Studies from NATIVE and NASH Clinical Research Network researchers take on better Tx, improved prognostics

A pair of trials published side-by-side in The New England Journal of Medicine aim to improve management and outcomes in nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD).

In the NATIVE study, lanifibranor—an investigational agent—was found to be effective and safe in patients with noncirrhotic, highly active NASH, and in the second study, researchers from the NASH Clinical Research Network found that patients with NAFLD and stages F3 and F4 fibrosis were at increased risk of liver-related complications and death.

Lanifibranor is a first-in-class pan peroxisome proliferator-activated receptor (pan-PPAR) agonist. In preclinical trials, it not only reduced liver fibrosis and inflammatory gene expression but also improved insulin sensitivity and macrophage activation better than single or dual PPAR agonists.

The nuclear receptors known as PPARs play key roles in not only metabolic regulation, but in regulating inflammation and fibrogenesis as well, explained lead author Sven M. Francque, MD, PhD, of Antwerp University Hospital and the Faculty of Medicine and Health Sciences, University of Antwerp, Belgium.

In an interview with BreakingMED, Francque explained the impetus behind this study of lanifibranor. “There is the whole context of NASH, for which we still have no good treatments, despite the fact that it is clearly a slowly progressive disease that will end up with a substantial number of liver-related complications in this patient population. There is an unmet need for the treatment of NASH, especially in patients with more active steatohepatitis, who are also the ones who will develop fibrosis and will go on to these endpoints,” he said.

“This drug, because of its mode of action in preclinical data, seemed a good candidate to me to be of potential interest… It was this context and then the specific mode of action of the drug that made it promising, because it tackles the metabolic drivers of the disease and also tackles the processes of damage and inflammation. So, it is kind of a combined approach,” he added.

For their phase IIb, double-blind, randomized, placebo-controlled trial, Francque and colleagues randomized patients with noncirrhotic, highly active NASH to treatment with lanifibranor (1,200 or 800 mg) or placebo once daily for 24 weeks. In all, 42% of patients had type 2 diabetes and 76% had moderate or advanced fibrosis.

The primary endpoint of the study was a decrease of ≥2 points in Steatosis, Activity, Fibrosis activity (SAF-A) score without worsening of fibrosis, and secondary endpoints included NASH resolution and fibrosis regression.

Significantly more patients treated with the 1,200-mg dosage of lanifibranor demonstrated decreases of at least 2 points in SAF-A scores without fibrosis worsening compared with those treated with placebo (55% versus 33%, respectively; P=0.007), but this was not true in those treated with the 800-mg dose (48% versus 33%; P=0.07).

Compared with placebo, more patients treated with both doses of lanifibranor experienced the following:

  • NASH resolution without worsening of fibrosis compared with placebo (49% for 1,200-mg and 39% for 800-mg doses versus 29% for placebo).
  • Fibrosis stage improvement of at least 1 without NASH worsening (48% and 34% versus 29%, respectively).
  • NASH resolution plus improved fibrosis stage of at least 1 (35% and 25% versus 9%).

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

“If you look at the primary endpoint, there was a trend for efficacy with the 800-mg dose. If you look, however, at the secondary endpoints, they were also positive for the 800-mg treatment. So, there is a subgroup of patients in whom 800 mg will most likely be enough. The trial was not big enough to well delineate [for] which patients 800 mg is enough, and which patients need 1,200 mg; therefore, we need a larger trial,” noted Francque.

Discontinuation rates due to adverse events were less than 5% and were similar across all groups. Patients treated with lanifibranor were more likely to experience diarrhea, nausea, peripheral edema, anemia, and weight gain than those treated with placebo.

Francque explained that both the FDA and the European EMA define efficacy of treatments for NASH by “resolution of NASH or regression of fibrosis, or, ideally, a combination of both” on biopsy.

“This is the first drug that is positive on both these endpoints, which makes sense because a drug that improves liver inflammation should also improve the scar tissue. This is the first drug that is positive on both these endpoints, which is an argument that it is a sufficiently powerful drug to achieve real benefit,” he told BreakingMED.

Also important are the time frame and safety results of the study, Francque added.

“And this result was achieved in only 6 months’ time. With some other drugs that have reported positive on either steatohepatitis resolution or fibrosis regression, the treatment period was 1.5 years. This result was achieved in only 6 months. And with a good safety profile; that’s also an important element. [Lanifibranor] has promising results in terms of efficacy and is not counterbalanced by problems,” Francque concluded.

In the second study, Arun J. Sanyal, MD, of the Virginia Commonwealth University School of Medicine, Richmond, and colleagues from the NASH Clinical Research Network, assessed the incidence of death and other outcomes across the full histologic spectrum of NAFLD in patients enrolled in the Nonalcoholic Fatty Liver Disease (AFLD) Database-2 noninterventional registry and the FLINT trial.

