Mixed results for experimental therapies for NASH

The recent International Liver Congress in Paris featured several presentations on investigational therapies for fatty liver disease. Drugs with a range of different mechanisms – including the thyroid hormone receptor agonist MGL-3196, the fibroblast growth factor analogue NGM282 and the acetyl-CoA carboxylase inhibitor GS-0976 – demonstrated promising activity in mid-stage clinical trials.

Now that direct-acting antivirals can cure more than 95% of people with hepatitis C and experts in some countries are discussing its elimination as a public health threat, fatty liver disease is responsible for a growing share of advanced liver disease – and is getting a rising amount of attention at liver conferences.

Non-alcoholic fatty liver disease (NAFLD) and its more severe form, non-alcoholic steatohepatitis (NASH) are often associated with obesity and the metabolic syndrome. The build-up of fat in the liver triggers inflammation and development of scar tissue (fibrosis), which over time can lead to cirrhosis, liver cancer and the need for a liver transplant. To date there are no good treatments for fatty liver disease and its management relies on lifestyle changes such as weight loss.

Stephen Harrison of Oxford University presented findings from a study of MGL-3196, a selective thyroid hormone receptor-beta (THR-beta) agonist being developed by Madrigal Pharmaceuticals.

Thyroid hormones play an important role in metabolism, and agents that increase the activity of THR-beta can lower cholesterol and triglyceride levels and reduce liver fat by breaking down fatty acids. Preclinical studies showed that MGL-3196 lowers lipid levels without detrimental effects on THA-alfa activity (such as increased heart rate and bone loss).

This phase II study of 125 people with NASH compared MGL-3196 versus a placebo. Just over half were men, most were white and the average age was about 50 years. They were representative of the NASH population, including people with diabetes and those taking statins.

The MGL-3196 group started at a dose of 80mg per day, which could be raised to 100mg day at week 4. Treatment lasted for 12 weeks, with follow-up ongoing to week 36.

Participants underwent repeated MRI-PDFF (magnetic resonance imaging estimation of proton density fat fraction), an imaging method for assessing liver fat. Liver biopsies were done at the start of the study and at week 36.

After 12 weeks of treatment, liver fat content according to MRI-PDFF declined from baseline by -10% in the placebo group, by -36% in the MGL-3196 group overall and by -42% in high-dose MGL-3196 recipients. Absolute fat decreases showed a similar pattern. Looking at the proportional decrease, 18%, 60% and 75%, respectively, saw a 30% or greater reduction. Liver fat decreased in people with both minimal (F0-F1) and substantial (F2-F3) fibrosis. Liver enzymes (ALT and AST) and fibrosis biomarkers also fell in the MGL-3196 group. All these declines were significantly greater with MGL-3196 compared to placebo.

MGL-3196 appeared safe and well tolerated, with mostly mild adverse events that were similar in the MGL-3196 and placebo groups. The three reported serious adverse events were not considered drug-related. No changes in heart rate or vital signs were seen.

MGL-3196 recipients had decreased blood pressure and lower lipid levels, suggesting it may also have cardiovascular benefits – important because cardiovascular disease is the most common cause of death for people with NASH, Harrison noted.

On 31 May, Madrigal announced the results of the 36-week follow-up liver biopsies, showing that significantly more MGL-3196 recipients compared with placebo recipients had a two-point reduction in NAFLD activity score (57% vs 32%). Among those with at least a 30% MRI-PDFF liver fat reduction at 12 weeks, 39% achieved NASH resolution.

Harrison also reported results from a study of NGM282, an engineered analogue of human fibroblast growth factor 19 (FGF19) being developed by NGM Bio. NGM282 targets multiple processes involved in the development of NASH, leading to improvements in steatohepatitis and fibrosis. A previous phase II trial showed that NGM282 produced rapid liver fat reduction according to MRI-PDFF.

This phase II trial compared paired liver biopsy results in 19 people with NASH treated with daily 3mg injections of NGM282 for 12 weeks. Three-quarters were men, the average age was 51 years, 53% had advanced (F3) fibrosis and a third had diabetes.

Again, NGM282 was associated with significant relative (-67%) and absolute (-11%) decreases in liver fat content according to MRI-PDFF at week 12. All participants had at least a 30% relative and 5% absolute fat reduction, Harrison reported. Nearly two-thirds saw their liver fat content normalize, or fall below 5%. Liver enzyme and fibrosis biomarkers also dropped significantly. All these changes were apparent by week 6.

