NASH

Fatigue in patients with advanced NASH may increase risk for adverse events

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Worse fatigue at baseline among patients with nonalcohol steatohepatitis-related advanced fibrosis and cirrhosis correlated with a higher risk adverse clinical events, according to published results.

“Although generally considered asymptomatic, almost half of patients with NASH have clinically significant fatigue which, in turn, has a profound negative impact on the overall patient experience,” Zobair M. Younossi, MD, MPH, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, and colleagues wrote in Clinical Gastroenterology and Hepatology. “In this context, ongoing clinical trials aim at finding a drug-based therapy for NASH that may reverse fibrosis and could also potentially improve fatigue. Given that, patient-reported outcome instruments are now commonly included in these trials in order to provide a comprehensive assessment of the impact of the investigational drugs on patients and their experience.”

HGI0522Younossi_Graphic_01

For 2 years, Younossi and colleagues followed 1,679 patients with biopsy-confirmed NASH, of whom 802 had bridging fibrosis (F3) and 877 had compensated cirrhosis (F4). Fatigue was quantified at baseline with the seven-point Chronic Liver Disease Questionnaire (CLDQ)- NASH fatigue domain, in which lower scores indicate worse fatigue. Time to liver-related clinical events, such as progression to histologic cirrhosis or hepatic decompensation in F3 or F4, was assessed with Cox proportional hazard model.

At a median follow-up of 16 months, investigators observed 15% (n = 123) of NASH F3 patients experienced liver-related events, mostly in progression to histologic cirrhosis, and 3.5% (n = 31) of NASH F4 patients experienced hepatic decompensation. Among F3 patients, the mean baseline CLDQ-NASH fatigue score was 4.77, with those who experienced liver-related events reporting lower baseline scores of 4.47 compared with 4.83. Among patients with F4, the mean fatigue score was 4.56, and in those who decompensated, the scores at follow-up were 3.74 compared with 4.59.

After adjusting for confounders, researchers observed a significant correlation between lower fatigue scores and risk for liver-related or decompensation events (adjusted HR = 0.85; 95% CI, 0.74-0.97, per 1 point in fatigue score in F3; aHR = 0.62; 95% CI, 0.48-0.81 in F4).

“This suggests that, in addition to commonly used clinical parameters, presence of clinically significant fatigue can identify NASH patients at risk for adverse events,” the authors wrote. “Since fatigue also negatively impacts patients [health-related quality of life] and work productivity, it adds to the disease burden related to NASH. Given the critical importance of fatigue in NASH, clinical trials of regimens for NASH should not only show improvement of surrogates of clinical endpoints, such as the stage of fibrosis or resolution of NASH, but also improvement in patient-reported endpoints, such as fatigue.”

Multiple Drugs Advance for Fatty Liver Disease

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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. Are the drugs going to have the impact that we expect them to have based on the clinical trial data?

“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?”

Pioglitazone may improve NASH, halt disease progression in type 2 diabetes

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Adults with type 2 diabetes randomly assigned Actos therapy were more likely to experience a reduction in nonalcoholic steatohepatitis activity vs. those assigned a placebo, according to study findings published in Annals of Internal Medicine.

In a single-center, parallel-group study, Kenneth Cusi, MD, FACP, FACE,chief of the division of endocrinology, diabetes and metabolism at the University of Florida in Gainesville and Endocrine Today Editorial Board member, and colleagues analyzed data from 101 patients with prediabetes or type 2 diabetes (confirmed via oral glucose tolerance test) and histologically confirmed nonalcoholic steatohepatitis activity (NASH). After baseline measurements (OGTT, euglycemic insulin clamp, DXA scan and liver biopsy), researchers assigned patients to a 500-kcal deficit diet and then randomly assigned them to 30 mg daily Actos (pioglitazone, Takeda Pharmaceuticals), titrated at 2 months to 45 mg daily (n = 50; mean age, 52 years; 72% men; 28% white; 48% with type 2 diabetes), or placebo (n = 51; mean age, 49 years; 69% men; 22% white; 55% with type 2 diabetes) for 18 months. At 18 months, patients again underwent metabolic measurements and a liver biopsy; those on pioglitazone were asked to continue therapy for another 18 months while participants in the placebo group whose NASH resolved were asked to discontinue use; those with persistent disease were invited to initiate pioglitazone therapy for 18 months.

Kenneth Cusi

Kenneth Cusi

The primary outcome was a reduction of at least two points in the nonalcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis at 18 months.

Within the cohort, 18 patients (nine in each group) withdrew from the study before 18 months after being informed in 2011 about a potential risk for bladder cancer with pioglitazone. An additional four patients in each group withdrew during the open-label phase (months 18 to 36) for similar reasons.

