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
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。