Division of Gastroenterology and Hepatology, Michigan Medicine, Ann Arbor, Michigan, USA.
Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri, USA.
Am J Gastroenterol. 2021 Feb 1;116(2):354-361. doi: 10.14309/ajg.0000000000000967.
Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects.
This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate.
Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo.
Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.
利那洛肽 290μg 的即释（IR）制剂可改善伴有便秘的肠易激综合征（IBS-C）患者的腹痛和便秘（APC）症状。在此基础上研发了迟释（DR）制剂，假设靶向回肠（迟释制剂 1[DR1]）或回盲肠交界处和盲肠（MD-7246，前身为 DR2）可以调节利那洛肽的分泌作用，同时保留缓解疼痛的作用。
这项 2b 期研究将 IBS-C 患者随机分为安慰剂组或 7 种利那洛肽日剂量（DR1 30、100 或 300μg；MD-7246 30、100 或 300μg；或 IR 290μg）组中的 1 种，治疗 12 周。主要疗效终点是从基线到治疗结束时腹痛的变化以及 6/12 周时 APC+1 应答率。
共有 532 例患者被随机分组；平均年龄为 45.1 岁，大多数为女性（83.3%）和白人（64.7%）。所有利那洛肽 DR1 和 MD-7246 组在整个治疗过程中，与基线相比，腹痛均有更大的改善。与安慰剂相比，利那洛肽 DR1 和 IR 使完全自发排便频率的改善程度更大，且 APC+1 应答率更高；MD-7246 的结果与安慰剂相似。DR1 和 IR 最常见的不良反应是腹泻；DR1 和 IR 与安慰剂的发生率相似。
改变药物在肠道内的输送部位可能会使利那洛肽的止痛作用与分泌作用脱钩。MD-7246 各剂量组均观察到持续性的中度腹痛改善，对肠道症状参数的影响有限，这一结果提示无论 IBS 亚型如何，MD-7246 作为一种治疗腹痛的新型药物值得进一步研究。
