Improving NAFLD and NASH Outcomes Through Novel Drug and Histologic Spectrum Focus

 

According to a recent article from Physician’s Weekly, two trials recently published are showing the results of striving to improve the management and outcomes in nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

Nonalcoholic Fatty Liver Disease (NAFLD)

Nonalcoholic fatty liver disease (NAFLD) is a condition in which there is an excess of fat in the liver that is not associated with the consumption of alcohol. This is an umbrella condition for nonalcoholic steatohepatitis (NASH) and simple fatty liver. 

Symptoms:

Initial symptoms include fatigue and pain in the upper right abdomen. As the condition progresses, symptoms will turn into an enlarged spleen, swelling in the abdomen, enlarged blood vessels, jaundice, and red palms.

There are also complications that come with NAFLD, such as cirrhosis, liver cancer, liver failure, and cardiovascular disease.

Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) is a disease where fat build-up in the liver causes inflammation and liver damage in non-drinkers or people who drink very little. It is not always symptomatic, and it does not always get worse. However, NASH can end up causing scar tissue which prevents the liver from functioning. It mimics the liver disease that affects long-term heavy drinkers.

NASH affects up to 25% of people in the United States. Although it affects those with no risk factors, it is more likely to develop in patients who are diabetic, have high cholesterol, or are obese.

Symptoms:

  • Weakness
  • Fatigue
  • Weight loss
  • Nausea/vomiting
  • Appetite loss
  • Jaundice
  • Itching
  • Mental confusion
  • Abdominal pain
  • Leg/abdomen swelling
  • Spider-like blood vessels

The Studies

There were two trials that were published alongside each other. One study, the NATIVE study, found that the investigational agent lanifibranor was safe and effective for patients diagnosed with noncirrhotic, highly active NASH. The other study (done by researchers from the NASH Clinical Research Network) discovered that patients diagnosed with NAFLD with stages F3 and F4 fibrosis had an increased risk of liver-related complications and even death.

Lanifibranor is a drug which acts upon the peroxisome proliferator-activated receptor. In the preclinical trials for the drug, the results showed that it reduced liver fibrosis and inflammatory gene expression. Furthermore, it improved insulin sensitivity and macrophage activation.

NASH is a slowly progressing disease and it leads to a significant amount of liver-related complications in patients. Currently, NASH has no treatments, which is what sparked researchers to complete these trials. The trial for NASH was a double-blind (which means neither the participants nor the researcher knows which treatment or intervention participants are receiving until the clinical trial is over making them less likely to be biased), randomized, and features placebos as a control. Each patiently either received lanifibranor (1,200 or 800mg doses) or a placebo once a day every day for 24 weeks. It was on a randomized basis that patients received either the medication or the placebo.

The endpoints of the trial were decreasing of points in Steatosis, Activity, Fibrosis activity (SAF-A) score without worsening fibrosis. Other endpoints were NASH resolution and fibrosis regression.

Results

The trial showed that the patients who received the 1,200-mg dose of lanifibranor had decreases in their SAF-A scores without worsening fibrosis. However, those who received the 800-mg dose did not yield the same results. In comparison to the placebos, patients who received lanifibranor at the 1,200-mg dose experienced NASH resolution without worsening fibrosis (49%), had a fibrosis stage improvement of at least one without their NASH worsening (48%), and had NASH resolution and also improved fibrosis stage of at least one (35%).

In both of the doses of the lanifibranor treatment group, patients had decreases in liver enzyme levels and in most of the biomarkers of lipid, inflammation, and fibrosis.

Lanifibranor in the 1,200 mg dosage was more effective overall in this particular trial. However, the 800-mg dose could also be effective in certain groups. This will depend on an individual patient’s needs and would require another, larger trial to evaluate.

The trial had less than 5% of adverse events that caused patients to discontinue the trial. The side effects of lanifibranor include diarrhea, nausea, peripheral edema, anemia, and weight gain.

The second study looked at the incidence of death and other outcomes across the full histologic spectrum of NAFLD in patients who were registered in the AFDL Database. The study looked at 1,773 patients with NAFLD and classified them based on their stage of fibrosis.

55% of patients had steatohepatitis, 20% had borderline steatohepatitis, and 25% had fatty liver without NASH. When looking at patients at the 4-year mark, 3% of patients in the study had died, and 37 patients had a new-onset decompensation event.

Researchers concluded that the mortality rates of patients increased when a patient’s stage of fibrosis increased. For those with stages F0-F2, there were only 0.32 deaths per 100 patients. However, those with stages F4 had a 1.76 deaths per 100 patients. In addition, the study also showed the number of liver-related complications also increased with the increase of the fibrosis stage.

It is important to remember that these studies did have limitations such as limited generalizability of the results.

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