New NASH therapies show promise in mid-stage studies

Phase II study results presented at the AASLD Liver Meeting this month in Boston show that a number of experimental therapies improve markers of liver health in people with non-alcoholic steatohepatitis (NASH). Larger studies are needed to determine if they offer long-term clinical benefits and whether they might work best in combination regimens.

Non-alcoholic fatty liver disease (NAFLD) and NASH, its more severe form, are responsible for a growing proportion of advanced liver disease. The build-up of fat in the liver triggers inflammation, which over time can lead to fibrosis, cirrhosis and liver cancer. Fatty liver disease is increasingly recognised as a manifestation of the metabolic syndrome, a cluster of conditions that include abdominal obesity, elevated blood glucose and abnormal blood lipids.

There are currently no effective medical therapies for NASH, and management relies on lifestyle changes such as weight loss. In recent years, several NAFLD/NASH drug candidates that appeared promising based on animal research and biomarkers in early human studies were found not to significantly improve fibrosis when tested alone in later-stage clinical trials. Results for two of these, the pan-caspase inhibitor emricasan and the ASK1 inhibitor selonsertib, were reported at the Liver Meeting.

Studies of four newer candidates – MSDC-0602K, tropifexor, licogliflozin and saroglitazar magnesium – were presented as late-breakers at the conference.

MSDC-0602K, from Cirius Therapeutics, is a second-generation insulin-sensitising drug. A medication of the same type, pioglitazone (Actos and generics), is approved for type 2 diabetes, but its use is limited by side effects such as swelling and bone loss. MSDC-0602K has less effect on PPAR-gamma, which is thought to be responsible for these adverse events.

"Insulin resistance is a cause of both diabetes and NAFLD, which lead to increased cardiovascular risk; therefore, a safe compound that increases a body's sensitivity to insulin has the potential to address the underlying pathophysiology of both diseases," Cirius chief medical officer Dr Howard Dittrich said in a company press release.

Dr Stephen Harrison of Pinnacle Clinical Research in Texas presented results from the phase IIb EMMINENCE trial, which included 392 people with biopsy-confirmed NASH and liver fibrosis. Nearly 60% were women and the median age was 57 years. About 40% had mild fibrosis (stage F1), nearly 60% had moderate to advanced fibrosis (stage F2-F3) and just over half had diabetes.

Participants were randomly assigned to receive one of three oral doses of MSDC-0602K (62.5mg, 125mg or 250mg) or a placebo. At 12 weeks they underwent a follow-up liver biopsy.

People treated with the two higher doses of MSDC-0602K experienced significant improvement in glucose metabolism and insulin resistance. They also saw reductions in the liver enzymes ALT, AST, GGT and alkaline phosphatase, which can signal liver damage and inflammation. A third of those taking the highest dose experienced ALT normalisation.

However, the study did not meet its primary endpoint of producing at least a 2-point decrease in NAFLD activity score with no worsening of fibrosis. This occurred in 30%, 30%, 33% and 40% of participants in the placebo, 62.5mg, 125mg and 250mg dose groups, respectively. This difference did not reach the threshold for statistical significance, in part because the response rate in the placebo group was higher than expected. A post-hoc analysis did show that the 250mg dose was significantly more likely than the placebo to lead to NASH resolution with least a 2-point score improvement and no worsening of fibrosis (27% vs 14%, respectively).

MSDC-0602K was generally safe and well tolerated. Overall adverse events and serious adverse events – including side effects such as swelling and bone fractures that are a concern with this drug class – occurred with similar frequency across all groups. However, weight gain was greater in those taking the study drug.

Dr Arun Sanyal of Virginia Commonwealth University School of Medicine presented findings from the phase II FLIGHT-FXR trial of tropifexor, a farnesoid X receptor (FXR) agonist from Novartis. FXR regulates bile acid synthesis and plays a role in lipid metabolism.

This analysis included 152 people with biopsy-confirmed NASH and stage F2-F3 fibrosis. About 65% were women and the mean age was about 55 years. The mean body mass index was about 35 (in the obese range), about 80% had diabetes and the mean hepatic fat fraction was nearly 20%.

Previously reported results showed that 10-90mcg daily of tropifexor reduced inflammation and liver fat. Sanyal presented 12-week interim findings from participants who received 140mcg or 200mcg daily tropifexor or a placebo for 48 weeks.

People taking tropifexor experienced a rapid and sustained decline in ALT levels, which fell by 8.9, 20.1 and 23.6 IU/l in the placebo, 140mcg and 200mcg groups, respectively. The difference between the placebo and higher dose group was statistically significant. GGT levels declined significantly in both dose groups.

Hepatic fat fraction declined by 10%, 17% and 31% in the three groups, with the higher dose again showing a significant benefit over placebo; 20% of people in the 140mcg group and 64% in the 200mcg group saw at least a 30% reduction in liver fat.

Participants in both tropifexor groups experienced significant weight loss. Looking at blood lipids, the drug led to an increase in LDL (bad) cholesterol and a decrease in HDL (good) cholesterol, but no one met the criteria for high LDL or low HDL.

