FXR激动剂EDP-305降低NASH中的ALT和肝脂肪

StephenW

FXR Agonist EDP-305 Lowers ALT andLiver Fat in NASH

EASL 2020, Digital International Liver Congress, August 27-29, 2020

Mark Mascolini

EDP-305, a non-bile acid farnesoid X receptor (FXR) agonist, lowered alanineaminotransferase (ALT) and reduced liver fat in a 12-week phase 2a trial [1]. Treatment-relateddiscontinuations proved greater with the higher dose of EDP-305 than with thelower dose.

French, US, and Canadian researchers who conducted this study note that NASHappears to be the fastest-growing cause of cirrhosis, liver cancer, and livertransplantation, yet no medications are licensed to treat NASH. As a farnesoidX receptor agonist, EDP-305 could affect hepatic metabolism, as well as inflammatoryand fibrogenic processes, in people with fatty liver disease. In a 2-week phase1 trial, EDP-305 proved generally safe at two doses and suitable for once-dailyoral dosing [2].

The double-blind placebo-controlled ARGON-1 trial randomized participants in a2-2-1 ratio to 1 mg of EDP-305 daily, 2.5 mg of EDP-305 daily, or placebo for12 weeks. Primary objectives were to assess change in ALT at week 12 and toevaluate safety and tolerability of the drug.

To be eligible for the trial, participants had to have (1) histologic evidenceof NASH with fibrosis and elevated ALT, or (2) a phenotypic diagnosis ofNASH based on elevated ALT and diagnosis of type 2 diabetes, and (3) aliver fat fraction above 8% by MRI-PDFF (magnetic resonanceimaging-derived proton density fat fraction). Participants could nothave another chronic disease, histologic or clinical evidence of cirrhosis,HbA1c at or above 9%, or significant alcohol use.

The intention-to-treat population included 55 people randomized to EDP-305 1mg, 53 randomized to EDP-305 2.5 mg, and 24 randomized to placebo. Those threegroups were similar in age (average 51.5, 52.3, 50.8), and they differedmarginally in proportion of women (52.7%, 54.7%, 45.8%), proportion of whites(76.4%, 88.7%, 70.8%), body mass index (34.5, 33.8, 36.1 kg/m2), ALT (91.9,79.5, 78.5 U/L), MRI-PDFF percent liver fat (22.1%, 19.0%, 20.3%), andproportion taking metformin for diabetes (63.6%, 56.6%, 70.8%).

By week 12 average ALT fell 27.9 U/L with 2.5 mg of EDP-305 (P = 0.049vs placebo), 21.7 U/L with 1 mg of EDP-305 (not significantly different fromplacebo), and 15.4 U/L with placebo. Improvements in other markers of liverinjury—AST and GGT—also proved greater with the 2.5-mg dose than with placebo.

Average MRI-PDFF absolute drop in liver fat was significantly greater with 2.5mg of EDP-305 than with placebo (7.1% vs 2.4%, P < 0.001). Averageliver fat fell 3.3% with 1 mg of EDP-305 (not significantly different fromplacebo). Proportions of participants with an absolute MRI-PDFF change frombaseline of at least 5%, and with a percent MRI-PDFF change from baseline of atleast 30%, were 42.9% and 44.9% with 2.5 mg of EDP-305, 31.4% and 25.5% with 1mg of EDP-305, and 20% and 25% with placebo.

Average 12-week drop in ALT with at least a 30% drop in MRI-PDFF liver fat was35.3 U/L with 2.5 mg of EDP-305, 31.8 U/L with 1 mg of EDP-305, and 15.9 U/Lwith placebo.

Through 12 weeks, a measure of EDP-305 target engagement (ALP) was greater with2.5 mg of EDP-305 than with 1 mg of the drug or with placebo. Improvement in twoother measures of target engagement (C4 and FGF19) also proved greater with 2.5mg of EDP-305 than with 1 mg or placebo.

Treatment-emergent pruritus affected 47.2% of participants taking 2.5 mg ofEDP-305, 9.1% taking 1 mg, and 4.2% taking placebo. Most treatment-emergentadverse events were mild or moderate. Serious adverse events affected 1 persontaking placebo, 1 taking 1 mg of EDP-305, and no one taking 2.5 mg. But thediscontinuation rate was higher with 2.5 mg (22.6%) than with 1 mg (1.8%) orplacebo (8.3%). Pruritus-related discontinuations occurred in 20.8% randomizedto 2.5 mg versus 1.8% assigned to 1 mg.

“Bad” LDL cholesterol rose through 12 weeks with 1 or 2.5 mg of EDP-305 whilefalling with placebo. “Good” HDL cholesterol fell more with 2.5 mg of EDP-305(about 8%) than with 1 mg (about 2%) or placebo (no change).

