Jaktinib Hydrochloride

Ruxolitinib is first‐line therapy for intermediate/high‐risk myelofibrosis (MF), but ∼50% of patients discontinue within 1 year due to loss of efficacy or intolerance. Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for ruxolitinib‐pretreated MF, with no head‐to‐head trials comparing their efficacy and safety. This study used matching‐adjusted indirect comparison (MAIC) to compare these four agents, aiming to provide evidence‐based insights for treatment decision‐making in ruxolitinib‐resistant or intolerant MF. Individual patient data (IPD) of gecacitinib (100 mg BID; ZGJAK006/ZGJAK017, n  = 78) and published data of comparators (fedratinib: JAKARTA‐2/FREEDOM2; pacritinib: PAC203; momelotinib: SIMPLIFY‐2/MOMENTUM) were analyzed. Eight baseline characteristics were matched. Efficacy outcomes (week‐24 SVR35, TSS50, transfusion independence [TI]) were reported as odds ratios (ORs); safety as risk differences (RDs). Gecacitinib showed superior SVR35 versus fedratinib (JAKARTA‐2: OR = 3.96, 95% CI = 1.37–11.39, P  = 0.0108), pacritinib (PAC203: OR = 6.10, 95% CI = 1.54–24.23, P  = 0.0101), and momelotinib (SIMPLIFY‐2: OR = 8.65, 95% CI = 1.86–40.31, P  = 0.0060), and superior TSS50 versus pacritinib (OR = 7.62 95% CI = 1.84–31.51, P  = 0.0050) and momelotinib (MOMENTUM: OR = 7.52, 95% CI = 1.63–34.61, P  = 0.0096). Numerically, gecacitinib had better TI. It also had significantly lower incidences of diarrhea, nausea, and AE‐related treatment discontinuation. Hematologic AE profiles of gecacitinib varied by comparator cohort. Gecacitinib showed favorable efficacy and tolerability signals versus several comparators, suggesting it may be a valuable second‐line option.

Gecacitinib is a novel, broad‐spectrum Janus kinase (JAK) inhibitor being developed for the treatment of myelofibrosis, severe alopecia areata, ankylosing spondylitis, and atopic dermatitis. This study aimed to develop population pharmacokinetic (PopPK) models for gecacitinib and its metabolites ZG0244 and ZG0245 to evaluate influential factors. Data from healthy subjects and patients across nine clinical trials were pooled. PopPK models were developed using NONMEM, and covariates of interest were tested. The PopPK structure for gecacitinib was a two‐compartment model with first‐order absorption and linear elimination. The metabolite ZG0244 was best described by a two‐compartment model with Michaelis–Menten formation and linear elimination, while for metabolite ZG0245, it was a one‐compartment model with Michaelis–Menten formation and linear elimination. Statistically significant factors affecting pharmacokinetic parameters included sex, age, indication, and co‐administration with a strong CYP3A inducer or inhibitor. The effects of sex, age, and strong CYP3A inducer on exposure were limited, requiring no dose adjustment. A strong CYP3A inhibitor increased exposure by approximately 1.3‐fold. The median time to reach 95% of steady‐state concentration was approximately 3 days for gecacitinib and ZG0244, and approximately 7 days for ZG0245. This study developed population pharmacokinetic models for gecacitinib and its metabolites, and quantified the effects of covariates.