Researchers found that more patients assigned to pioglitazone achieved the primary outcome vs. those assigned placebo (58% vs. 17%; P < .001); more patients in the pioglitazone group also had resolution of NASH vs. placebo (51% vs. 19%; P < .001). Pioglitazone therapy also was associated with improvement in individual histologic scores, including fibrosis score, with progression of any fibrosis during 18 months occurring in 12% of pioglitazone patients vs. 28% of placebo patients (P = .039).

Pioglitazone also reduced hepatic triglyceride content from 19% to 7% vs. 15% to 11% in the placebo group, and improved adipose tissue, hepatic and muscle insulin sensitivity (P < .001 for all). All 18-month metabolic and histologic improvements persisted during 36 months of therapy.

There were no between-group differences for adverse events; weight gain was greater with pioglitazone (2.5 kg).

“This histologic benefit, combined with improvement in the mean fibrosis score, suggests that pioglitazone may alter the natural history of the disease,” the researchers wrote. “Evidence of this was the reduction in fibrosis progression over 18 months in patients treated with pioglitazone compared with those receiving placebo.”

The study results are likely to change management of patients with type 2 diabetes and fatty liver, Cusi told Endocrine Today. Pioglitazone, he said, could potentially become for NASH what metformin is to the treatment of type 2 diabetes.

“Until this study, we lacked definitive long-term treatment evidence of safety and benefit for such patients,” Cusi said in an interview. “This study shows now that if you have type 2 diabetes, or even prediabetes, and you take pioglitazone, more than half [of patients] have resolution of NASH. What this means is that endocrinologists will have to think about whether the patient has a fatty liver or not as they consider their second-line therapy after metformin.

“This really is a big game changer,” Cusi said. “NASH may lead to end-stage liver disease, and is currently the second cause of liver transplantation in the United States. We have a drug that may change the natural history of liver disease, prevent the onset of type 2 diabetes as shown in ACT NOW, and ameliorate the risk for coronary artery disease or that of stroke, as recently shown by Kernan et al this year in the New England Journal of Medicine. The cost of pioglitazone will decrease over time, as it currently has a generic formulation, and its safety profile has been tested for over 15 years with issues such as bladder cancer having been cleared from the study published by Lewis et al in JAMA last year. Now endocrinologists will think about and diagnose NASH more often in daily practice, having a safe and effective treatment option at hand.– by Regina Schaffer

Bariatric surgery yields genetic changes among patients with NAFLD.

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Patients with nonalcoholic fatty liver disease who undergo bariatric surgery may experience DNA-altering effects that can reverse their disease symptoms, according to a recent study.

Researchers evaluated snap-frozen liver biopsies collected from 18 normal controls and 18 healthy obese, 12 obese with steatosis and 15 obese with NASH patients. Follow-up biopsies were performed in seven healthy obese patients, 10 with steatosis and six with NASH at 5 to 9 months after participants had undergone bariatric surgery.

Across the groups, 467 CpG loci were methylated differently at a false discovery threshold of q=.05, with the NASH and normal liver samples as the extreme groups in PCA and heatmap analysis. Nine of 294 genes annotated to these CpGs had 5% or more methylation difference between controls and the NASH group and more than 0.2 log2 change to mRNA expression (P<.05 after correction for multiple testing). These genes code for key enzymes for insulin and insulin-like signaling and intermediate metabolism.

Investigators observed a weak but significant inverse correlation in the changes to DNA methylation between NASH samples and controls before and after bariatric surgery in the CpG loci (P=.004). Methylation was partially reversible at the HOBX1, PRKCZ, SLC38A10 and SECTM1 loci.

Paired analysis before and after surgery indicated 113 sites with different methylation (q=.05), with strong correlations observed between the differences in the control and NASH groups and bariatric surgery (P<2.2 x 10–16). Among the sites, 80 were mapped to 32 gene loci, and researchers noted differential expression of the gene encoding protein-tyrosine phosphatase epsilon before and post-surgery.

Binding sites for TFs GRP20 (P<3.8 x 10–233), SREBP2 (P<3.8 x 10–272), PGC1A (P<1 x 10–300) and ZNF274(P<1 x 10–300) were significantly enriched in the phenotype and bariatric remodeling groups.

“While the presented study is limited … it represents a genome-wide assessment of CpG methylation in NAFLD and its dynamic change induced by the weight loss after bariatric surgery,” the researchers concluded. “Some of the candidate epigenetic driver genes may represent attractive targets for future mechanistic studies and therapeutic inventions.”

Source: Endocrine Today