Rovadicitinib

Patients with myelofibrosis (MF) who were relapsed or refractory, or intolerant to Ruxolitinib, have limited effective treatment options, and the outcome after discontinuation of Ruxolitinib is poor. Rovadicitinib (TQ05105) is a first-in-class, oral, small-molecule Janus kinase (JAK)/Rho-associated kinase (ROCK) inhibitor. Rovadicitinib has demonstrated significant clinical benefits in MF patients for spleen responses and reduced symptom burden. Here, we report safety and efficacy from a single-arm, multicenter, open-label, phase Ib study evaluating Rovadicitinib in MF patients resistant or intolerant to prior Ruxolitinib (NCT06388759). Between August 1, 2022, and September 05, 2023, patients were assessed for eligibility, and 9 patients were enrolled. The median duration of prior Ruxolitinib exposure was 40.6 months. At a median Rovadicitinib exposure of 12.5 months, the most common grade ≥3 treatment-emergent adverse event was thrombocytopenia (33.3 %). No report of a bleeding event and only one of 9 patients (11.1 %) permanently discontinued Rovadicitinib treatment. The spleen volume response rate (≥35 % spleen volume decrease from baseline to end of cycle 6 [EOC6]) was 25.0 %. Symptom response rate (≥50 % reduction from baseline to EOC6 in total symptom score on the modified Myelofibrosis Symptom Assessment Form) was 37.5 %. This study suggests that patients with MF who are intolerant or resistant to Ruxolitinib or other JAK inhibitors might achieve significant clinical benefit after treatment with Rovadicitinib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT06388759.

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.