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标题: Nidufexor降低NASH患者在第12周的ALT和肝脂肪 [打印本页]

作者: StephenW    时间: 2020-8-29 12:48     标题: Nidufexor降低NASH患者在第12周的ALT和肝脂肪

Nidufexor Lowers ALT and Liver Fat at12 Weeks in NASH Patients

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

Mark Mascolini

Twelve weeks of nidufexor for people with nonalcoholic steatohepatitis (NASH) loweredalanine aminotransferase (ALT), liver fat, and weight in a phase 2 comparisonwith placebo [1]. This non-bile acid FXR agonist had good target engagement andachieved dose-proportional systemic exposure in this 121-person trial.

Bile acids produced by cholesterol can alter gene expression in the liver andsmall intestine by activating nuclear receptors including farnesoid X receptor(FXR) [2]. Signaling through FXR plays roles in hepatic metabolic,inflammatory, and fibrogenic processes. Researchers are studying several FXRagonists for treatment of NASH, including nidufexor [3].

An international team conducted this phase 2 randomized, double-blind,placebo-controlled trial to explore the safety, pharmacokinetics, and efficacyof nidufexor dosed at 50 or 100 mg daily for 12 weeks in people with NASH.

The CLMB763X2201 trial enrolled 121 people with biopsy-confirmed or phenotypicNASH randomized in a 2-to-1 ratio to 50 or 100 mg of nidufexor once daily orplacebo. Cohort 1 had an ALT at or above 60 U/L (men) or 40 U/L (women) andreceived 100 mg of nidufexor or placebo. Cohort 2 had an ALT at or above 43 U/L(men) or 28 U/L (women) and got 50 mg of nidufexor or placebo. Participants hadto be at least 18 years old and have a hepatic fat fraction at or above 10%. Theycould not have type 1 or uncontrolled type 2 diabetes (HbA1c >/= 9.5%),calculated estimated glomerular filtration rate below 60 mL/min, or other formsof chronic liver disease, cirrhosis, decompensation, or a significant historyof alcohol consumption.

Average age was similar across the 100-mg, 50-mg, and combined placebo groups(51.3, 49.5, 51.6), and similar proportions were women (59%, 52%, 60%) andwhite (86%, 84%, 78%). The 100-mg, 50-mg, and combined placebo groups were alsosimilar in average body mass index (34, 34.5, 35.1 kg/m2) and hepatic fatfraction (19.5%, 19.9%, 20.5%). The 100-mg nidufexor group had a higher averageALT (72.4 U/L) than the 50-mg group (53.2 U/L) or the placebo group (63.0 U/L).

Fifteen of 37 people (40.5%) in the 100-mg nidufexor group stopped treatment(11 for adverse events), as did 5 of 44 (11.4%) randomized to 50 mg and 7 of 40(17.5%) randomized to placebo (4 for adverse events).

ALT dropped quickly with either nidufexor dose and stayed lower through 12weeks when compared with placebo. The adjusted mean changes from baselinethrough 12 weeks were significantly greater with nidufexor than with placebo (P< 0.05).

Relative change in percent hepatic fat was greater with 100 mg than with 50 mgof nidufexor, and both declines were greater than with placebo. About 70% ofpeople assigned to 100 mg of nidufexor, 50% assigned to 50 mg, and under 5%assigned to placebo had at least a 30% drop in hepatic fat measured by MRI-PDFF(magnetic resonance imaging-derived proton density fat fraction).Average percent change in body weight was significantly greater with 100 mg ofnidufexor (-1.44 kg) or 50 mg (-2.02 kg) than with placebo (P <0.01).

Total cholesterol and “bad” LDL cholesterol did not change through 12 weekswith nidufexor or placebo. “Good” HDL cholesterol fell marginally with the FXRagonist but not with placebo.

Systemic exposures measured by area under the curve and maximum concentrationwere proportionately greater with 100 than 50 mg of nidufexor.

Twelve of 37 people (32%) randomized to 100 mg of nidufexor had an adverseevent leading to dose reduction or discontinuation, compared with nonerandomized to 50 mg and 4 of 40 (10%) randomized to placebo. Two people on the100-mg dose (5.4%) and 3 on the 50-mg dose (6.8%) had serious adverse events.The most frequent adverse events (with 100 mg, 50 mg, and placebo) werepruritus (54.1%, 29.5%, 15.0%), nausea (18.9%, 11.4%, 5.0%), increased urineprotein/creatinine ratio (18.9%, 18.2%, 7.5%), and hyperglycemia (10.8%, 9.1%,0%). Most adverse events were grade 1 or 2.

There are no licensed therapies for NASH.

References
1. Aspinall R, Shennak M, Stoica G, et al. Nidufexor, a non-bile acid FXRagonist, decreases ALT and hepatic fat fraction in patients with NASH after 12weeks dosing. EASL 2020, Digital International Liver Congress, August 27-29,2020. Abstract GS07.
2. Matsubara T, Li F, Gonzalez FJ, et al. FXR signaling in the enterohepaticsystem. Mol Cell Endocrinol. 2013;368(1-2):17-29. doi:10.1016/j.mce.2012.05.004.
3. Chianelli D, Rucker PV, Roland J, et al. Nidufexor (LMB763), a novel FXRmodulator for the treatment of nonalcoholic steatohepatitis. J Med Chem.2020;63:3868–3880. https://doi.org/10.1021/acs.jmedchem.9b01621.

