2-(3-(4-(1H-Indazol-5-ylamino)-2-quinazolinyl)phenoxy)-N-(1-methylethyl)acetamide

In the open label prelicensure clinical trials of belumosudil in patients with refractory chronic GvHD, serum aminotransferase elevations occurred in up to 7% of treated subjects. The elevations were typically mild and transient and values above 5 times the upper limit of normal (ULN) occurred in only 1% to 2% of patients. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to belumosudil. Since approval and more widescale availability of belumosudil, there have been no published reports of hepatotoxicity associated with its use.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Belumosudil appears to inhibit several pro-fibrotic and pro-inflammatory processes in order to prevent and treat the damage incurred by graft-versus-host disease. Given its mechanism of action and findings in animal trials, belumosudil is considered to carry embryo-fetal toxicity and may cause significant harm to a developing fetus should a pregnant mother be exposed. Female patients of reproductive potential, or male patients with female partners of reproductive potential, should be advised to use effective contraception during treatment with belumosudil and for one week after the last dose.

Chronic graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation in which the transplanted donor T-cells recognize the recipient's tissues as foreign and mount an immune response. During the conditioning regimen prior to stem cell transplantation (e.g. involving irradiation or chemotherapy) the host tissues can become damaged which results in downstream inflammatory responses and the generation of inflammatory mediators like TNF-alpha and IL-1. These cytokines increase the expression of host major histocompatibility (MHC) antigens and adhesion molecules which enhances the ability of mature donor T-cells to recognize these molecules. The activation of these donor T-cells results in the activation of mononuclear phagocytes, whose effector functions are triggered by stimulatory molecules generated by the damage incurred during the conditioning phase of treatment. Activated macrophages and cytotoxic T-lymphocytes begin to directly lyse target cells and/or cause their apoptosis, which eventually leads to local tissue damage and further inflammatory responses. Belumosudil is an inhibitor of Rho-associated coiled-coil kinase 2 (ROCK2), a protein that plays a vital role in the pathogenesis of immune and fibrotic diseases. The inhibition of ROCK2 has been shown to resolve immune dysregulation by down-regulating pro-inflammatory Th17 cells and up-regulating regulatory T-cells by manipulating the phosphorylation of STAT3 and STAT5.