From the Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University Health Network, Toronto General Hospital, Toronto (G.M.H.); the Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Sacramento (C.L.B.), and CymaBay Therapeutics, Newark (K.Y., Y.-J.C., D.B.C., C.A.M.) - both in California; the University of Texas Southwestern Medical School, Dallas (M.J.M.), and the Departments of Medicine and Surgery, Baylor College of Medicine, Houston (J.M.V.) - both in Texas; the Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (A.E.K.); Liver Institute Northwest, Seattle (K.V.K.); the Division of Digestive Health and Liver Diseases, University of Miami, Miami (C.L.); the Liver Autoimmunity Unit, Hospital Italiano de Buenos Aires, Buenos Aires (A.V.); Centro de Investigación y Gastroenterología, Mexico City (A.L.L.G.C.); the Department of Basic Medical Sciences, Faculty of Public Health in Bytom, Medical University of Silesia, Bytom, Poland (E.J.); the Gastroenterology Institute, Tel Aviv Sourasky Medical Center, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (E.Z.); the Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University, College of Medicine, Seongnam, South Korea (S.-H.J.); the Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Turkey (Y.Y.); Barts Liver Centre, Blizard Institute, Queen Mary University of London, London (Y.K.); the Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis, French Network for Rare Liver Disease in Children and Adults FILFOIE, European Reference Network RARE-LIVER, Saint-Antoine Hospital and Research Center, Assistance Publique-Hôpitaux de Paris, Sorbonne University, Paris (C.C.); Liver Centre Hamburg at Ifi-Institute, Hamburg, Germany (P.B.); the Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, and the European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori - both in Monza, Italy (P.I.); the Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBEREHD, European Reference Network on Hepatological Diseases (ERN-LIVER), University of Barcelona, Barcelona (M.C.L.H.); and Saberg Clinical Research, the Hague, the Netherlands (S.B.). Dr. Hirschfield is the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at Toronto General Hospital.
N Engl J Med. 2024 Feb 29;390(9):783-794. doi: 10.1056/NEJMoa2312100. Epub 2024 Feb 21.
BACKGROUND: Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits. METHODS: In this phase 3, 12-month, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients who had had an inadequate response to or who had a history of unacceptable side effects with ursodeoxycholic acid to receive oral seladelpar at a dose of 10 mg daily or placebo. The primary end point was a biochemical response, which was defined as an alkaline phosphatase level less than 1.67 times the upper limit of the normal range, with a decrease of 15% or more from baseline, and a normal total bilirubin level at month 12. Key secondary end points were normalization of the alkaline phosphatase level at month 12 and a change in the score on the pruritus numerical rating scale (range, 0 [no itch] to 10 [worst itch imaginable]) from baseline to month 6 among patients with a baseline score of at least 4 (indicating moderate-to-severe pruritus). RESULTS: Of the 193 patients who underwent randomization and treatment, 93.8% received ursodeoxycholic acid as standard-of-care background therapy. A greater percentage of the patients in the seladelpar group than in the placebo group had a biochemical response (61.7% vs. 20.0%; difference, 41.7 percentage points; 95% confidence interval [CI], 27.7 to 53.4, P<0.001). Normalization of the alkaline phosphatase level also occurred in a greater percentage of patients who received seladelpar than of those who received placebo (25.0% vs. 0%; difference, 25.0 percentage points; 95% CI, 18.3 to 33.2, P<0.001). Seladelpar resulted in a greater reduction in the score on the pruritus numerical rating scale than placebo (least-squares mean change from baseline, -3.2 vs. -1.7; least-squares mean difference, -1.5; 95% CI, -2.5 to -0.5, P = 0.005). Adverse events were reported in 86.7% of the patients in the seladelpar group and in 84.6% in the placebo group, and serious adverse events in 7.0% and 6.2%, respectively. CONCLUSIONS: In this trial involving patients with primary biliary cholangitis, the percentage of patients who had a biochemical response and alkaline phosphatase normalization was significantly greater with seladelpar than with placebo. Seladelpar also significantly reduced pruritus among patients who had moderate-to-severe pruritus at baseline. The incidence and severity of adverse events were similar in the two groups. (Funded by CymaBay Therapeutics; RESPONSE ClinicalTrials.gov number, NCT04620733; EudraCT number, 2020-004348-27.).
背景：原发性胆汁性胆管炎患者的有效治疗方法有限。过氧化物酶体增殖物激活受体 δ 激动剂 Seladelpar 具有潜在的益处。
方法：在这项为期 12 个月、双盲、安慰剂对照的 3 期临床试验中，我们将对熊去氧胆酸应答不足或有不可接受的副作用史的患者进行随机分组（2:1 比例），分别接受每日 10 毫克口服 Seladelpar 或安慰剂治疗。主要终点是生化应答，定义为碱性磷酸酶水平低于正常上限的 1.67 倍，与基线相比下降 15%或更多，并且在第 12 个月时总胆红素水平正常。关键次要终点是第 12 个月时碱性磷酸酶水平正常化，以及基线评分至少为 4（表示中度至重度瘙痒）的患者从基线到第 6 个月时瘙痒数字评分量表（范围 0[无瘙痒]至 10[最严重的瘙痒]）的变化。
结果：在 193 名接受随机分组和治疗的患者中，93.8%接受了熊去氧胆酸作为标准治疗的背景治疗。Seladelpar 组中有生化应答的患者比例高于安慰剂组（61.7% vs. 20.0%；差异 41.7 个百分点；95%置信区间 [CI]，27.7 至 53.4，P<0.001）。Seladelpar 组中碱性磷酸酶水平正常化的患者比例也高于安慰剂组（25.0% vs. 0%；差异 25.0 个百分点；95%CI，18.3 至 33.2，P<0.001）。与安慰剂相比，Seladelpar 导致瘙痒数字评分量表评分的降幅更大（自基线的最小二乘均数变化，-3.2 对-1.7；最小二乘均数差值，-1.5；95%CI，-2.5 至 -0.5，P=0.005）。Seladelpar 组有 86.7%的患者和安慰剂组有 84.6%的患者报告了不良事件，分别有 7.0%和 6.2%的患者发生了严重不良事件。
结论：在这项涉及原发性胆汁性胆管炎患者的试验中，Seladelpar 组有生化应答和碱性磷酸酶正常化的患者比例显著高于安慰剂组。Seladelpar 还显著降低了基线时有中度至重度瘙痒的患者的瘙痒程度。两组的不良事件发生率和严重程度相似。（由 CymaBay Therapeutics 资助；临床试验.gov 编号，NCT04620733；EudraCT 编号，2020-004348-27。）
N Engl J Med. 2024-2-29
N Engl J Med. 2024-2-29
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