Burakoff Robert, Barish Charles F, Riff Dennis, Pruitt Ronald, Chey William Y, Farraye Francis A, Shafran Ira, Katz Seymour, Krone Charles L, Vander Vliet Martha, Stevens Christopher, Sherman Matthew L, Jacobson Eric, Bleday Ronald
Brigham & Women's Hospital, Boston, Massachusetts, USA.
Inflamm Bowel Dis. 2006 Jul;12(7):558-65. doi: 10.1097/01.ibd.0000225337.14356.31.
Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease.
We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity.
STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%).
Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.
与克罗恩病相关的肠道炎症以1型辅助性T细胞反应和白细胞介素（IL）-12水平升高为特征。我们报告了一种新型口服IL-12/IL-23抑制剂（STA 5326）治疗活动性克罗恩病的临床经验。
我们对73例活动性克罗恩病患者（克罗恩病活动指数[CDAI]为220 - 450，含该范围）进行了口服小分子免疫调节剂STA 5326的开放标签、剂量递增试验。五组患者分别接受每日两次14 mg（bid）、每日35 mg（qd）、每日两次28 mg、每日两次35 mg或每日70 mg的治疗，持续4周。研究终点包括安全性以及通过CDAI和克罗恩病内镜严重程度指数衡量的临床活动改善情况。
STA 5326耐受性良好。各剂量组报告的不良事件相似。观察到的最常见（>15%）与药物相关的不良事件为头晕、恶心、头痛和疲劳。对于反应和缓解的临床终点，在第28/29天观察到，每日剂量28 mg及以上时临床活动情况如下：CDAI降低70分或更多（患者比例范围为42% - 82%）；CDAI降低100分或更多（患者比例范围为38% - 64%），且CDAI < 150（患者比例范围为15% - 36%）。
对于中度至重度活动性克罗恩病患者，每日口服STA 5326剂量高达70 mg，持续4周，耐受性良好。每日剂量28 mg及以上时观察到临床活动改善。
