Correlation of miR-124 Upregulation and PK Parameters in Blood of Patients With Moderate-to-Severe Ulcerative Colitis Receiving Obefazimod for 16 Weeks

Introduction: Obefazimod is an oral small molecule that has demonstrated short- and long-term efficacy and good safety profile in patients with moderate-to-severe ulcerative colitis (UC) (1,2). Obefazimod modulates inflammation by upregulating a specific anti-inflammatory micro-RNA (miR-124). In humans, obefazimod is metabolized via UGT1A9 as a main active metabolite (N-Glu). We examined whether the pharmacodynamics of obefazimod with regard to miR-124 upregulation in blood of patients receiving obefazimod during a 16-week phase 2b induction study (EudraCT number: 2018-003558-26) were correlated with AUC and Cmax of the parent drug and its metabolite. Methods: Absolute quantification (QuantaSoft Pro) of the miR-124 copy number was performed by using droplet digital PCR technology on 205 whole blood samples from 205 patients receiving obefazimod (25, 50, 100 mg once daily) for 16 weeks. For pharmacokinetics assessment (Cmax and AUC of obefazimod and its metabolite), blood samples were collected in all patients on week 16 of study treatment. The correlation between miR-124 upregulation and Cmax and AUC was tested with Spearman's non-parametric correlation analysis. Results: Daily obefazimod treatment (25, 50, 100 mg) dose dependently increased the number of miR-124 copies in blood of UC patients (Table 1). miR-124 upregulation at week 16 in blood of obefazimod-treated patients was significantly correlated with AUC for obefazimod and its metabolite. The miR-124 upregulation showed a significant correlation with Cmax of N-Glu, while no significant correlation was observed with the parent compound. There was a dose-dependent correlation between miR-124 upregulation and Cmax of the metabolite. Conclusion: The pharmacodynamics of obefazimod with regard to miR-124 upregulation in blood of patients receiving obefazimod for 16 weeks correlates significantly with AUC and Cmax of N-Glu, and to a lesser extent with the parent drug. These findings are indicative of a dominant effect of N-Glu on miR-124 expression, which is consistent with the longer half-life and higher exposure of the metabolite compared to obefazimod. The lack of significant PKPD correlation between miR-124 increase and PK values with the highest dose of obefazimod suggests a saturation effect. References: 1. Vermeire S, et al, Lancet Gastroenterol Hepatol 2022, 7 (11): 1024-1035. 2. Vermeire S, et al, J Crohns Colitis 2023. doi: 10.1093/ecco-jcc/jjad067. Table 1. - Number of miR-124 copies - Correlation of miR-124 upregulation and PK parameters OBE 25 mg (N=56) OBE 50 mg (N=50) OBE 100 mg (N=49) Number of miR-124 copies Median (Mean) [Min-Max] 2289 (4154) [28-28426] 5038 (7723) [0-42113] 8672 (13268) [0-40583] Coefficient of correlation between miR-124 and: All doses 25 mg 50 mg 100 mg OBE Cmax 0.132 0.027 -0.186 0.021 AUC 0.173* 0.100 -0.057 -0.106 N-Glu AUC 0.394*** 0.413** 0.303* -0.021 Cmax 0.349*** 0.288* 0.268 0.052 OBE: obefazimod; N: number of patients; * P< 0.05; ** P< 0.005; *** P< 0.001 (Spearman’s correlation analysis).