F. Hoffmann-La Roche AG, Basel, Switzerland.
Roche Products Limited, Welwyn Garden City, UK.
Clin Transl Med. 2023 Nov;13(11):e1471. doi: 10.1002/ctm2.1471.
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 T 1 h post-dose. Mean plasma concentrations stayed above the IL-1β IC level throughout the dosing interval (mean C 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 IC . 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 IC 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.
NLRP3 炎性小体驱动包括白细胞介素（IL）-1β 和 IL-18 在内的促炎细胞因子的释放，是溃疡性结肠炎（UC）的潜在治疗靶点。Selnoflast（RO7486967）是一种口服活性、强效、选择性和可逆的小分子 NLRP3 抑制剂。我们进行了一项随机、安慰剂对照的 1b 期研究，以评估 selnoflast 的安全性、耐受性、药代动力学（PK）和药效学（PD）。
19 名既往诊断为 UC 且目前患有活动性中重度疾病的成年人被随机分为 selnoflast 或安慰剂组，进行 7 天治疗。选择 450mgQD（每日一次）的剂量以实现血浆和结肠组织中 90%的 IL-1β 抑制。连续采集血液、乙状结肠活检和粪便样本以分析各种 PD 标志物。还评估了安全性和 PK。
Selnoflast 耐受良好。口服给药后血浆浓度迅速升高，达给药后 1 小时（T 1h）。在整个给药间隔内，平均血浆浓度均保持在 IL-1β IC 水平以上（第 1 天和第 5 天的平均 C 值分别为 2.55μg/mL 和 2.66μg/mL）。在稳态时，乙状结肠（5-20μg/g）中的 post-dose selnoflast 浓度高于 IC 。用脂多糖（LPS）进行离体刺激后，全血中 IL-1β 的产生减少（在 selnoflast 组）。血浆 IL-18 水平无变化。乙状结肠组织中与 IL-1 相关基因特征的表达无明显差异，粪便生物标志物的表达也无差异。
Selnoflast 安全且耐受良好。Selnoflast 450mgQD 可达到预测的维持 IL-1β IC 的血浆和组织暴露，以维持整个给药间隔。然而，PD 生物标志物结果表明，治疗组之间没有明显差异，这表明 UC 中不应期望有主要的治疗作用。本研究的局限性在于样本量小和对组织中 IL-1β 效应的间接评估。
ISRCTN83631152。
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