Register now to R3i !
Your Login
Your Password
Confirm Password  
Your Email
I agree to receive
the R3i newsletter

R3i EDITORIAL

20 July 2020

Why multidrug approaches are needed in NASH: insights with pemafibrate

Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

An Editorial from the R3i Trustees
Prof. Jean Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco Nonalcoholic fatty liver disease (NAFLD) is a major challenge for the 21st century. Already more than 25% of the global population is affected 1, with similar rates among industrialised and less developed countries 2. As the prevalences of obesity, dyslipidaemia and diabetes escalate, NAFLD is likely to become even more common. Progression to nonalcoholic steatohepatitis (NASH), the most severe form of NAFLD, is also increasing in line with the pandemics of insulin resistance and obesity. Indeed, the most significant clinical burden in individuals with diabetes and NAFLD is among those with NASH 3; in the USA, cirrhosis from NASH is the leading cause of liver transplantation in women and the second leading cause of liver transplantation in men, and is a major contributor to the increased incidence of hepatocellular carcinoma 4. To date, however, no therapeutic agents are approved for the management of NASH.

Understanding the pathogenesis of NASH is critical to developing novel treatments. During disease progression, lipotoxicity and interactions between myeloid cells and sinusoidal endothelial cells in the liver are pivotal 5. Triglycerides (TG) accumulation is also thought to play a key role, although the underlying pathogenetic mechanisms are not fully clarified. Since peroxisome proliferator-activated receptor alpha (PPARα) is integral to the transcriptional regulation of lipoprotein metabolism, fatty acid transport and beta-oxidation, and impaired PPARα function is one factor involved in NASH development, targeting this receptor may offer potential. Pemafibrate, a selective PPARα modulator (SPPARMα), with enhanced potency and PPARα subtype specificity compared with traditional PPARα agonists, has demonstrated efficacy in managing hypertriglyceridaemia, especially in insulin-resistant conditions, reducing TG by up to 50% 6, with a favourable safety profile 7. Furthermore, a recent study has also suggested potential benefit in experimental NASH 8. Together, these insights provided a rationale to investigate pemafibrate in a preclinical NASH model, highly relevant given the unmet clinical need.

This study 9 used the STAM mouse model, which is characterised by almost complete destruction of pancreatic insulin-secreting β-cells with severe hyperglycaemia, representative of diabetes-based NASH in the clinical setting. Briefly, C57BL/6J mice were injected with 200 μg of anti-β-cells toxin streptozocin 2 days after birth and fed with a high fat diet from 4 weeks. At 6 weeks of age, mice were allocated to pemafibrate 0.1 mg/kg or a vehicle control for 3 weeks. Findings were compared with normal mice fed a normal chow diet. Investigations included measurement of lipids, liver histology, NAFLD activity score and gene transcriptome analysis.

It was hypothesised that pemafibrate would reduce hepatic TG accumulation and thereby improve NASH. While pemafibrate did significantly improve liver histology and the NAFLD activity score, as well as inflammatory and fibrosis marker gene expression, there was no change in hepatic TG content. Global gene analysis showed that pemafibrate induced TG hydrolysis and fatty acid beta-oxidation, as well as TG re-esterification, and also induced the expression of genes involved in lipolysis and lipid droplet formation. Additionally, dosing with pemafibrate modulated inflammation by reducing expression of the cell adhesion molecule VCAM-1, myeloid markers, and inflammation and fibrosis-related genes in STAM mice 8. In vitro studies showed that pemafibrate reduced VCAM-1 expression induced by high glucose levels 8.

In conclusion, the results of studies with pemafibrate in experimental NASH models suggest that while pemafibrate reduces steatosis and lipotoxicity by reducing excess free fatty acids, TG reduction in the liver may be insufficient 8,9. This is because PPARα is mainly involved in regulating nutrient flux to peripheral tissues, rather than providing an energy source to the liver. Instead, pemafibrate may prevent NASH by targeting immune cell interactions in the liver. Overall, these findings underline the need for multidrug approaches to manage NASH. This could explain why the search for new treatments for NASH, which has broadly focused on modulation of metabolic pathways, inflammatory cascades, and/or mechanisms impacting fibrosis, has been tortuous. Clinicians will also face challenges in identifying patients with advanced liver fibrosis who are likely to derive most benefit from treatment.

References

1. Younossi ZM, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.
2. Review Team, LaBrecque DR, Abbas Z, et al; World Gastroenterology Organisation. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol 2014;48:467–73.
3. Younossi ZM, et al. Economic and clinical burden of non alcoholic steatohepatitis in patients with type 2 diabetes in the U.S. Diabetes Care 2020;43:283-9.
4. White DL, et al. Incidence of hepatocellular carcinoma in all 50 United States, from 2000 through 2012. Gastroenterology 2017;152:812‐20.
5. Miyao M, et al. Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression. Lab. Invest 2015;95:30–44.
6. Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα Modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep 2020;221:5.
7. Yamashita S, et al. Efficacy and safety of pemafibrate, a novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): pooled analysis of phase 2 and 3 studies in dyslipidemic patients with or without statin combination. Int J Mol Sci 2019; doi: 10.3390/ijms20225537.
8. Honda, Y. et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep 2017;7:42477.
9. Sasaki Y, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep 2020;10:7818.
10. Alkhouri N, et al. Looking into the crystal ball: predicting the future challenges of fibrotic NASH treatment. Hepatol Commun 2019;3:605-13.
11. Colca J. NASH (nonalcoholic steatohepatitis), diabetes, and macrovascular disease: multiple chronic conditions and a potential treatment at the metabolic root. Expert Opin Investig Drugs 2020;29:191-6.