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General Description:

Garetosmab, identified by CAS number 2097125-54-5, is a notable compound with significant therapeutic applications. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of episodic, progressive heterotropic ossification. FOP is characterized by episodic inflammatory episodes, which may be precipitated by trauma, including immunizations and minor tissue damage, which usually result in ossification of the lesion. Patients experience abnormal cartilage formation, growth plate dysplasia, and joint issues, resulting in progressive immobility and associated comorbidities. The discovery of an activating mutation in the ACVR1 receptor that renders it responsive to the (normally antagonistic) Activin A led to an interest in Activin A as a therapeutic target. Garetosmab is under investigation in clinical trial NCT04577820 (Study to Assess the Efficacy and Safety of Garetosmab in Japanese Adult Patients With Fibrodysplasia Ossificans Progressiva (FOP)).

Absorption:

The absorption characteristics of Garetosmab are crucial for its therapeutic efficacy: Garetosmab, administered as a single intravenous dose to healthy females had a mean C_max of between 8.10 ± 0.929 and 378 ± 39.7 mg/L for doses ranging between 0.3-10 mg/kg. The C_max was achieved in a median of 0.06-0.10 days, regardless of dose. Over the same dose range, the AUC_0-∞ ranged from 72.2 ± 15.4 to 7520 ± 809 mg\*day/L. When administered as a single subcutaneous dose of 300 mg, garetosmab had a C_max of 31.6 ± 7.94 mg/L, a T_max of 20.9 (range 6.88-21.0) days, and an AUC_0-∞ of 1334 ± 376 mg\*day/L. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Volume of Distribution:

Garetosmab is distributed throughout the body with a volume of distribution of: Garetosmab had a steady-state volume of distribution between 41.4 ± 4.66 and 47.8 ± 4.70 ml/kg following a single IV dose of 0.3-10 mg/kg in healthy women. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Garetosmab is a critical factor in determining its safe and effective dosage: When administered as a single IV dose of 0.3-10 mg/kg in healthy women, Garetosmab clearance decreases with increasing dose from 4.35 ± 1.11 mL/day/kg at 0.3 mg/kg down to 1.34 ± 0.149 mL/day/kg at 10 mg/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Mechanism of Action:

Garetosmab functions by: Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder of episodic, progressive heterotropic ossification. Approximately 97% of FOP patients share the same c.617G > A; R206H mutation in the _ACVR1_ gene encoding a type I TGFβ/BMP family ligand-receptor that binds BMPs to signal through Smad1/5/8. This mutation is predicted to destabilize the intracellular glycine-serine (GS) activation domain. Activin A signals typically through a complex of the type I receptor ACVR1B and one of the type II receptors ACVR2A, ACVR2B, or BMPR2 that interfaces with Smad2/3. However, Activin A can also form a non-signalling complex (NSC) together with ACVR1 that sequesters both the ligand and cognate receptors resulting in an apparent inhibition of ACVR1-mediated BMP signalling. Surprisingly, the R206H _ACVR1_ mutation confers signalling sensitivity to the Activin A-ACVR1-type II receptor NSC, causing aberrant activation of Smad1/5/8 pathways and ossification of FOP lesions. At the same time, the mutant ACVR1 receptor retains its ability to signal through BMPs. Garetosmab is a human IgG4κ antibody specific for Activin A. By inhibiting Activin A signalling through the mutant R206H receptor, garetosmab will likely improve the course of heterotropic ossification in FOP while not interfering with normal TGFβ/BMP family functions. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Classification:

Garetosmab belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.