm motility at exposures less than the recommended human doses of PASATRU 10 mg/kg or 3 mg/kg every 4 weeks.
The efficacy of PASATRU was evaluated in Study 1 (NCT05394116), a randomized, double-blind, parallel-group, multicenter, placebo-controlled trial in 63 adults with FOP confirmed by an ACVR1 FOP-causing mutation.
Patients were randomized to receive PASATRU 10 mg/kg (N=23), PASATRU 3 mg/kg (N=19), or placebo (N=21), intravenously every 4 weeks for 56 weeks using an infusion pump. Upon completion of the first 56 weeks, 61 patients continued to receive their original assigned study treatment in a double-blind extension phase.
The median age of patients was 25 (range: 18 to 42) years; 60% of patients were female; 67% of patients were White, 30% were Asian, 19% were Hispanic or Latino, and 2% were Black or African American. Ninety-five percent (95%) of patients had the R206H genetic mutation. The mean Cumulative Analog Joint Involvement Scale (CAJIS) score (range: 0 to 30) at baseline was 13 (range: 0 to 19).
The primary efficacy endpoint was the number of new HO lesions at Week 56 assessed by low-dose, whole-body computed tomography (WBCT) imaging, with the treatment effect evaluated using the estimated rate ratio for the number of new HO lesions. The key secondary endpoints included the number of clinician-assessed flare-ups through Week 56, the proportion of patients with new HO lesions at Week 56; and the total volume of new HO lesions at Week 56.
Statistically significant reductions in the number of new HO lesions at Week 56 were observed in patients receiving PASATRU 10 mg/kg every 4 weeks or 3 mg/kg every 4 weeks compared to placebo (90% reduction or 94% reduction for PASATRU 10 mg/kg or 3 mg/kg, respectively, compared to placebo). There were a total of 19 new HO lesions observed in 5/21 (24%) patients receiving placebo compared to 2 total lesions in 2/23 (9%) patients or 1 lesion in 1/19 (5%) patients treated with PASATRU 10 mg/kg or 3 mg/kg every 4 weeks, respectively, at Week 56 (see Table 2).
The number of clinician-assessed flare-ups through Week 56 was 9, 53, and 66 for PASATRU 10 mg/kg, 3 mg/kg, and placebo, respectively. The rate ratio (95% CI) compared to placebo was 0.12 (0.03, 0.42) for PASATRU 10 mg/kg, and 0.85 (0.26, 2.73) for PASATRU 3 mg/kg. Changes in the proportion of patients with patient-reported flare-ups through Week 56 were not significantly different between placebo and PASATRU treatment groups.
The mean new HO volume at Week 56 was 10.5 cm3 in patients receiving placebo compared to 0.02 cm 3 (mean difference vs. placebo: -10.4 cm3 [95% CI: -27.5, -0.3]) in patients receiving PASATRU 10 mg/kg every 4 weeks and 0.01 cm3 (mean difference vs. placebo: -10.4 cm3 [95% CI: -27.5, -0.3]) in patients receiving PASATRU 3 mg/kg every 4 weeks. These findings were not statistically significant based on the pre-specified Wilcoxon rank-sum test.
Table 2. Efficacy Results in Adults with FOP in Study 1 at Week 56:
| Placebo | PASATRU 10 mg/kg every 4 weeks | PASATRU 3 mg/kg every 4 weeks | |
| (N=21) | (N=23) | (N=19) | |
| Number of new HO lesions at Week 56, total* (rate†) | 19 (0.90) | 2 (0.09) | 1 (0.05) |
| Rate Ratio vs. Placebo | - | 0.10‡ | 0.06‡ |
| (95% CI) | (0.01, 0.76) | (0, 0.73) | |
| % Reduction vs. Placebo | 90% | 94% |
* Total number is defined as the sum of the number of new HO lesions observed in each treatment group at Week 56.
† Rate is defined as the mean number of new HO lesions per patient at Week 56.
‡ Statistically significant (multiplicity-adjusted p-value <0.05).
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