■Icanbelimod(以前的CBP-307)是下一代S1PR调制器,瞄准S1PR1。在这项首次人类研究中,在澳大利亚的健康男性中对icanbelimod进行了调查。
■参与者被随机分为3:1,双盲,在四个单剂量队列(0.1毫克,0.25毫克,0.5毫克[每个队列n=8],2.5mg[n=4])或在两组中每天一次治疗28天(0.15mg,0.25mg[每组n=8])。0.25mg队列的参与者在第1天接受0.1mg。禁食后口服治疗;一周冲洗后,在0.5mg队列中,早餐后服用了伊坎贝莫德。
■伊坎贝里莫德暴露在单次和多次给药(Tmax4-7小时)中迅速增加并呈剂量依赖性。单个后淋巴细胞计数迅速下降(-11%,0.1mg;-40%,0.25毫克;-71%,0.5mg;-77%,2.5毫克)和多剂量(-49%,0.15mg;-75%,0.25毫克),并迅速恢复,给药后7天。单剂量0.5毫克后,尽管高脂肪早餐与禁食并没有影响最大的下降,在大多数时间点至72小时内,早餐后淋巴细胞计数趋于降低。28名参与者(63.6%)主要经历了轻度治疗引起的不良事件(TEAE)。在单剂量伊坎贝莫德之后,最常见的TEAE是头痛(28.6%,n=6)和头晕(19.0%,n=4)。三名参与者经历了短暂的心动过缓,一个严肃的,单剂量2.5毫克康贝莫德。多次服用伊坎贝莫德后,最常见的TEAE是头痛(50.0%,n=6)和淋巴细胞减少(41.7%,n=5),两名参与者因非严重TEAE退出。向上滴定减弱心率降低。
■Icanbelimod在0.5mg时耐受性良好,可有效降低淋巴细胞计数。
■ClinicalTrials.gov,标识符NCT02280434。Procedures.
UNASSIGNED: Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia.
UNASSIGNED: Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort.
UNASSIGNED: Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions.
UNASSIGNED: Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts.
UNASSIGNED: ClinicalTrials.gov, identifier NCT02280434.b.