Although numerous drugs for nonalcoholic steatohepatitis (NASH) have shown positive results in phase 2 clinical trials, the cure might lie in combinations of drugs with different mechanisms, experts say.

In fact, curing NASH might turn out to be as challenging as curing type 2 diabetes, said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.

Unlike hepatitis C, which can be treated with the blockbuster antiviral drugs that have recently proven so effective, NASH is more complicated because there are no effective drugs to treat it.

With the obesity epidemic, NASH is increasingly common, and results from phase 2 trials attracted throngs of conference-goers with questions here at The Liver Meeting 2018.

Some of the results look encouraging, Barritt told Medscape Medical News. “I think they’re clinically significant.”

Phase 2 results have been positive for MGL-3196 (Madrigal Pharmaceuticals), GS-9674 (Gilead Sciences), NGM282 (NGM Bio), arachidyl amido cholanoic acid (Aramchol, Galmed Pharmaceuticals), tropifexor (Novartis), and VK2809 (Viking Therapeutics).

All the drugs reduced liver fat measured with MRI-derived proton density fat fraction (PDFF). The drugs also improved various other measures of the disease, such as NASH Activity Score, fibrosis, and alanine aminotransferase.

These NASH agents add to the four already in phase 3 trials: obeticholic acid (Ocaliva, Intercept Pharmaceuticals), elafibranor (Genfit), selonsertib (Gilead), and cenicriviroc (Tobira Therapeutics).

But no clear winner has emerged from these studies. It’s hard to know how well the biomarkers measured in trials will protect patients from sickness and death, Barritt explained. NASH destroys the liver gradually; most of its victims die from the heart disease or cancer that results from this damage, which takes decades.

“The real test is going to be real-world efficacy,” he said. “Are the drugs going to have the impact that we expect them to have based on the clinical trial data?”

The development of NASH is mostly related to lifestyle factors, such as overeating and lack of exercise, so there is no obvious target for a drug as there is with a virus. As a result, drug makers have focused on various aspects of inflammation, fat accumulation, and scar formation.

Like obeticholic acid, GS-9674 and tropifexor are farnesoid X receptor (FXR) agonists, which help regulate bile acids, carbohydrate and lipid metabolism, and insulin sensitivity. They also play a role in growth and regeneration after liver injury.

MGL-3196 and VK2809 are thyroid hormone-receptor beta agonists designed to mediate the effects of the thyroid hormone on the liver, on low-density-lipoprotein cholesterol, on triglycerides, on fatty liver, and on insulin sensitivity.

Arachidyl amido cholanoic acid inhibits stearoyl CoA desaturase. It has a “dual mode of action on liver fibrosis, downregulation of steatosis, and a direct effect on hepatic stellate cells, the human collagen-producing cells,” according to Galmed Pharmaceuticals.

The potential for all these approaches was evident in the phase 2 results presented. But the most effective treatments might be a combination of drugs that act on different pathways, said Keyur Patel, BM, from Duke University in Durham, North Carolina, who is a GS-9674 investigator.

In a separate phase 2 trial now underway, Gilead is testing the combination of GS-9674 plus selonsertib, a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), plus GS-9676, an acetyl-CoA carboxylase inhibitor, Patel told Medscape Medical News.

A Strong Placebo Effect

Combining the drugs makes sense because the drugs now in phase 3 trials have not shown the potential to cure NASH on their own, according to Jerry Colca, PhD, chief scientific officer of Cirius Therapeutics in Kalamazoo, Michigan. “They have shown minimal effects in phase 2b,” he said.

One of the challenges that researchers have is the strong placebo effect, Colca told Medscape Medical News. Patients in placebo groups typically diet and exercise, which addresses the underlying cause of NASH, and drugs don’t always show much improvement over that.

Cirius is currently conducting a phase 2b study of MSDC-0602K, an insulin sensitizer “designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition,” the company reports.

The effect of MSDC-0602K on NASH might be broader than that of competing drugs because it acts further upstream, Colca noted.

In the phase 2 studies presented, the drugs appear to be well tolerated, although some adverse events, such as pruritus and diarrhea, were reported.

Many of the questions about these drugs might not be addressed until they are already on the market.

“What we don’t know from these trials is what the expected duration of therapy will be,” Barritt said. “Are they drugs for 1 to 3 years to reset the clock while the patient addresses diet and exercise? Or are they going to be lifetime medications?”