Chronic graft-versus-host disease (cGvHD) and
systemic sclerosis (scleroderma [SSc]) share clinical characteristics, including skin and internal organ
fibrosis.
Fibrosis, regardless of the cause, is characterized by extracellular matrix deposition, of which
collagen type I is the major constituent. The progressive accumulation of connective tissue results in destruction of normal tissue architecture and internal organ failure. In both SSc and cGvHD, the severity of skin and internal organ
fibrosis correlates with the
clinical course of the disease. Thus, there is an unmet need for well-tolerated antifibrotic
therapy.
Halofuginone is an inhibitor of
collagen type I synthesis in cells derived from various tissues and species and in animal models of
fibrosis in which excess
collagen is the hallmark of the disease.
Halofuginone decreased
collagen synthesis in the tight skin mouse (Tsk) and murine cGvHD, the 2 experimental systems that show many features resembling those of human GvHD. Inhibition of
collagen synthesis by
halofuginone is achieved by inhibiting
transforming growth factor beta-dependent Smad3 phosphorylation. Dermal application of
halofuginone caused a decrease in
collagen content at the treated site of a cGvHD patient, and reduction in skin scores was observed in a pilot study with SSc patients. The results of the human studies provide basis for using
halofuginone treatment for dermal
fibrosis. As a first step toward future treatment of internal organ involvement, an
oral administration study was performed in which
halofuginone was well tolerated and plasma levels surpassed the predicted therapeutic exposure.