Background: Jaktinib is a novel selective janus kinase 1/2 inhibitor. The phase I first-in-human study evaluated the tolerance and pharmacokinetics of jaktinib in healthy Chinese subjects.Methods: A randomized, double-blind, placebo-controlled study were designed. A total of 126 healthy subjects were enrolled into the single ascending dose, multiple ascending dose and food effect study. Safety endpoints included adverse events, abnormal vital signs, 12-lead ECGs, abdominal ultrasound, chest x-ray, physical examination and clinical laboratory tests. Blood, urine and feces samples were collected at predetermined time points for pharmacokinetic analysis of jaktinib, the metabolites ZG0244 and ZG0245, which are formed by oxidation or hydrolysis metabolic pathway, respectively.Results: Jaktinib was absorbed with a median time to peak plasma concentration of 1.25–3.5 h and was eliminated with a half-life of 2.952–9.040 h. Linear pharmacokinetic characteristic was presented over the dose range from 25 to 400 mg. No obvious accumulation was observed after multiple doses for 10 days. Administration after a high-fat breakfast significantly increased the absorption of jaktinib. The accumulated fraction of jaktinib and the determined metabolites excreted in urine and feces was 19.478%. Jaktinib was well tolerated in all single dose cohorts. In multiple dose cohorts, 200 mg q24 h method was evaluated as maximally tolerated dose. Neutropenia, diarrhea, dizziness and headache were the most frequently reported treatment related adverse events. No deaths, serious or Grade ≥4 adverse events was developed.Conclusion: Jaktinib was well tolerated when single dose ranging from 25 to 400 mg and multiple dose up to 200 mg q24 h. The safety and pharmacokinetic characteristics support the next trial in myelofibrosis patients.

In this work, in situ confinement polymerization was developed for the formation of silver nanoclusters (AgNCs) homogeneously distributed on nitrogen-doped carbon (NCS) utilizing N-vinyl functionalized imidazolium ionic liquids (ILs) as stabilizers and carbon precursors. The fabricated AgNC@NCSs exhibited excellent electrochemical and catalytic properties due to their controlled structure and morphology, the unique layered structure of the carbon carriers, and the confinement effect. The AgNC@NCS material was further fabricated for a printing electrode, which also acted as an internal reference for ratiometric and accurate detection. Nitrite was used as a target to verify the feasibility of self-calibrating detection at the AgNC@NCS printing electrode. The present electrochemical sensor demonstrated superior nitrite sensing characteristics, accompanied by a wide linear range (1.12–1400 μM), low detection limit (0.38 μM), high stability, and strong anti-interference ability. Importantly, high reliability of this self-calibrating detection was obtained for nitrate determination in food samples. Our work provides an efficient strategy for the design of self-calibrating electrodes in the area of electrochemical sensing.

Although ruxolitinib improves splenomegaly and constitutional symptoms in patients with myelofibrosis (MF), a substantial proportion of patients discontinue ruxolitinib because of intolerance. This phase 2 trial investigated the safety and efficacy of jaktinib, a novel JAK inhibitor in patients with ruxolitinib‐intolerant MF. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR35) at week 24. The secondary endpoints included change of MF‐related symptoms, anemic response, and safety profiles. Between December 18, 2019, and November 24, 2021, 51 patients were enrolled, 45 treated with jaktinib 100 mg bid (100 mg bid group) and six received non‐100 mg bid doses (non‐100 mg bid group). The SVR35 at week 24 in the 100 mg bid group was 43.2% (19/44, 95% CI 29.7%–57.8%). There were 41.9% (13/31) of transfusion‐independent patients with hemoglobin (HGB) ≤100 g/L who had HGB elevation ≥20 g/L within 24 weeks. The proportion of patients with a ≥50% decrease in the total symptom score (TSS 50) at week 24 was 61.8% (21/34). The most commonly reported grade ≥3 treatment‐emergent adverse events (TEAEs) in the 100 mg bid group were anemia 31.1%, thrombocytopenia 22.2%, and infectious pneumonia 17.8%. A total of 16 (35.6%) in the 100 mg bid group had serious adverse events, and 4 (8.9%) were considered possibly drug related. These results indicate jaktinib can provide a treatment option for patients with MF who are intolerant to ruxolitinib.

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Ruxolitinib has demonstrated efficacy in patients with myelofibrosis (MF). However, substantial number of patients may not respond after 3–6 months of treatment or develop resistance over time. In this phase 2 trial, patients with a current diagnosis of intermediate or high‐risk MF who either had an inadequate splenic response or spleen regrowth after ruxolitinib treatment were enrolled. All patients received jaktinib 100 mg Bid. The primary endpoint was the proportion of patients with ≥35% reduction in spleen volume (SVR 35) at week 24. The secondary endpoints included change of MF‐related symptoms, anemic response, and safety profile. From July 6, 2021, to January 24, 2022, 34 ruxolitinib‐refractory or relapsed patients were enrolled, 52.9% (18 of 34) were DIPSS intermediate 2 or high risk. SVR 35 at week 24 was 32.4% (11 of 34, 95% CI 19.1%–49.2%) in all patients and 33.3% (6 of 18, 95% CI 16.3%–56.3%) in the intermediate 2 or high‐risk group. A total of 50% (8 of 16) transfusion‐independent patients with hemoglobin (HGB) <100 g/L at baseline had HGB elevation ≥20 g/L within 24 weeks. Furthermore, 46.4% (13 of 28) of patients had a ≥ 50% decrease in the total symptom score (TSS 50) at week 24. The most common grade ≥3 treatment‐emergent adverse events (TEAEs) were thrombocytopenia (32.4%), anemia (32.4%), and leukocytosis (20.6%). In total, 13 (38.2%) of 34 patients had serious adverse events (SAE), of which drug‐related SAEs were found in 5 patients (14.7%). These results indicate that jaktinib can be a promising treatment option for patients with MF who have either become refractory to or relapsed after ruxolitinib treatment.