Vuppalanchi Raj, González-Huezo Ma Saraí, Payan-Olivas Ramon, Muñoz-Espinosa Linda E, Shaikh Farheen, Pio Cruz-Lopez Jose L, Parmar Deven
Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Consultorio de la Dra. Sarai Gonzalez, Metepec, Estado de México, Mexico.
Clin Transl Gastroenterol. 2021 Mar 26;12(4):e00327. doi: 10.14309/ctg.0000000000000327.
Patients with primary biliary cholangitis (PBC) without biochemical response to ursodeoxycholic acid (UDCA) are at increased risk of liver-related mortality. Saroglitazar is a novel peroxisome proliferator-activated receptor (PPAR) agonist with dual PPAR agonistic properties (α/γ). There is a strong mechanistic rationale for studying saroglitazar in PBC because PPARα is a molecular target of fibrates that showed improvements in liver tests in patients with PBC.
In this 16-week, open-label, phase 3 study, 37 patients were screened across 3 clinical centers to enroll 7 patients. All patients received daily dose of saroglitazar 4 mg for 16 weeks in addition to their ongoing treatment with UDCA. The primary efficacy endpoint was the reduction in alkaline phosphatase (ALP) level at week 16 as compared to baseline.
Mean age of the study population was 51.1 ± 10.0 years, all patients were female of Mexican descent, and mean body mass index was 25.5± = 4.8 kg/m2. Six (85.7%) patients reported taking ursodiol at baseline and continued throughout the study with a mean daily dosage of 417 mg. Among these, the daily dosage of UDCA 500 mg in 4 and 250 mg in 2 subjects, respectively. The mean baseline ALP level was 230 ± 103 U/L. The primary efficacy endpoint, mean change (reduction) from baseline in ALP concentration at week 16 based on the modified intent-to-treat population was -94 ± 53 U/L (P = 0.003), corresponding to a reduction of 48 ± 23%. Treatment with saroglitazar 4 mg resulted in a rapid and sustained decrease of ALP levels at week 4 (-84 ± 47 U/L, P = 0.003). Six patients who completed the study achieved mean ALP reduction of at least 40% at week 4 and all subsequent visits.
Although the study was terminated because of lack of enrollment, saroglitazar daily for 16 weeks resulted in rapid and sustained improvements in ALP with an acceptable safety profile in patients with PBC.
对熊去氧胆酸（UDCA）无生化反应的原发性胆汁性胆管炎（PBC）患者肝脏相关死亡率增加。司美格鲁扎是一种新型过氧化物酶体增殖物激活受体（PPAR）激动剂，具有双重PPAR激动特性（α/γ）。在PBC中研究司美格鲁扎有很强的机制依据，因为PPARα是贝特类药物的分子靶点，贝特类药物已显示可改善PBC患者的肝功能检查。
在这项为期16周的开放标签3期研究中，在3个临床中心筛选了37例患者，最终纳入7例。所有患者在继续接受UDCA治疗的基础上，每日服用4mg司美格鲁扎，持续16周。主要疗效终点是第16周时碱性磷酸酶（ALP）水平相对于基线的降低。
研究人群的平均年龄为51.1±10.0岁，所有患者均为墨西哥裔女性，平均体重指数为25.5±4.8kg/m²。6例（85.7%）患者在基线时报告服用熊去氧胆酸，并在整个研究过程中持续服用，平均每日剂量为417mg。其中，4例患者的UDCA每日剂量为500mg，2例患者为250mg。平均基线ALP水平为230±103U/L。基于改良意向性治疗人群，主要疗效终点为第16周时ALP浓度相对于基线的平均变化（降低）为-94±53U/L（P=0.003），相当于降低48±23%。服用4mg司美格鲁扎治疗导致第4周时ALP水平迅速且持续下降（-84±47U/L，P=0.003）。6例完成研究患者在第4周及随后各次访视时ALP平均降低至少40%。
尽管该研究因入组不足而终止，但对于PBC患者，每日服用司美格鲁扎16周可使ALP迅速且持续改善，安全性可接受。
