Experimental NASH Drugs Improve Fibrosis and Liver Health
An investigational drug package from Gilead Sciences has been shown to improve fibrosis and other measures of liver health despite failing to meet a study’s primary endpoint of reducing significantly fibrosis of the liver without worsening non-alcoholic steatohepatitis (NASH), according to results presented at the 2020 Digital International Liver Congress.
NASH and its milder form, non-alcoholic fatty liver disease (NAFLD), are responsible for an increasing proportion of advanced liver disease. Linked to obesity and diabetes, NAFLD / NASH is increasingly recognized as a manifestation of metabolic syndrome. The accumulation of fat in the liver triggers inflammation, which over time can lead to fibrosis (scarring), cirrhosis, and cancer of the liver. In the absence of approved therapies, management relies on lifestyle changes, such as weight loss and exercise.
The development of treatments for NAFLD and NASH has proven difficult, and several drugs that looked promising in early studies failed to demonstrate significant benefits in larger trials. Part of the difficulty lies in determining the biomarkers that predict clinical benefits. Considering the number of different biological processes that play a role in the development of NAFLD / NASH and its complications, many experts believe that optimal treatment will require the combination of drugs with different mechanisms of action.
Gilead’s ATLAS Phase IIb trial evaluated three of the Company’s NASH candidates alone and in various combinations.
Selonsertib (formerly GS-4997) is an inhibitor of the kinase 1 regulating the apoptosis signal (ASK1), firsocostat (GS-0976) is an inhibitor of acetyl-CoA carboxylase (ACC) and cilofexor (GS- 9674) is a nonsteroidal farnesoid X receptor (FXR) agonist. ASK1 promotes inflammation and fibrosis, ACC is involved in lipogenesis (conversion of carbohydrates into fatty acids) and FXR regulates bile acid synthesis and plays a role in lipid and glucose metabolism.
ATLAS included 392 participants with advanced fibrosis confirmed by biopsy (stage F3) or compensated cirrhosis (stage F4) due to NASH, an unexplained cirrhosis with at least two features of the metabolic syndrome (abdominal obesity, high blood sugar , abnormal blood lipids and high blood pressure)) or non-invasive measures suggesting advanced fibrosis. About 65% were female and the median age was around 60 years. The average body mass index was in the obesity range, and nearly three-quarters had diabetes. More than half (56%) had cirrhosis at baseline.
Participants were randomly assigned to one of seven arms, receiving selonsertib, firsocostat, or cilofexor alone, one of three dual combinations, or a placebo. Liver biopsies were taken at baseline and at week 48, and analyzes for liver stiffness and liver fat content were performed at baseline and at weeks 24 and 48.
At last year’s AASLD Liver Meeting, researchers reported that selonsertib alone did not work better than placebo in improving liver fibrosis or reducing the risk of cirrhosis in STELLAR phase III trials. 3 and STELLAR-4. The ATLAS selonsertib monotherapy arm was discontinued following publication of these results.
Last December, Gilead announced that neither firsocostat or cilofexor as monotherapy, nor any combination of the two drugs significantly increased the likelihood of achieving at least one improvement in fibrosis without worsening NASH, which is often used as a criterion. primary endpoint in fatty liver studies. .
However, as Rohit Loomba, MD of the University of California San Diego reported at the recent conference, some of the single agents and combinations led to significant improvements in various secondary endpoints.
After 48 weeks of treatment, 21% of participants assigned to receive firsocostat / cilofexor and 19% of those taking selonsertib / cilofexor experienced at least improvement in fibrosis without worsening NASH. The corresponding rates were 15% with selonsertib / firsocostat, 12% with firsocostat or cilofexor as monotherapy and 11% in the placebo group. In the STELLAR trials, 10-14% of patients taking selonsertib alone met this endpoint.
The likelihood of progression to cirrhosis was lower in all treatment groups compared to the placebo group, in which 41% progressed. Selonsertib / cilofexor obtained the best results, with only 8% development of cirrhosis. Progression rates were 15% with firsocostat as monotherapy or selonsertib / firsocostat, 20% with cilofexor as monotherapy, and 23% with firsocostat / cilofexor.
Resolution of NASH without worsening fibrosis was rare in all treatment groups. No one in the cilofexor monotherapy or placebo groups met this endpoint, increasing to 1.4% with selonsertib / firsocostat, 1.5% with selonsertib / cilofexor, 3.0% with firsocostat monotherapy, and 4%. 5% with firsocostat / cilofexor.
People assigned to firsocostat / cilofexor or firsocostat as monotherapy were most likely to see a reduction of at least two points in their overall NAFLD activity score and all three components of that score: steatosis (fat accumulation), inflammation lobular and swelling of hepatocytes. The firsocostat / cilofexor combination was found to be significantly better than placebo for all of these measures.
When bile duct fibrosis and proliferation were assessed using a machine learning algorithm, firsocostat / cilofexor led to greater overall improvements, although firsocostat and cilofexor monotherapy was shown to be beneficial. good results on some measures.
Fibroscan hepatic stiffness scores and improved liver function (ELF) scores improved the most in the arm on firsocostat monotherapy. For hepatic stiffness, 55% of firsocostat recipients, 45% of firsocostat / cilofexor recipients, and 38% of cilofexor recipients were classified as responders, compared to 20% in the placebo group. For ELF scores, the corresponding proportions were 44%, 31% and 24% versus 19%.
Firsocostat / cilofexor led to significant reductions in biomarkers of liver injury, inflammation and liver function, including liver enzymes ALT and AST, bilirubin and bile acids; those taking firsocostat or cilofexor alone saw smaller improvements.
Finally, people who received firsocostat / cilofexor had significantly greater reductions in body weight and insulin levels and greater improvement in kidney function compared to the placebo group, Loomba reported.
All treatments were generally safe and well tolerated. Serious side effects were uncommon, observed in two people (3%) in the firsocostat / cilofexor arm, one (1%) in the selonsertib / cilofexor arm, and none in the other groups. Across all groups, 3-5% of participants discontinued treatment due to adverse events.
The most common adverse event overall was pruritus or itching, which can be a symptom of the cirrhosis itself. This was most common in the selonsertib / cilofexor and firsocostat / cilofexor groups (29% and 28%, respectively). The rate of pruritus was approximately 20% in the other treatment groups and 15% in the placebo group.
Triglyceride levels increased in all treatment groups, but there was no change in the placebo group. The largest increases were observed in the firsocostat / cilofexor and firsocostat monotherapy groups (44 and 42 milligrams per deciliter). None of the groups saw a significant increase in harmful LDL cholesterol. The pruritus and high triglycerides were considered “manageable,” according to the researchers.
Overall, these results show that although it was difficult to achieve the endpoint of at least one-step improvement in fibrosis without worsening NASH, various agents cause beneficial changes in d ‘other indicators of liver health, especially when used in combination. These results suggest that further studies of combination therapies for advanced fibrosis due to NASH, particularly firsocostat / cilofexor, are warranted, Loomba said.
Click here to learn more about NAFLD and NASH.