在非肝硬化性NASH中治疗24周后，panPPAR激动剂Lanifibranor既诱导

StephenW

The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial.

Multimechanism Drug Improves NASH and Fibrosis in 24-Week Trial

AASLD The Liver Meeting Digital Experience, November 13-16, 2020

Mark Mascolini

Lanifibranor, an experimental agent directed against several mechanisms behind nonalcoholic steatohepatitis (NASH), both reduced NASH activity and improved fibrosis in a 247-person, 24-week, phase 2b, placebo-controlled trial [1]. The novel panPPAR agonist also improved markers of liver damage, inflammation, and glucose control.

Metabolic, inflammatory, and fibrosis-related factors combine to worsen NASH and complicate attempts to reverse this sometimes fatal liver disease. Peroxisome proliferator-activated receptors (PPAR) play roles in governing all three mechanisms. The panPPAR agonist lanifibranor affects all three types of PPAR [2] and thus may simultaneously address several factors involved in NASH progression.

To assess the safety and efficacy of lanifibranor in people with NASH, researchers conducted a phase 2b, double-blind, placebo-controlled trial [3]. Participants had to have biopsy-proven NASH with high activity denoted by a steatosis-activity-fibrosis (SAF) score of 1-3 for steatosis, 3-4 for activity, and below 4 for fibrosis. They could not have cirrhosis.

Researchers randomized participants in a 1-1-1 ratio to 800 or 1200 mg of lanifibranor once daily (by mouth with food) or to placebo. The primary endpoint was a decrease of 2 or more points in the SAF activity score by week 24. Researchers assessed outcomes in two groups: the full analysis set of 247 people who received at least one dose of lanifibranor or placebo, and a per-protocol set of 194 people with biopsies before and after the 24 weeks of treatment and without deviations from the trial plan that could affect results.

The 83 people randomized to 800 mg of lanifibranor, the 83 randomized to 1200 mg, and the 81 randomized to placebo did not differ substantially in age (average 53.6 overall), proportions of whites (94% overall), body mass index (average 32.9 kg/m2 overall), or proportions with diabetes (42% overall). Women made up 65% of the 800-mg lanifibranor group, 59% of the 1200-mg group, and 51% of the placebo group. SAF activity score was similar in the three study arms, averaging 3.3 overall.

In the 247-person full-analysis set, 49% getting 1200 mg of lanifibranor had at least a 2-point drop in SAF activity score and no worsening of fibrosis, compared with 27% in the placebo group, a significant difference (P = 0.004). In the 800-mg lanifibranor group, 41% achieved this goal, through the difference from the placebo group fell just short of statistical significance (P = 0.061). In the 194-person per-protocol group, response rates were 55% in the 1200-mg lanifibranor group (P = 0.015 vs placebo), 51% in the 800-mg group (not significant at P = 0.058 vs placebo), and 34% in the placebo group. Responses were consistent in people with versus without diabetes and in an analysis limited to people with F2-F3 fibrosis.

In the 247-person full-analysis set,  response rates for secondary endpoints always proved significantly greater with 1200 mg of lanifibranor than with placebo: resolution of NASH with no fibrosis worsening (45% vs 19%, P < 0.001), improvement in fibrosis by at least 1 stage and no NASH worsening (42% vs 24%, P = 0.011), and resolution of NASH and improvement in fibrosis (31% vs 7%, P < 0.001). Response rates in the 800-mg group were significantly greater versus placebo for the first and third of those endpoints. Results were similar in people with or without diabetes.

Absolute change from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) improved significantly with either dose of lanifibranor versus placebo by treatment week 4, and those differences remained significant through 24 weeks. These results remained consistent in people with or without diabetes.

Compared with the placebo group, people receiving lanifibranor had significant improvements through 24 weeks in fibrosis biomarkers (ProC3, TIMP1/TIMP2 ratio), an apoptosis marker (CK18M30), and inflammation markers (ferritin, hsCRP). “Good” high-density lipoprotein cholesterol rose significantly in both lanifibranor groups and stayed largely flat in the placebo arm over 24 weeks, while triglycerides fell significantly with lanifibranor while remaining unchanged with placebo. Low-density lipoprotein cholesterol did not change significantly in any study arm. Glucose control indicated by fasting glucose, fasting insulin, and HbA1c improved significantly in both lanifibranor groups versus placebo through 24 weeks.

Rates of drug-related treatment-emergent adverse events were 27.7% with 1200 mg of lanifibranor, 30.1% with 800 mg, and 23.5% with placebo. Respective rates of drug-related adverse events leading to drug withdrawal were 2.4%, 1.2%, and 2.5%. Two people in the placebo group and none receiving lanifibranor had a drug-related serious adverse event.

The researchers concluded that lanifibranor is the first drug to improve both NASH and fibrosis—and in only 24 weeks. They also noted that this is the first trial to use the SAF activity score to define study inclusion criteria, and that resulted in a study population with more active NASH and significant fibrosis. Phase 3 trials of lanifibranor are planned for 2021.

References
1. Francque S, Bedossa P, Ratziu V, et al. The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 12.
2. Boubia B, Poupardin O, Barth M, et al. Design, synthesis, and evaluation of a novel series of indole sulfonamide peroxisome proliferator activated receptor (PPAR) α/γ/δ triple activators: Discovery of lanifibranor, a new antifibrotic clinical candidate. J Med Chem. 2018;61:2246-2265.
3. ClinicalTrials.gov. Phase 2b study in NASH to assess IVA337 (NATIVE). ClinicalTrials.gov identifier NCT03008070.

