Rovadicitinib

Rovadicitinib (TQ05105) is a novel, oral dual Janus kinase 1/2 and rho-associated coiled-coil–containing protein kinase-1/2 inhibitor targeting inflammatory and fibrotic components of chronic graft-versus-host disease (cGVHD). This phase 1b/2a, multicenter, open-label study enrolled patients with moderate or severe glucocorticoid-refractory or -dependent cGVHD to evaluate the safety and efficacy of rovadicitinib. The study followed a 3+3 design with 2 escalating doses (rovadicitinib 10 and 15 mg twice daily) and a dose expansion cohort. Primary end points included safety and recommended phase 2 dose (RP2D); the best overall response (BOR) was the key secondary end point. A total of 44 patients were enrolled (29 at 10 mg, 15 at 15 mg twice daily). Rovadicitinib was well tolerated without dose-limiting toxicity at both dosages, and no rovadicitinib-related adverse events (AEs) led to discontinuation. The most prevalent hematological AE was anemia (38.6%), with grade ≥3 of 4.6%. The RP2D was 10 mg twice daily. The BOR was 86.4% (95% confidence interval [CI], 72.6-94.8), with no difference between the 2 dosage cohorts. Besides, BOR was 72.7% in the steroid-refractory cohort and 90.9% in the steroid-dependent cohort. All affected organs exhibited responses regardless of prior therapy. The failure-free survival rate was 85.2% (95% CI, 64.5-94.3) at 12 months. Rovadicitinib reduced corticosteroid doses in 88.6% of patients and improved cGVHD symptoms in 59.1%. Rovadicitinib has favorable tolerability and notable clinical response rates, ameliorating the quality of life and reducing corticosteroid dose requirements in patients with glucocorticoid-refractory or -dependent cGVHD. This trial was registered at www.ClinicalTrials.gov as #NCT04944043.

Chronic graft-versus-host disease (cGVHD) is the most common cause of late non-relapse mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Rho-associated coiled-coiled kinases (ROCK) inhibitors have been shown to balance the pro-inflammatory and regulatory T-cell subsets in addition to reducing fibrosis in cGVHD, resulting in the development of multiple ROCK2 inhibitors including belumosudil.

We describe the pathophysiology of cGVHD and the role of ROCK2 in cGVHD. This includes a review of the current and ongoing clinical data with belumosudil, and an overview of current ROCK2 inhibitors in development for cGVHD, including rovadicitinib, zelasudil, and GV-101.

Many of the recent novel agents with unique mechanisms such as ROCK2 inhibitors (i.e. belumosudil) provide high response rates but rarely yield complete responses in cGVHD. The future of management of cGVHD will rely on investigating combination therapy upfront that may achieve deeper complete responses, developing newer preventative therapies, and advancements in biomarker detection/risk stratification for cGVHD.