Garetosmab (DB16379): A Comprehensive Review of an Investigational Anti-Activin A Antibody for Fibrodysplasia Ossificans Progressiva and Other Potential Indications

1. Introduction to Garetosmab and Fibrodysplasia Ossificans Progressiva (FOP)

1.1. Overview of Garetosmab

Garetosmab is an investigational, fully human monoclonal antibody of the immunoglobulin G4 kappa (IgG4κ) isotype, designed to target and neutralize Activin A.[1] Its primary therapeutic application under investigation is for the management of fibrodysplasia ossificans progressiva (FOP), a rare and severely disabling genetic disorder.[1] Beyond FOP, Garetosmab is also being explored for its potential in other conditions, notably obesity, reflecting a broader interest in the physiological roles of Activin A.[2]

1.2. Pathophysiology of Fibrodysplasia Ossificans Progressiva (FOP)

Fibrodysplasia ossificans progressiva is an exceptionally rare, autosomal dominant genetic disorder characterized by episodic and progressive heterotopic ossification (HO).[1] This pathological process involves the formation of mature, lamellar bone in extraskeletal soft tissues, including muscles, tendons, ligaments, and fascia.[1] Flare-ups, which are episodic inflammatory events often precipitated by trauma (including minor tissue damage, immunizations, or viral illnesses), typically precede and trigger ossification of the affected lesion.[1]

The consequences of progressive HO are devastating. Patients experience abnormal cartilage formation, growth plate dysplasia, and severe joint ankylosis, leading to cumulative and irreversible loss of mobility.[1] This progressive immobility results in significant disability, with many patients becoming wheelchair-bound or confined to fixed positions, and is associated with numerous comorbidities, including restrictive lung disease, difficulties with mastication and nutrition, and a markedly curtailed lifespan.[5]