Discussion
NAFLD, toxicity, non-cirrhotic NASH, fibrosis, NASH, necrosis
ADVERSE REACTIONS, LIVER STEATOSIS, LIVER, LIVER FIBROSIS, FIBROSIS, CELL DAMAGE, NECROSIS
This randomized, double-blinded, placebo-controlled, multiple-dose phase Ib/IIa trial assessed the safety, pharmacokinetics, and efficacy of ZSP1601 in the treatment of patients with NAFLD. To the best of our knowledge, this is the first clinical trial to evaluate the efficacy of ZSP1601 in NAFLD. The results obtained in this exploratory small-scale study of short treatment duration are promising. Firstly, the efficacy of ZSP1601 in the treatment of NAFLD was assessed, and the major findings were as follows: (1) Serum ALT was significantly decreased from the baseline in ZSP1601 50 mg BID, and 100 mg BID versus placebo after the end of treatment; (2) The number and proportion of NAFLD patients with a reduction of ALT levels ≥ 30% from baseline was significantly higher in the ZSP1601 100 mg BID than the placebo as early as 22 days following the treatment; (3) The number and proportion of NAFLD patients with a ≥ 30% reduction in LFC from baseline was greater in ZSP1601 50 mg BID and 100 mg BID groups when compared with the placebo group; (4) Other exploratory efficacy indicators, such as FibroScan parameters, were decreased in response to ZSP1601 treatment. Secondly, ZSP1601 (50 mg QD, 50 mg BID, 100 mg BID) was safe and well-tolerated by the study subjects. Thirdly, pharmacokinetic profiles revealed the dose-proportional increase in exposure in ZSP1601 treatment groups.At present, no pharmacological therapies are approved for NASH except that saroglitazar was approved for non-cirrhotic NASH by the Drug Controller General in India, and the treatment is restricted to lifestyle modificationsThis study has some limitations. Firstly, the number of enrolled patients is relatively small, which limits the power of the study, thus it is likely that only very common and short-term adverse reactions would be detected. Also, we acknowledge that there was an imbalance in age and sex between the ZSP1601 and placebo groups, which may have resulted from the randomization process in this study with a small sample size. Although age and sex are not the main factor affecting efficacy, the analysis of results will take into account age and sex for a more comprehensive analysis in a larger Phase II/III clinical trial with a larger sample size. Secondly, liver biopsy is currently the gold standard for the definitive diagnosis of NASH and the management of NAFLD worldwide. Liver biopsies enable an accurate evaluation of liver steatosis, cell damage, inflammatory necrosis, and the degree of fibrosis, and histological findings based on liver biopsies have been widely used as the primary therapeutic endpoint in clinical trials of new drugs for NASH. In this study, the majority of the patients were diagnosed by clinical features with only two cases diagnosed by liver biopsy, and no comparison of histopathologic changes in study participants were made via liver biopsies before and after treatment. Thirdly, the treatment period of 28 days was relative short, thus we were unable to determine potential long-term benefits of ZSP1601 in the attenuation of liver fibrosis in patients with NAFLD. Fourthly, the small number of women included in this study may be insufficient to detect even common adverse reactions in women. With the promising results gained from this phase Ib/IIa clinical trial, long-term treatment benefits of ZSP1601 should be further tested and sufficient toxicity data should be obtained in the future clinical trials using a larger sample size and extended treatment durations in patients with NASH.In conclusion, the findings from this phase Ib/IIa randomized, double-blinded, placebo-controlled, multiple-dose trial in patients with NAFLD have suggested that ZSP1601 is well-tolerated and safe, and effective in the improvement of efficacy indicators for NAFLD, including statistically significant reductions compared with placebo in LFC, liver enzymes, and liver fibrosis. Thus, ZSP1601 is a potential novel medication that may be used in the treatment of NAFLD. Further clinical studies will be needed to assess long-term benefits and safety of ZSP1601 in a larger sample size of patients with NASH.