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Patients with active nonalcoholic steatohepatitis (NASH) who received the investigational oral drug lanifibranor (IVA337) showed greater reduction in disease activity compared to placebo, a randomized phase IIb trial found.

In a three-arm analysis involving nearly 250 patients, 55% of those who received 1,200 mg of lanifibranor for 24 weeks experienced a 2-point decrease on the activity part of the Steatosis, Activity, Fibrosis scoring system (SAF-A) without any worsening of fibrosis, as compared to 33% of those assigned to placebo (risk ratio [RR] 1.7, 95% CI 1.2-2.3, P=0.007), reported Sven Francque, MD, PhD, of Antwerp University Hospital in Belgium, and colleagues.

The group receiving the 1,200 mg dose of lanifibranor -- a pan-PPAR (peroxisome proliferator-activated receptor) agonist -- also had more resolution of NASH without worsening fibrosis versus the placebo group (49% vs 22%, respectively), improvement in at least 1 stage of fibrosis without worsening NASH (48% vs 29%), and a resolution of NASH with improvement in at least 1 stage of fibrosis (35% vs 9%), the group wrote in the .

"As we know by now, fibrosis is the most important predictor for clinical outcomes," said Na Li, MD, PhD, of the Ohio State University Wexner Medical Center in Columbus, who was not involved in this study.

"I'm pleased to see lanifibranor induced significant improvement on fibrosis within 6 months of the study period and such finding makes the agent a very promising treatment for patients with NASH," Li told 番茄社区.

Francque and colleagues noted that "resolution of NASH and regression of fibrosis are currently considered to be likely surrogate outcomes for the prevention of progression to cirrhosis and associated complications."

For the NATIVE () study, the team randomized 247 patients 1:1:1 to receive daily lanifibranor at a dose of 800 mg (n=83) or 1,200 mg (n=83) versus placebo (n=81) over 24 weeks from February 2017 to July 2019. Patients were noncirrhotic adults with severe NASH, who had SAF-A scores of at least a grade 1 with lobular inflammation, confirmed by biopsy. Stage F4 fibrosis patients were excluded.

The primary endpoint assessed a minimum 2-point decrease in SAF-A score (range 0 to 4). Fibrosis regression and NASH resolution were secondary endpoints.

"No drug so far reported positive results on both these endpoints, these are both stringent, high-barrier endpoints (likely to translate in clinical benefit)," Francque told 番茄社区.

He added that this was achieved after only 6 months of treatment compared to a drug like semaglutide (Ozempic) "that only reached the NASH resolution endpoint, but not the stage 1 fibrosis regression endpoint after 18 months of treatment."

In this study, patients had a mean age of 54. About 60% were women, nearly all were white (94%), and the mean BMI was 33. Almost three-quarters had "high disease activity," the authors said. Over three-quarters of patients had significant or advanced fibrosis, and 42% had type 2 diabetes.

Francque highlighted decreased liver enzyme levels and improvements in biomarkers for fibrosis, inflammation, and lipids among the lanifibranor-treated patients.

"There were significant improvements in cardiovascular risk factors, both in patients with and without diabetes, further making the results encouraging for NASH patients," he said.

For the 800-mg lanifibranor group, there was a trend toward improvement versus placebo for the primary endpoint (48% vs 33%, respectively; RR 1.5, 95% CI 1.0-2.1, P=0.07).

Adverse events (AEs) in the lanifibranor groups were mild to moderate, with nausea, diarrhea, peripheral edema, anemia, and weight gain occurring more frequently. Three patients from each group had serious AE.

No kidney or bone effects were reported. Four patients in the lanifibranor groups had peripheral edema related to the study drug.

"Those receiving lanifibranor had an increased risk of several side effects, including gastrointestinal side effects, which could become problematic, especially if patients are expected to use the medication long-term," said Michelle Long, MD, of Boston Medical Center, who was not involved with the research.

"While these results are exciting and encouraging, especially for a disease with no approved therapies, we await phase III studies," she told 番茄社区.

Li added that medication-induced anemia was improved by an iron supplement, which suggests a clinical concern of possible gastrointestinal bleeding.

Francque said a large phase III trial has already started; drugmaker Inventiva Pharma has received FDA for a possible approval of lanifibranor in NASH.

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