References
1. Ratziu V, Rinella M, Neuschwander-Tetri B, et al. EDP-305, a non-bile acid farnesoidX receptor (FXR) agonist, showed statistically significant improvements inliver biochemistry and hepatic steatosis  in the phase 2a ARGON-1 study.EASL 2020, Digital International Liver Congress, August 27-29, 2020. AbstractAS078.
2. ClinicalTrials.gov. A study to assess the safety, tolerability,pharmacokinetics and efficacy of EDP-305 in subjects with non-alcoholicsteatohepatitis. ClinicalTrials.gov identifier NCT03421431. https://clinicaltrials.gov/ct2/show/NCT03421431

StephenW

FXR激动剂EDP-305降低NASH中的ALT和肝脂肪

EASL 2020，数字国际肝脏大会，2020年8月27日至29日

马克·马斯科利尼

在为期12周的2a期试验中，一种非胆汁酸法尼醇X受体（FXR）激动剂EDP-305降低了丙氨酸转氨酶（ALT）并降低了肝脏脂肪[1]。较高剂量的EDP-305与较低剂量的治疗相关的中止证明更大。

进行这项研究的法国，美国和加拿大研究人员指出，NASH似乎是肝硬化，肝癌和肝移植增长最快的原因，但尚未获得用于治疗NASH的任何药物许可。作为一种法尼醇X受体激动剂，EDP-305可能会影响脂肪性肝病患者的肝脏代谢以及炎症和纤维化过程。在为期2周的1期临床试验中，EDP-305已证明一般安全，分两次服用，适合每日口服一次[2]。

双盲安慰剂对照的ARGON-1试验将参与者以2-2-1的比例随机分为每天1 mg EDP-305，每天2.5 mg EDP-305或安慰剂12周。主要目标是评估第12周时ALT的变化并评估药物的安全性和耐受性。

为了符合该试验的资格，参与者必须具有（1）具有纤维化和ALT升高的NASH的组织学证据，或（2）基于ALT升高和2型糖尿病的诊断为NASH的表型诊断，以及（3）肝脏MRI-PDFF（磁共振成像得出的质子密度脂肪分数）可得出8％以上的脂肪分数。参加者不得患有其他慢性疾病，肝硬化的组织学或临床证据，HbA1c不低于9％或大量饮酒。

意向性治疗人群包括随机分配给EDP-305 1 mg的55人，随机分配给EDP-305 2.5 mg的53人和随机分配给安慰剂的24人。这三组的年龄相似（平均51.5、52.3、50.8），女性比例（52.7％，54.7％，45.8％），白人比例（76.4％，88.7％，70.8％），身体比例略有不同。质量指数（34.5、33.8、36.1 kg / m2），ALT（91.9、79.5、78.5 U / L），MRI-PDFF肝脂肪百分比（22.1％，19.0％，20.3％）和服用二甲双胍的糖尿病比例（63.6 ％，56.6％，70.8％）。

到第12周时，使用2.5 mg EDP-305的平均ALT下降了27.9 U / L（相对于安慰剂，P = 0.049）；使用1 mg EDP-305的平均ALT下降了21.7 U / L（与安慰剂无显着差异），而使用EDP-305的平均ALT下降了15.4 U / L安慰剂。 2.5 mg剂量的肝损伤其他标志物AST和GGT的改善也证明比安慰剂好。

2.5 mg EDP-305的肝脂肪平均MRI-PDFF绝对下降比安慰剂显着更大（7.1％vs 2.4％，P <0.001）。使用1 mg EDP-305，平均肝脂肪下降3.3％（与安慰剂无显着差异）。相对于基线，MRI-PDFF的绝对变化至少为5％，与基线相比MRI-PDFF的变化百分比至少为30％，分别为2.5 mg EDP-305、31.4％和42.9％和44.9％。使用1 mg EDP-305时为25.5％，使用安慰剂时为20％和25％。

ALT平均下降12周，MRI-PDFF肝脂肪下降至少30％，使用2.5 mg EDP-305时为35.3 U / L，使用1 mg EDP-305时为31.8 U / L，和15.9 U / L与安慰剂。

在12周内，使用2.5 mg EDP-305的EDP-305目标参与度（ALP）大于使用1 mg药物或使用安慰剂的EDP-305目标参与度。 2.5 mg EDP-305的其他两种靶标结合量（C4和FGF19）的改善也证明比1 mg或安慰剂好。

出现治疗性瘙痒症的参与者中，服用EDP-305 2.5毫克的受试者为47.2％，服用1 mg的受试者为9.1％，服用安慰剂的受试者为4.2％。大多数出现治疗的不良事件为轻度或中度。严重不良事件影响了1名服用安慰剂的人，1名服用1 mg EDP-305的人，没有人服用2.5 mg。但是2.5 mg（22.6％）的停用率高于1 mg（1.8％）或安慰剂（8.3％）的停用率。瘙痒相关停药发生率为20.8％，随机分配至2.5 mg，而1.8％为1 mg。

使用1或2.5毫克EDP-305的“不良” LDL胆固醇在12周内上升，而使用安慰剂则下降。 2.5 mg EDP-305（约8％）的“良好” HDL胆固醇下降幅度大于1 mg（约2％）或安慰剂（无变化）。

参考文献
1. Ratziu V，Rinella M，Neuschwander-Tetri B等。 EDP​​-305是一种非胆汁酸法尼醇X受体（FXR）激动剂，在2a ARGON-1期研究中显示出肝脏生物化学和肝脂肪变性的统计学显着改善。 EASL 2020，数字国际肝脏大会，2020年8月27-29日。摘要AS078。
2. ClinicalTrials.gov。评估EDP-305在非酒精性脂肪性肝炎患者中的安全性，耐受性，药代动力学和功效的研究。 ClinicalTrials.gov标识符NCT03421431。 https://clinicaltrials.gov/ct2/show/NCT03421431