StephenW

在非肝硬化性NASH中治疗24周后，panPPAR激动剂Lanifibranor既诱导了NASH的分解，又诱导了纤维化的消退：天然2b期试验的结果。

多机制药物可在24周试验中改善NASH和纤维化

AASLD肝脏会议数字体验，2020年11月13日至16日

马克·马斯科利尼

Lanifibranor是一种针对非酒精性脂肪性肝炎（NASH）背后多种机制的实验药物，在一项247人，24周的2b期安慰剂对照试验中，既降低了NASH活性，又改善了纤维化[1]。新型panPPAR激动剂还改善了肝损害，炎症和葡萄糖控制的标志物。

代谢，炎症和纤维化相关因素共同导致NASH恶化，并使这种有时致命的肝病逆转的尝试变得复杂。过氧化物酶体增殖物激活受体（PPAR）在控制所有三种机制中发挥作用。 panPPAR激动剂Lanifibranor影响所有三种类型的PPAR [2]，因此可以同时解决NASH进展中涉及的几个因素。

为了评估lanifibranor在NASH患者中的安全性和有效性，研究人员进行了2b期，双盲，安慰剂对照试验[3]。参与者必须经过活组织检查证明具有高活性的NASH，以脂肪变性-活性纤维化（SAF）评分表示脂肪变性为1-3，活性为3-4，纤维化低于4。他们不能有肝硬化。

研究人员每天以1-1-1的比例将参与者随机分配给800或1200 mg lanifibranor（通过与食物一起口服）或安慰剂。主要终点是到第24周时SAF活动评分降低2个或更多点。研究人员评估了两组的结果：接受至少一种剂量的Lanifibranor或安慰剂的247人的完整分析，以及每项方案在治疗24周之前和之后，由194名活检人员组成，并且没有偏离可能影响结果的试验计划。

83例患者随机分配了800 mg lanifibranor，83例患者随机分配了1200 mg，81例患者随机分配了安慰剂，年龄（平均53.6），白人比例（总体94％），体重指数（平均32.9）没有显着差异千克/平方米）或糖尿病患者比例（占42％）。女性在800毫克兰尼佛罗组中占65％，在1200毫克组中占59％，在安慰剂组中占51％。三个研究部门的SAF活动得分相似，总体平均为3.3。

在247人的全套分析中，49％的1200 mg lanifibranor的SAF活性评分至少降低了2分，且纤维化没有恶化，而安慰剂组为27％，差异有统计学意义（P = 0.004）。在800毫克的lanifibranor组中，有41％的人通过与安慰剂组的差异达不到统计学意义（P = 0.061）达到了这一目标。在每个方案的194人组中，lan​​mgbranor 1200 mg组的缓解率是55％（与安慰剂相比P = 0.015），在800 mg组中有51％（在P = 0.058 vs安慰剂时不显着），以及安慰剂组占34％。在患有或未患有糖尿病的人群中反应是一致的，并且分析仅限于患有F2-F3纤维化的人群。

在247人的全面分析中，使用lanifibranor 1200 mg的次要终点反应率始终被证明比安慰剂要高得多：NASH的分辨率无纤维化恶化（45％比19％，P <0.001），纤维化改善至少分1步进行，NASH没有恶化（42％vs 24％，P = 0.011），NASH的分辨率和纤维化改善（31％vs 7％，P <0.001）。在这些终点的第一个和第三个终点中，800 mg组的反应率明显高于安慰剂。有或没有糖尿病的人的结果相似。

lanifibranor与安慰剂的剂量相比，第4周治疗时丙氨酸氨基转移酶（ALT），天冬氨酸氨基转移酶（AST）和γ-谷氨酰转移酶（GGT）相对于基线的绝对变化显着改善，并且这些差异在24周内仍保持显着性。这些结果在有或没有糖尿病的人中保持一致。

与安慰剂组相比，接受lanifibranor治疗的人在24周内的纤维化生物标志物（ProC3，TIMP1 / TIMP2比），凋亡标志物（CK18M30）和炎症标志物（铁蛋白，hsCRP）有显着改善。在两个lanifibranor组中，“良好”的高密度脂蛋白胆固醇均显着升高，并且在安慰剂组中在24周内基本保持平稳，而甘油三酸酯在lanifibranor中显着下降，而在安慰剂中则保持不变。在任何研究组中，低密度脂蛋白胆固醇均无明显变化。空腹血糖，空腹胰岛素和HbA1c指示的血糖控制在两个lanbrabranor组中均较安慰剂显着改善了24周。
服用lanifibranor 1200 mg的药物相关的治疗性不良事件发生率为27.7％，使用800 mg的30.1％，使用安慰剂的23.5％。导致停药的与药物相关的不良事件的发生率分别为2.4％，1.2％和2.5％。安慰剂组中有两个人，没有一个人服用lanifibranor，发生了与药物相关的严重不良事件。

研究人员得出结论，仅在24周内，lanifibranor是第一种同时改善NASH和纤维化的药物。他们还指出，这是第一个使用SAF活性评分定义研究纳入标准的试验，这导致研究人群中NASH活跃且纤维化明显。 lanifibranor的3期试验计划于2021年进行。

参考文献
1. Francque S，Bedossa P，Ratziu V等。在非肝硬化性NASH中治疗24周后，panPPAR激动剂Lanifibranor既诱导了NASH的分解，又诱导了纤维化的消退：天然2b期试验的结果。 AASLD肝脏会议数字体验，2020年11月13日至16日。摘要12。
2. Boubia B，Poupardin O，Barth M等。设计，合成和评估一系列新的吲哚磺酰胺过氧化物酶体增殖物激活受体（PPAR）α/γ/δ三重激活剂：发现新的抗纤维化候选药物lanifibranor。 J Med化学2018; 61：2246-2265。
3. ClinicalTrials.gov。 NASH 2b期研究评估IVA337（NATIVE）。 ClinicalTrials.gov标识符NCT03008070。