Experimental NASH treatments: Gilead candidates miss primary endpoint but show some benefits

Combinations of experimental drugs for non-alcoholic steatohepatitis (NASH) failed to meet a study's primary endpoint by significantly improving liver fibrosis without worsening NASH, but one combination in particular – firsocostat plus cilofexor – did lead to improvements in other measures of fibrosis and liver health, according to results presented at the 2020 Digital International Liver Congress.

Non-alcoholic fatty liver disease (NAFLD) and its more sever form, NASH, are responsible for a growing burden of advanced liver disease worldwide. Linked to obesity and diabetes, NAFLD/NASH is increasingly recognised as a manifestation of the metabolic syndrome. The build-up of fat in the liver triggers cell death and inflammation, which over time can lead to fibrosis, cirrhosis, liver cancer and liver failure.

Developing treatments for NAFLD and NASH has been challenging. Several drugs that appeared promising in early studies did not demonstrate significant benefits in larger trials. Part of the difficulty lies in determining which biomarkers may predict clinical benefits. With no approved therapies, lifestyle modification and weight loss are the mainstays of NAFLD/NASH management.

After the failure of several different single agents – and given the multiple different biological processes that play a role in the development of NAFLD/NASH and its complications – many experts think optimal treatment may require combining drugs with different mechanisms of action.

Gilead Sciences' phase IIb ATLAS trial evaluated three of the company's NASH candidates alone and in various combinations.

Selonsertib (formerly GS-4997) is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor; firsocostat (GS-0976) is an acetyl-CoA carboxylase (ACC) inhibitor; 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 in the liver) and FXR regulates bile acid synthesis and plays a role in lipid and glucose metabolism.

As previously reported, in two phase III trials (STELLAR 3 and 4), selonsertib alone did not significantly increase the proportion of patients who saw at least a one-stage improvement in fibrosis without worsening NASH, a commonly used endpoint in NAFLD/NASH studies. In these trials, 10 to 14% of patients assigned to different doses of selonsertib achieved this primary endpoint, compared with 13% in the placebo arm.

ATLAS included 392 participants in five countries with histologically confirmed bridging fibrosis (stage F3) or compensated cirrhosis (stage F4) due to NASH, unexplained cirrhosis accompanied by two or more metabolic syndrome components or non-invasive measures suggestive of advanced fibrosis. About 65% were women and the median age was approximately 60 years. The average body mass index was in the obese range and nearly three-quarters had diabetes. Just over half had cirrhosis at baseline.

Participants were randomly assigned to one of seven arms, receiving selonsertib, firsocostat or cilofexor alone, one of the three dual combinations or a placebo. Liver biopsies were done at the start of the study and at week 48 and scans for liver stiffness and liver fat content were done at baseline and weeks 24 and 48.

The selonsertib monotherapy arm was halted after the STELLAR results were reported. Last December, Gilead announced that neither of the other single agents nor any of the dual combinations improved fibrosis without worsening NASH significantly more often than the placebo.

However, some of the single agents and combinations led to significant improvements in various secondary endpoints. Prof. Rohit Loomba of the University of California at San Diego described these findings in more detail at the recent conference, focusing on the best-performing combination, firsocostat plus cilofexor.

At 48 weeks, the proportions of people with at least a one-stage improvement in fibrosis without worsening NASH were as follows:

• firsocostat monotherapy: 12%
• cilofexor monotherapy: 12%
• selonsertib/firsocostat: 15%
• selonsertib/cilofexor: 19%
• firsocostat/cilofexor: 21%
• placebo: 11%

The likelihood of progression to cirrhosis was lower in all treatment groups (15%, 20%, 15%, 8%, and 23%, respectively) compared with the placebo group (41%).

NASH resolution without worsening fibrosis was uncommon in all treatment groups. No one in the cilofexor monotherapy or placebo group achieved this endpoint, rising 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 were most likely to see at least a 2-point reduction in NAFLD activity score (35% vs 9-29% across the other arms) and at least one grade of improvement in components of that score:

• steatosis (fat accumulation): 26% vs 6-29%
• lobular inflammation: 57% vs 21-38%
• ballooning of hepatocytes: 29% vs 13-24%

When fibrosis and bile duct proliferation were assessed using a machine learning algorithm, firsocostat/cilofexor led to significantly greater improvements than the placebo. Firsocostat monotherapy also performed well on fibrosis measures while cilofexor monotherapy did well on the bile duct measure.

Fibroscan liver stiffness scores and enhanced liver function (ELF) scores declined most in the firsocostat monotherapy arm. For liver stiffness, 55% of firsocostat recipients, 45% of firsocostat/cilofexor recipients and 38% of cilofexor recipients were classified as responders, compared with 20% in the placebo group. For ELF scores, the corresponding proportions were 44%, 31%, 24% and 19%.

Participants who received firsocostat/cilofexor also had significant reductions in biomarkers of liver injury, inflammation and liver function, including ALT and AST liver enzymes, bilirubin, total bile acids and CK18 protein fragments, while those taking either drug alone saw smaller reductions.

Finally, people who received firsocostat/cilofexor had significantly greater reductions in body weight and insulin levels and greater improvement in kidney function compared with the placebo group.

All treatments were generally safe and well tolerated. Severe (grade 3 or 4) drug-related adverse events were uncommon, seen in just two people (3%) in the firsocostat/cilofexor arm, one (1%) in the selonsertib/cilofexor arm and none in the other groups. Three people (4%) taking firsocostat/cilofexor discontinued treatment due to adverse events, similar to the rates in the other treatment arms.

The most common adverse event overall was pruritus, or itching, which can be a symptom of cirrhosis itself. This was most common in the selonsertib/cilofexor groups (29%) and the firsocostat/cilofexor group (28%); pruritus rates were 18-20% in the other treatment arms and 15% in the placebo group.

Triglyceride levels rose in all treatment groups while there was no change in the placebo arm. The largest changes were seen in the firsocostat/cilofexor and firsocostat monotherapy arms (44 and 42 mg/dl). However, none of the groups had a significant increase in harmful LDL cholesterol. Both pruritus and triglyceride increases were considered "manageable," according to the researchers.

Although it has been difficult for experimental therapies to meet the endpoint of fibrosis improvement without worsening NASH, they do lead to beneficial changes in 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 – in particular firsocostat/cilofexor – are warranted, Prof. Loomba said.