Abstract：
RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD).
This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects.
In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures.
To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.
This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects.
In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures.
To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease.
摘要：
背景:RPT193是口服施用的人C-C基序趋化因子受体4(CCR4)的小分子拮抗剂,其抑制2型T辅助细胞(Th2)的迁移和下游活化。我们调查了健康受试者中RPT193的单次和多次递增剂量，中重度特应性皮炎（AD）患者的多剂量RPT193。
方法：这是首次在人体内随机分组，安慰剂对照1a/1b期单一疗法研究（NCT04271514）以评估安全性，耐受性,药代动力学，药效学,合格的健康受试者和中度至重度AD受试者的CCR4表面受体占有率。RPT193单一疗法的临床功效和皮肤生物标志物作用被评估为AD受试者中的探索性终点。
结果：在健康（n=72）和AD受试者（n=31）中，每天一次的RPT193治疗通常耐受性良好，未报告严重不良事件,所有因治疗引起的不良事件均报告为轻度/中度.在AD科目中，到治疗期结束（第29天），与安慰剂相比，RPT193单药治疗在临床疗效终点方面有更大的改善，具有统计学上的显着改善，与第29天和安慰剂相比，在治疗结束后2周(第43天)观察到几个终点(p<0.05)。此外，在第29天时,在RPT193治疗的受试者与安慰剂治疗的受试者的皮肤活检中观察到转录谱的显著变化,这也与临床疗效指标的改善显著相关.
结论：据我们所知，这是首次使用口服CCR4拮抗剂进行的临床研究,该研究在炎症性皮肤病中显示出临床改善和皮肤转录组学谱的调节.
方法：这是首次在人体内随机分组，安慰剂对照1a/1b期单一疗法研究（NCT04271514）以评估安全性，耐受性,药代动力学，药效学,合格的健康受试者和中度至重度AD受试者的CCR4表面受体占有率。RPT193单一疗法的临床功效和皮肤生物标志物作用被评估为AD受试者中的探索性终点。
结果：在健康（n=72）和AD受试者（n=31）中，每天一次的RPT193治疗通常耐受性良好，未报告严重不良事件,所有因治疗引起的不良事件均报告为轻度/中度.在AD科目中，到治疗期结束（第29天），与安慰剂相比，RPT193单药治疗在临床疗效终点方面有更大的改善，具有统计学上的显着改善，与第29天和安慰剂相比，在治疗结束后2周(第43天)观察到几个终点(p<0.05)。此外，在第29天时,在RPT193治疗的受试者与安慰剂治疗的受试者的皮肤活检中观察到转录谱的显著变化,这也与临床疗效指标的改善显著相关.
结论：据我们所知，这是首次使用口服CCR4拮抗剂进行的临床研究,该研究在炎症性皮肤病中显示出临床改善和皮肤转录组学谱的调节.