These improvements in non-invasive markers correlated with changes in liver histology. Repeat liver biopsies at week 12 showed that 84% of people had an improvement in NAFLD activity score, 74% had improved steatosis, 53% had reduced 'ballooning' of liver cells and 42% had reduced liver inflammation. Looking at fibrosis, 42% demonstrated improvement of at least one stage, 47% stayed the same and 11% worsened. Three people had a two-stage improvement, from F3 to F1.

NGM282 had favourable safety and tolerability, with the most common side-effect being mild diarrhoea. NGM282 can cause an increase in LDL cholesterol. In this study, LDL levels returned to baseline or below 100 mg/dl after people started treatment with rosuvastatin, if needed.

“It is unprecedented to see such profound histological improvement in well-established NASH after only twelve weeks of treatment, confirming that NGM282 is potently impacting many clinical dimensions of the disease,” Harrison said in a NGM Bio press release.

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

Harrison, again, presented findings from a proof-of-concept study evaluating combinations of three experimental drugs from Gilead Sciences: the apoptosis signal-regulating kinase 1 (ASK1) inhibitor selonsertib (formerly GS-4997), the acetyl-CoA carboxylase (ACC) inhibitor GS-0976 and the selective non-steroidal farnesoid X receptor (FXR) agonist GS-9674.

ASK1 promotes inflammation and fibrosis, ACC is involved in de novo lipogenesis (conversion of carbohydrates into fatty acids in the liver) and FXR regulates bile acid synthesis and plays a role in lipid metabolism.

An earlier phase 2 trial showed that up to 43% of people with NASH taking selonsertib saw at least a one-stage reduction in liver fibrosis and up to 26% had at least a 30% reduction in liver fat according to MRI-PDFF. Another study, presented at last year's AASLD Liver Meeting, showed that GS-0976 led to significant decreases in liver fat accumulation and improved fibrosis in people with NASH.

The present analysis included 70 people with NASH and stage F2-F3 fibrosis. Two-thirds were women and the median age was about 55 years.

Participants were randomly assigned to receive either selonsertib, GS-0976, GS-9674, selonsertib plus GS-0976, or selonsertib plus GS-9674, all once daily for 12 weeks. (Harrison did not report results from a triple therapy arm using all three drugs.)

The best results were seen in people treated with GS-0976. De novo lipogenesis declined significantly in the groups taking GS-0976 alone or with selonsertib. Those taking selonsertib plus GS-0976 showed the greatest decrease in lumican fractional synthesis rate, a marker of fibrosis.

Relative declines in liver fat content according to MRI-PDFF were -43% in the GS-0976 monotherapy arm, -32% in the selonsertib plus GS-0976 arm, -16% in the GS-9674 monotherapy arm and -9% in the selonsertib plus GS-9674 arm. However, fat content rose by 7% in those taking selonsertib alone. Seventy per cent of GS-0976 monotherapy recipients and 50% of those taking selonsertib plus GS-0976 saw their liver fat decrease by at least 30%.

ALT levels fell in the groups taking GS-0976 (alone or in combination) or GS-9674 monotherapy. GS-9674 (alone or in combination) led to declines in another liver enzyme, GGT.

All regimens were generally safe and well tolerated. There were only two serious adverse events, neither of which appeared treatment-related. Three people taking GS-0976 had severe triglyceride elevations.

Based on these findings, Gilead has initiated a phase IIb study of selonsertib with the ACC inhibitor and the FXR agonist, the company said in a press release. The phase III STELLAR-3 and STELLAR-4 trials are currently evaluating selonsertib monotherapy. A preclinical study presented at the conference showed that GS-0976 plus GS-9674 showed better activity than either drug alone in mice and rats.

As previously reported, another drug in the fatty liver disease pipeline, cenicriviroc, continues to show anti-fibrosis activity in people with NASH after two years of follow-up. Cenicriviroc is also being studied in combination with an FXR agonist from Novartis.

"Patients with advanced fibrosis due to NASH urgently need effective therapeutic options because they may face more serious health risks, including development of complications of end-stage liver disease, liver cancer and the need for liver transplantation," Harrison said in the Gilead press release. "Combination therapy may be a way forward to achieving greater benefit for this patient population."