PDF(Pubmed)
Abstract：
The NLRP3 inflammasome drives release of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18 and is a potential target for ulcerative colitis (UC). Selnoflast (RO7486967) is an orally active, potent, selective and reversible small molecule NLRP3 inhibitor. We conducted a randomized, placebo-controlled Phase 1b study to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of selnoflast.
Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL-1β inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated.
Selnoflast was well-tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post-dose. Mean plasma concentrations stayed above the IL-1β IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 μg/mL and 2.66 μg/mL, respectively). At steady state, post-dose selnoflast concentrations in sigmoid colon (5-20 μg/g) were above the IC90 . Production of IL-1β was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL-18 levels. There were no meaningful differences in the expression of an IL-1-related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers.
Selnoflast was safe and well-tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL-1β IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL-1β in tissue.
ISRCTN16847938.
Nineteen adults with previous diagnosis of UC and current active moderate to severe disease were randomized 2:1 to selnoflast or placebo for 7 days. A dose of 450 mg QD (once daily) was selected to achieve 90% IL-1β inhibition in plasma and colon tissue. Consecutive blood, sigmoid colon biopsies and stool samples were analyzed for a variety of PD markers. Safety and PK were also evaluated.
Selnoflast was well-tolerated. Plasma concentrations increased rapidly after oral administration, reaching Tmax 1 h post-dose. Mean plasma concentrations stayed above the IL-1β IC90 level throughout the dosing interval (mean Ctrough on Day 1 and Day 5: 2.55 μg/mL and 2.66 μg/mL, respectively). At steady state, post-dose selnoflast concentrations in sigmoid colon (5-20 μg/g) were above the IC90 . Production of IL-1β was reduced in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) (in the selnoflast arm). No changes were observed in plasma IL-18 levels. There were no meaningful differences in the expression of an IL-1-related gene signature in sigmoid colon tissue, and no differences in the expression of stool biomarkers.
Selnoflast was safe and well-tolerated. Selnoflast 450 mg QD achieved plasma and tissue exposure predicted to maintain IL-1β IC90 over the dosing interval. However, PD biomarker results showed no robust differences between treatment arms, suggesting no major therapeutic effects are to be expected in UC. The limitations of this study are its small sample size and indirect assessment of the effect on IL-1β in tissue.
ISRCTN16847938.
摘要：
背景：NLRP3炎性体驱动促炎细胞因子（包括白介素（IL）-1β和IL-18）的释放，是溃疡性结肠炎（UC）的潜在靶标。Selnoflast（RO7486967）是一种口服活性物质，强力，选择性和可逆的小分子NLRP3抑制剂。我们做了一个随机的,安慰剂对照1b期研究，以评估安全性，耐受性,塞诺司特的药代动力学（PK）和药效学（PD）。
方法：将19例先前诊断为UC且目前患有活动性中度至重度疾病的成年人以2：1的比例随机分配至selnoflast或安慰剂治疗7天。选择450mgQD(每日一次)的剂量以在血浆和结肠组织中实现90%IL-1β抑制。连续的血，分析乙状结肠活检和粪便样本的各种PD标志物。还评估了安全性和PK。
结果：Selnoflast耐受性良好。口服后血浆浓度迅速增加，给药后1小时达到Tmax。在整个给药间隔内，平均血浆浓度保持在IL-1βIC90水平以上（第1天和第5天的平均Ctrough：2.55μg/mL和2.66μg/mL，分别)。在稳定状态下,乙状结肠中的给药后氟烷酮浓度（5-20μg/g）高于IC90。在用脂多糖(LPS)离体刺激后,全血中的IL-1β的产生减少(在selnoflast臂中)。未观察到血浆IL-18水平的变化。在乙状结肠组织中IL-1相关基因签名的表达没有有意义的差异，粪便生物标志物的表达无差异。
结论：Selnoflast是安全且耐受性良好的。Selnofflast450mgQD实现了血浆和组织暴露，预测在给药间隔内维持IL-1βIC90。然而,PD生物标志物结果显示治疗组之间没有显著差异，提示在UC中没有重大的治疗效果。这项研究的局限性在于其样本量小和对组织中IL-1β的影响的间接评估。
背景：ISRCTN16847938。
方法：将19例先前诊断为UC且目前患有活动性中度至重度疾病的成年人以2：1的比例随机分配至selnoflast或安慰剂治疗7天。选择450mgQD(每日一次)的剂量以在血浆和结肠组织中实现90%IL-1β抑制。连续的血，分析乙状结肠活检和粪便样本的各种PD标志物。还评估了安全性和PK。
结果：Selnoflast耐受性良好。口服后血浆浓度迅速增加，给药后1小时达到Tmax。在整个给药间隔内，平均血浆浓度保持在IL-1βIC90水平以上（第1天和第5天的平均Ctrough：2.55μg/mL和2.66μg/mL，分别)。在稳定状态下,乙状结肠中的给药后氟烷酮浓度（5-20μg/g）高于IC90。在用脂多糖(LPS)离体刺激后,全血中的IL-1β的产生减少(在selnoflast臂中)。未观察到血浆IL-18水平的变化。在乙状结肠组织中IL-1相关基因签名的表达没有有意义的差异，粪便生物标志物的表达无差异。
结论：Selnoflast是安全且耐受性良好的。Selnofflast450mgQD实现了血浆和组织暴露，预测在给药间隔内维持IL-1βIC90。然而,PD生物标志物结果显示治疗组之间没有显著差异，提示在UC中没有重大的治疗效果。这项研究的局限性在于其样本量小和对组织中IL-1β的影响的间接评估。
背景：ISRCTN16847938。
