Sinew Pharma Inc. Rm C516, Building C, No.99, Lane 130, Sec. 1, Academia Rd., Nangang Dist, Taipei City, 11571, Taiwan.
Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd., Neihu District, Taipei, 11420, Taiwan.
J Transl Med. 2024 Oct 14;22(1):936. doi: 10.1186/s12967-024-05686-7.
Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630's potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH.
SNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers.
SNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis.
SNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH.
ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566.
代谢相关脂肪性肝炎（MASH）是一种日益严重的全球性健康问题，目前尚无有效的药物治疗方法。SNP-630 是一种新开发的具有多种作用机制的合成分子，其两种活性代谢物的混合物（SNP-630-MS）可抑制 CYP2E1 的表达，从而防止活性氧的产生，减少肝内甘油三酯的堆积，并降低趋化因子的水平。本研究旨在探讨 SNP-630 缓解 MASH 肝损伤的潜力及其在 MASH 小鼠模型和患者中的疗效，以确定一种针对 MASH 多个相关通路的候选药物。
分别给 MASH 小鼠模型使用 SNP-630 和 SNP-630-MS。还评估了 SNP-630-MS 在 35 例 MASH 患者中的耐受性、安全性和疗效。研究的主要终点是从基线到第 12 周时血清丙氨酸氨基转移酶（ALT）水平的变化，次要终点包括评估肝炎症、脂肪变性和纤维化参数和标志物。
与 MASH 对照组相比，SNP-630 治疗可改善炎症、肝脂肪变性和纤维化。SNP-630 和 SNP-630-MS 治疗均可显著降低 ALT 水平、肝内甘油三酯含量和炎症细胞因子单核细胞趋化蛋白 1（MCP-1）和纤维化胶原（即 Col1a1、Col3a1 和 Timp1）的表达。在临床试验中，与基线相比，SNP-630-MS 治疗的患者在第 12 周时 ALT 水平显著改善，且无严重不良事件报告。这种 ALT 水平的改善超过了大多数其他 MASH 候选药物的改善。SNP-630-MS 显示出潜在的抗纤维化作用，这表现在纤维化相关生物标志物如 CCL4、CCL5 和半胱氨酸蛋白酶 3 的水平显著降低。使用 FibroScan 测量的亚组分析进一步表明 SNP-630-MS 可改善 MASH 患者的肝纤维化。
SNP-630 和 SNP-630-MS 在小鼠中显示出良好的结果。SNP-630-MS 在 MASH 小鼠和患者中具有良好的耐受性。疗效分析表明，SNP-630-MS 改善了 MASH 患者的肝脂肪变性和损伤，提示 SNP-630 和 SNP-630-MS 是 MASH 的有前途的治疗选择。仍需要更大规模的临床试验来评估 SNP-630 在 MASH 中的疗效和安全性。
ClinicalTrials.gov NCT03868566。注册日期：2019 年 3 月 6 日-回顾性注册，https://clinicaltrials.gov/study/NCT03868566。