作者: StephenW    时间: 2020-8-29 12:49

Nidufexor降低NASH患者在第12周的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

与安慰剂相比,在非酒精性脂肪性肝炎(NASH)患者的十二周尼杜昔(nedufexor)在第二阶段降低了丙氨酸转氨酶(ALT),肝脂肪和体重[1]。在这项121人的试验中,这种非胆汁酸FXR激动剂具有良好的靶标参与度,并实现了与剂量成比例的全身暴露。

胆固醇产生的胆汁酸可通过激活包括法尼醇X受体(FXR)在内的核受体来改变肝脏和小肠中的基因表达[2]。通过FXR发出的信号在肝脏代谢,炎症和纤维化过程中发挥作用。研究人员正在研究用于治疗NASH的几种FXR激动剂,包括nidufexor [3]。

一个国际团队进行了该阶段2随机,双盲,安慰剂对照试验,以研究在NASH患者中连续12周每天服用50或100 mg Nidufexor的安全性,药代动力学和功效。

这项CLMB763X2201试验招募了121名经活检证实或表型NASH的患者,以2比1的比例随机分配给50或100毫克尼得富司或每日一次或安慰剂。队列1的ALT等于或高于60 U / L(男性)或40 U / L(女性),并接受100毫克的尼得氟沙星或安慰剂。第2组患者的ALT等于或高于43 U / L(男性)或28 U / L(女性),并服用50 mg的Nidufexor或安慰剂。参加者必须年满18岁,且肝脂肪分数等于或高于10%。他们不能患有1型或不受控制的2型糖尿病(HbA1c> / = 9.5%),估计的肾小球滤过率估计值低于60 mL / min或其他形式的慢性肝病,肝硬化,失代偿期或有大量饮酒史。

100毫克,50毫克和组合安慰剂组的平均年龄相似(51.3、49.5、51.6),女性(59%,52%,60%)和白人(86%,84%, 78%)。 100 mg,50 mg和组合安慰剂组的平均体重指数(34、34.5、35.1 kg / m2)和肝脂肪分数(19.5%,19.9%,20.5%)也相似。 100 mg Nidufexor组的平均ALT(72.4 U / L)比50 mg组(53.2 U / L)或安慰剂组(63.0 U / L)高。

100毫克尼屈氟沙星组中的37人中有15人(40.5%)停止了治疗(11例为不良事件),随机分配给50 mg的44人中有5人(11.4%)和安慰剂随机分配了40人中的7人(17.5%)(4对于不良事件)。

与安慰剂相比,无论使用尼杜昔尔剂量,ALT均迅速下降,并在12周内保持较低水平。 Nidufexor从基线到12周的校正后平均变化显着大于安慰剂组(P <0.05)。

100 mg的尼得富司相对于肝脂肪百分数的相对变化更大,两次下降均大于安慰剂。通过MRI-PDFF(磁共振成像衍生的质子密度脂肪)测量,约有70%的人分配了100 mg的尼氟沙星,50%的分配给50 mg,低于5%的分配给安慰剂的人的肝脂肪下降了至少30%分数)。 100 mg尼得富沙(-1.44 kg)或50 mg(-2.02 kg)的平均体重变化百分比显着大于安慰剂(P <0.01)。

使用尼得富沙或安慰剂治疗的总胆固醇和“不良” LDL胆固醇在12周内没有变化。 FXR激动剂使“良好”的HDL胆固醇略有下降,而安慰剂则没有。

用尼杜非索100 mg时,曲线下面积和最大浓度所测得的全身暴露量成比例地大于100 mg。

随机分配给100 mg尼屈氟沙星的37人中有12人(占32%)发生不良事件,导致剂量降低或中断,而随机分配至50 mg的人中没有12人(随机分配给安慰剂)有4人(10%)。 100 mg剂量(5.4%)的两个人和50 mg剂量(6.8%)的三个人发生严重不良事件。最常见的不良事件(分别为100 mg,50 mg和安慰剂)为瘙痒(54.1%,29.5%,15.0%),恶心(18.9%,11.4%,5.0%),尿蛋白/肌酐比率增加(18.9%) ,18.2%,7.5%)和高血糖症(10.8%,9.1%,0%)。大多数不良事件为1级或2级。

没有用于NASH的许可疗法。

参考文献
1. Aspinall R,Shennak M,Stoica G等。 Nidufexor是一种非胆汁酸FXR激动剂,在服药12周后可降低NASH患者的ALT和肝脂肪分数。 EASL 2020,数字国际肝脏大会,2020年8月27-29日。摘要GS07。
2. Matsubara T,Li F,Gonzalez FJ等。肠肝系统中的FXR信号传导。摩尔细胞内分泌。 2013; 368(1-2):17-29。 doi:10.1016 / j.mce.2012.05.004。
3. Chianelli D,Rucker PV,Roland J等。 Nidufexor(LMB763),一种新型的FXR调节剂,用于治疗非酒精性脂肪性肝炎。 J Med化学2020; 63:3868-3880。 https://doi.org/10.1021/acs.jmedchem.9b01621




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