A First-in-Class JAK/ROCK Inhibitor, Rovadicitinib, for Glucocorticoid-Refractory or -Dependent Chronic GVHD

• Dual blockade of inflammatory and fibrotic pathway using rovadicitinib represents a novel therapeutic approach for the treatment of cGVHD.

• Rovadicitinib was well tolerated in patients with steroid-refractory cGVHD, eliciting a high response rate, improved quality of life.

Rovadicitinib (TQ05105) is a novel, oral dual JAK1/2 and ROCK1/2 inhibitor targeting inflammatory and fibrotic components of chronic graft-versus-host disease (cGVHD). We aimed to evaluate the safety and efficacy of rovadicitinib for glucocorticoid-refractory or -dependent cGVHD. This phase 1b/2a, multicenter, open-label study (NCT04944043) enrolled patients with moderate or severe glucocorticoid-refractory or -dependent cGVHD. The study followed a 3+3 design with two escalating doses (rovadicitinib 10 and 15 mg twice daily) and a dose expansion cohort. Primary endpoints included safety and recommended phase 2 dose (RP2D); the best overall response (BOR) was the key secondary endpoint. Forty-four patients were enrolled, with 29 in the 10 mg twice-daily cohort and 15 in the 15 mg twice-daily cohort. Rovadicitinib was well tolerated without dose-limiting toxicity at both dosages, and no rovadicitinib-related 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 two dosage cohorts. Besides, BOR achieved 72.7% (8/11) in the steroid-refractory cohort and 90.9% (30/33) 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 treatment reduced the corticosteroid dose in 88.6% of patients. cGVHD-related symptoms were improved in 59.1% of patients. 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.