ZSP1601, a novel pan-phosphodiesterase inhibitor for the treatment of NAFLD, A randomized, placebo-controlled phase Ib/IIa trial.

Non-alcoholic fatty liver disease is a growing health burden with limited treatment options worldwide. Herein we report a randomized, double-blind, placebo-controlled, multiple-dose trial of a first-in-class pan-phosphodiesterase inhibitor ZSP1601 in 36 NAFLD patients (NCT04140123). There were three cohorts. Each cohort included twelve patients, nine of whom received ZSP1601 50 mg once daily, 50 mg twice daily, or 100 mg twice daily, and three of whom received matching placebos for 28 days. The primary outcomes were the safety and tolerability of ZSP1601. A total of 27 (27/36, 75%) patients experienced at least one treatment-emergent adverse event (TEAE). Most TEAEs were mild to moderate. There was no Serious Adverse Event. Diarrhea, transiently elevated creatinine and adaptive headache were frequently reported adverse drug reaction. We conclude that ZSP1601 is well-tolerated and safe, showing effective improvement in liver chemistries, liver fat content and fibrosis in patients with NAFLD.

Non-invasive evaluation of NAFLD and the contribution of genes: an MRI-PDFF-based cross-sectional study.

OBJECTIVE: To investigate the clinical, laboratory and genetic features of NAFLD patients based on MRI-PDFF in China. DESIGN: Patients with high ALT and with a diagnosis of fatty liver were included in this cross-sectional study. Fasting blood was collected to test biomarkers and SNPs. A total of 266 patients underwent MRI-PDFF and FibroScan examinations, and 38 underwent liver biopsy. Diagnostic models (decision tree, LASSO, and elastic net) were developed based on the diagnosis from MRI-PDFF reports. RESULTS: Approximately, 1/3 of the patients were found to have NASH and fibrosis. After quantifying liver steatosis by MRI-PDFF (healthy: n = 47; mild NAFLD: n = 136; moderate/severe NAFLD: n = 83; liver fat content (LFC): 3.6% vs. 8.7% vs. 19.0%), most biomarkers showed significant differences among the three groups, and patients without obesity were found to have a similar LFC as those with obesity (11.1% vs. 12.3%). Models including biomarkers showed strong diagnostic ability (accuracy: 0.80-0.91). Variant alleles of PNPLA3, HSD17B13 and MBOAT7 were identified as genetic risk factors causing higher LFC (8.7% vs. 12.3%; 11.0% vs. 14.5%; 8.5% vs. 10.2%, p < 0.05); those with the UQCC1 rs878639 variant allele showed lower LFC (10.4% vs. 8.4%; OR = 0.58, p < 0.05). Patients with more risk alleles had higher LFCs (8.1% vs. 10.7% vs. 11.6% vs. 14.5%). CONCLUSIONS: Based on MRI-PDFF, a combination of several specific biomarkers can accurately predict disease status. When the effects of genes on liver steatosis were first quantified by MRI-PDFF, the UQCC1 rs878639 G allele was identified as a protective factor, and the MBOAT7 T allele was identified as a risk only among nonobese individuals.