Aim: Coagulation factor XI (FXI) plays a crucial role in the intrinsic coagulation pathway, and inhibitors targeting it may mitigate the risk of hemorrhage compared to anticoagulants currently on the market. SKB336, a novel selective inhibitor of FXI/FXIa, has been shown to prolong the activated partial thromboplastin time (APTT) in in-vitro and in-vivo studies. This study aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of SKB336 in healthy subjects. Methods: In this randomized, single-blinded, placebo-controlled, and dose-escalation phase I study, 60 healthy subjects were allocated to six cohorts (0.1 mg/kg, 0.3 mg/kg, 0.6 mg/kg, 1.25 mg/kg, 2.5 mg/kg, and 4 mg/kg) and received SKB336 injection or placebo in a 4:1 ratio. The safety, tolerability, pharmacokinetics, and immunogenicity were measured up to 85 days post-dose. Exploratory analysis consisted of FXI activity and APTT. Results: SKB336 was well tolerated in all six cohorts, without any hemorrhagic events, reported deaths, or serious adverse events. No significant dose-dependent correlation was observed with the incidence of adverse events. Dose-dependent increases in the Cmax and AUC were observed. The mean t1/2 was 21.3–33.5 days, indicating a potential monthly dosing frequency. The maximum inhibition rate of FXI activity for all six cohorts reached 0, 17%, 28%, 48%, 54%, and 59%, respectively. The maximum APTT ratio to baseline reached 1.09-, 1.26-, 1.47-, 1.77, 1.91-, and 2.00-fold, respectively. Conclusion: SKB336 was generally tolerated, without any bleeding events in healthy volunteers. Besides, SKB336 presented a persistent dose-dependent prolongation of APTT and duration of FXI inhibition.

Background: Intestinal Fusobacterium nucleatum (F. nucleatum) infection has been implicated into the progression of colorectal cancer (CRC). However, F. nucleatum as a biomarker in 5-fluorouracil (5-FU) resistance of CRC has not been fully analyzed by comparing with other types of gut microbiota. This meta‑analysis aimed to compare the diagnostic performance of intestinal Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli in 5-FU resistance to colorectal cancer and provide evidence‑based data to clinical practice. Methods: Comprehensive searches of PubMed, Embase, Cochrane Library and Web of Science databases were conducted by the following key words: “Fusobacterium nucleatum”, “5-Fluorouracil resistance”, “Bacteroides fragilis”, “Escherichia coli” and “colorectal cancer(s)”. A total of 11 studies were selected according to the preestablished inclusion and exclusion criteria and analyzed by Review Manager 5.4 software. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and their corresponding 95% confidence interval (CI) of each eligible study were summarized. Results: Overall sensitivity and specificity of F. nucleatum detection in 5-FU resistance of CRC were 0.65 (95% CI:0.60-0.69) and 0.70 (95% CI:0.59-0.87), respectively. Its PLR and NLR in detecting colorectal cancer were 2.57 (95% CI:1.47-3.21) and 0.52 (95% CI:0.43-0.63). DOR value was 4.92 (95% CI:2.23-7.33), which significantly exceeds the performance of B. fragilis (DOR: 0.53, 95% CI:0.31-0.82) and E. coli (DOR: 0.63, 95% CI: 0.57-0.76) for indicating 5-FU resistance of CRC. Conclusion: Compared with B. fragilis and E. coli, intestinal F. nucleatum is a valuable biomarker for 5-FU resistance to colorectal cancer.

Aim: The objective of this study was to evaluate the safety, pharmacokinetics, and pharmacodynamics of SHR2285, a novel small molecule FXIa inhibitor, in Chinese healthy volunteers. Methods: The study consisted of single ascending doses part (part A: 25 - 600 mg) and multiple ascending doses part (part B: 100, 200, 300, and 400 mg). In both parts, subjects were randomized in a 3:1 ratio to receive SHR2285 or placebo. Plasma and urine samples were collected to describe its pharmacokinetics and pharmacodynamics (PD) profile. Results: SHR2285 were well tolerated. SHR2285 was absorbed rapidly with median Tmax of 1.50 to 3.00 h. The geometric median of t1/2 of SHR2285 varied from 8.74-12.1 h across 25 to 600 mg single dose. Total systemic exposure of metabolite SHR164471 was approximately 1.77-3.61 fold that of the parent drug. The plasma concentration of SHR2285 and SHR164471 reached steady state by the morning of Day 7 with low accumulation ratio (0.956-1.20 and 1.18-1.56 respectively). The increase in PK exposure of SHR2285 and SHR164471 was less than dose proportional. Food has minimal effect on the pharmacokinetics of SHR2285 and SHR164471. SHR2285 produced an exposure dependent prolongation of APTT, and decrease in FXI activity. The maximum FXI activity inhibition rate (geometric mean) at steady state was 73.27%, 85.58%, 87.77% and 86.27% for 100 to 400 mg, respectively. Conclusions: SHR2285 exhibit a predictable PK profile and exposure related PD profile. These results suggest that SHR2285 is a promising novel oral FXI inhibitor warranting further evaluation.