They classified 1,773 patients with NAFLD according to stage of fibrosis, with stages F0-F2 defined as no, mild, or moderate fibrosis; stage F3 as bridging fibrosis; and stage F4 as cirrhosis. Mean age of these patients was 52 years, 64% were women, 85% were of White and European ancestry, and 12% were Hispanic.

Most (55%) had definite steatohepatitis, 20% had borderline steatohepatitis, and 25% had fatty liver without NASH. Thirty percent of patients had stage F3 or F4 fibrosis, as assessed by the NASH CRN staging system. Comorbidities included hypertension (61%), diabetes (42%), chronic kidney disease (6%), and prior nonhepatic primary cancer (10%).

During a median follow-up of 4 years, 3% of patients died (0.57 per 100 person-years), and 37 patients had a new-onset decompensation event.

Sanyal and fellow researchers found that all-cause mortality increased with increasing stages of fibrosis, from 0.32 deaths per 100 person-years in those with stage F0-F2, to 0.89 deaths per 100 person-years for stage F3, to 1.76 deaths per 100 person-years for stage F4.

Similarly, the incidence of liver-related complications increased with increasing fibrosis stage:

  • Variceal hemorrhage: F0 to F2: 0.00; F3: 0.06; F4: 070.
  • Ascites: 0.04 versus 0.52 versus 1.20, respectively.
  • Encephalopathy: 0.02 versus 0.75 versus 2.39.
  • Hepatocellular cancer: 0.04 vs 0.34 vs 0.14.

In addition, the incidence of any of these hepatic decompensation events was associated with an increase in all-cause mortality after adjusting for age, sex, race, diabetes status, and baseline histologic severity (adjusted HR: 6.8; 95% CI: 2.2-21.3).

Patients with stage 4 fibrosis had a higher incidence of type 2 diabetes compared with those with stage F0 to F2 fibrosis (7.53 vs 4.45 events per 100 person-years, respectively) , as well as a higher incidence of decreases of >40% in estimated glomerular filtration rate (2.98 vs 0.97 events per 100 person-years). The incidence of cardiac events and nonhepatic cancers were similar across all stages of fibrosis.

“The availability of new therapies that are effective in ameliorating the histologic features in NASH, as shown by Francque et al, represents an invaluable opportunity. The challenge, as gleaned by Sanyal et al., is in improving definitions of the patient population, outcomes, and clinical trial design that would prove that these therapies improve clinical outcomes,” wrote Guadalupe Garcia-Tsao, MD, of Yale University School of Medicine, New Haven, and the Digestive Diseases Section, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut, in her accompanying editorial.

Limitations of the study from Sanyal et al include the limited generalizability of results.

  1. Treatment with lanifibranor in patients with active NASH decreased Steatosis, Activity, Fibrosis activity (SAFA-A) scores without worsening fibrosis.

  2. In patients with NAFLD, stages F3 and F4 fibrosis were associated with increased risk for liver-related complications and death.

Liz Meszaros, Deputy Managing Editor, BreakingMED™

The NATIVE trial was supported by Inventiva Pharma.

Francque disclosed financial agreeements with Abbvie, Actelion Pharmaceuticals, Aligos, Allergan, Bayer, Bristol-Myers Squibb, Coherus, Dr. Falk Pharma, Enyo, Galapagos, Galmed, Genentec, Genfit, Gilead Sciences, GympsBio, Intercept Pharmaceuticals, Inc., Inventiva, Johnson & Johnson Health Care Systems, Inc., Julius Clinical, Madrigal, Medimmune, Medvision, Merck, NGM Bio, Novo Nordisk, Novartis Pharma, Promethera Biosciences, Roche, and Supersonic.

The NASH Clinical Research Group Study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

Sanyal disclosed consulting or grant agreements with B9Bio, Albireo, Allergen, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Echosens North America, Inc., Eli Lilly and Company, Exhalens, Genentech, Genfit, Gilead Sciences, Histoindex, Intercept Pharmaceuticals, Inc., Inventiva, Madrigal, Mallinckrodt LLC., Merck, NGM Biopharmaceuticals, Novartis Pharma, Novo Nordisk, Perspectum, Pfizer, Regeneron Pharmaceuticals, Sanyal Bio, Sequana, Siemens, Sun Pharmaceutical Industries Inc., Terns, Valeant Pharmaceuticals North America LLC, and Zydus.

Garcia-Tsao reports being employed by the New England Journal of Medicine as Associate Editor.

Cat ID: 111

Topic ID: 77,111,730,111,188,192,925