ATI-1777 a topical JAK1/3 inhibitor may benefit atopic dermatitis without systemic drug exposure, results from preclinical development and Phase 2a randomized-control study ATI-1777-AD-201. ATI-1777 a topical JAK1/3 inhibitor may benefit atopic dermatitis without systemic drug exposure, results from preclinical development and Phase 2a randomized-control study ATI-1777-AD-201

Atopic dermatitis (AD), a chronic, pruritic skin disease, affects 10%-30% of children and up to 14% of adults in developed countries. Since current AD treatments may lead to systemic drug exposure and AD pathophysiology is partially mediated by JAK1/3 signaling, ATI-1777, a potent and selective JAK1/3 inhibitor, was designed with multiple sites of metabolism to deliver local efficacy in the skin and limit systemic exposure. In preclinical studies, ATI-1777 selectively inhibited JAK1/3 with limited systemic exposure and without any adverse effects. ATI-1777-AD-201 (NCT04598269), a Phase 2a, first-in-human, randomized, double-blind,vehicle-controlled, parallel-group study, evaluated the efficacy, safety, tolerability, and pharmacokinetics of ATI-1777 topical solution in 48participants with AD over 4 weeks. The primary outcome was reduction of a modified EASI score from baseline; reduction was significantly greater in the ATI-1777 group at Day28 compared to vehicle (percent reduction from baseline 74.45% [SE6.455] and 41.43% [SE6.189], respectively [p<0.001]). Average plasma concentrations of ATI-1777 were <5% of the IC50 of ATI-1777 for inhibiting JAK1/3. No deaths or serious adverse events were reported. This demonstrates that topical ATI-1777 does not lead to pharmacologically relevant systemic drug exposure and may reduce clinical signs of AD. Overall design: We developed a pharmacodynamic porcine topical model to assess the effects of ATI-1777 on JAK1/3 signaling and selected a suitable formulation for the compound. To select the most robustly induced genes by intradermal injection (ID) of IL-15 in the Yorkshire swine skin, we performed the RNA seq for 8 skin biopsy samples. For each of two pigs, two sites were injected with ID IL15 and two sites without injection, resulting in a total of 4 samples for IL-5 and 4 samples for control. Biopsy samples of these sites were extracted for RNA, followed by RNA Seq and qPCR to determine the gene expression, and select optimal genes for the readouts.

特应性皮炎（Atopic dermatitis, AD）是一种慢性瘙痒性皮肤病，在发达国家中，儿童患者患病率达10%~30%，成人患者患病率最高可达14%。鉴于当前AD治疗手段可能引发全身性药物暴露，且AD的病理生理过程部分由JAK1/3信号通路介导，研究人员开发了强效且选择性JAK1/3抑制剂ATI-1777：该药物通过多代谢位点设计，旨在实现皮肤局部药效并限制全身性暴露。临床前研究显示，ATI-1777可选择性抑制JAK1/3通路，且全身性暴露水平极低，未观察到任何不良反应。ATI-1777-AD-201（NCT04598269）是一项2a期首次人体随机双盲安慰剂对照平行分组试验，旨在评估ATI-1777外用溶液在48名AD患者中连续4周给药的疗效、安全性、耐受性及药代动力学特征。该试验的主要终点为改良特应性皮炎面积和严重程度指数（modified EASI）评分较基线的降幅；结果显示，给药第28天时，ATI-1777组的评分降幅显著高于安慰剂组：两组较基线的降幅分别为74.45%（标准误6.455）与41.43%（标准误6.189），差异具有统计学意义（p<0.001）。ATI-1777的平均血浆浓度不足其抑制JAK1/3的半数抑制浓度（IC50）的5%。本试验未报告死亡病例或严重不良事件。上述结果表明，外用ATI-1777不会引发具有药理学意义的全身性药物暴露，且可缓解AD的临床体征。试验整体设计：本研究首先构建了猪外用药效学模型，用于评估ATI-1777对JAK1/3信号通路的影响，并筛选出该化合物的适宜制剂。为筛选出约克夏猪皮肤内皮内注射白细胞介素15（IL-15）后诱导表达最稳定的基因，本研究对8份皮肤活检样本进行了RNA测序（RNA-seq）。每头实验猪的2个皮肤位点接受皮内注射IL-15，另外2个位点不予注射；最终共获得4份IL-5相关样本与4份对照样本。提取上述位点的活检样本RNA，随后通过RNA测序与实时定量聚合酶链式反应（qPCR）检测基因表达水平，筛选出适用于检测终点的最优基因。