Tropifexor was generally safe and serious adverse events were uncommon. However, about a quarter of those in the 200mcg group reduced their dose or stopped treatment due to adverse events. The most notable side effect was itching (pruritus), reported by 12% in the placebo group, 44% in the 140mcg group and 53% in the 200mcg group; about 5% and 7% in the two tropifexor groups experienced severe itching.

Forthcoming results from liver biopsies to be undertaken at 48 weeks will reveal more about tropifexor's effects on liver health.

Licogliflozin, also from Novartis, is an inhibitor of sodium-glucose co-transporters 1 and 2 (SGLT1/2) that blocks glucose absorption from the gut and reabsorption by the kidneys.

Harrison presented findings from a phase IIa study of 77 people who either had biopsy-confirmed NASH with stage F1-F3 fibrosis or who were overweight and had type 2 diabetes and elevated ALT. More than half were women and the median age was about 50 years. The average body mass index was about 35 and the mean liver fat fraction was about 21%.

Participants were randomly assigned to receive 30mg or 150mg licogliflozin or a placebo for 12 weeks.

ALT levels declined in both licogliflozin groups while remaining stable in the placebo group. At the end of the study, ALT levels were 36% lower in the 30mg group and 43% lower in the 150mg group, with the latter difference being statistically significant. AST and GGT levels declined significantly in both dose groups, as did blood glucose levels as indicated by HbA1c.

Liver fat decreased by an average of -5.28% and -7.02% in the 30mg and 150mg groups, compared with -2.57% in the placebo group. At the end of treatment, 63%, 44% and 19%, respectively, experienced at least a 5% absolute liver fat reduction, while 67%, 40% and 25%, respectively, had at least a 30% relative reduction; these differences were significant for the higher-dose group.

Most biomarkers of liver fibrosis did not change significantly in either licogliflozin dose group overall, but some significant decreases were seen when limiting the analysis to those with more extensive fibrosis at baseline.

Body weight declined significantly in both licogliflozin groups – a loss of -3.88% of baseline body weight in the low-dose group and -4.54% in the high-dose group – while remaining stable in the placebo group. Waist circumference decreased by an average of -2.44cm and -4.02cm in the licogliflozin groups but increased by 1.47cm in the placebo group.

Licogliflozin, too, was generally safe and well tolerated. The most common side effect was diarrhoea, which was about twice as common in the 150mg group compared with the 30mg and placebo groups (77%, 40% and 39%, respectively), but it was mostly mild. One person in each group stopped treatment because of adverse events.

Finally, Dr Samer Gawrieh of Indiana University presented findings from a study of saroglitazar magnesium. This novel non-thiazolidinedione dual PPAR-alpha-gamma agonist, developed by Zydus, induces fatty acid oxidation and reduces triglyceride production in the liver, thereby improving insulin sensitivity and glucose metabolism.

The phase II EVIDENCES IV trial included 106 people diagnosed with NAFLD who had either imaging scans showing fatty liver disease or a biopsy showing NASH or simple steatosis. Participants were randomly assigned to take 1mg, 2mg or 4mg saroglitazar or a placebo for 16 weeks.

At week 16, ALT levels declined by 27%, 33% and 44% in the respective saroglitazar groups while rising by 4% in the placebo group; all three doses showed significant benefit. About 19% in the 1mg group, 17% in the 2mg group and 52% in the 4mg group experienced at least a 50% ALT reduction.

Liver fat content declined by 4% in the 4mg saroglitazar group, though the change was negligible in two lower-dose groups. In this group, 56% experienced a greater than 10% reduction in liver fat, 48% had a greater than 20% reduction and 41% had a greater than 30% reduction. Fasting insulin levels and insulin resistance (HOMA-IR) decreased significantly in the 4mg group. Triglycerides, total cholesterol and LDL levels declined while HDL rose.

Looking at markers of liver fibrosis, APRI and extended liver fibrosis (ELF) scores fell significantly in the 4mg saroglitazar group while rising in the placebo group. Liver stiffness decreased in all saroglitazar groups, but the declines did not reach the threshold for significance. BMI rose in the 2mg and 4mg groups, but again this change was not significant.

Saroglitazar was also well tolerated, and only one person stopped treatment because of an adverse event deemed probably related to treatment (mild skin rash).

Given the number of different biological processes that play a role in the development of fatty liver disease, optimal treatment may involve combining agents that work by different mechanisms.

These four new agents, along with emricasan and selonsertib, produced modest but generally positive effects on biomarkers of metabolism and liver health. Harrison suggested that drugs that do not work well on their own but show positive effects may have potential as components of combination therapy.

Studies of such regimens are now underway. The ELIVATE study, for example, will evaluate licogliflozin plus tropifexor in people with NASH and liver fibrosis. The ATLAS trial is testing selonsertib plus Gilead Science's FXR receptor, cilofexor, and the acetyl-CoA carboxylase inhibitor firsocostat.