Phase II data underscores lanifibranor potential for NASH

In the phase IIb NATIVE* trial, the pan-PPAR** agonist lanifibranor demonstrated histologic benefits for patients with nonalcoholic steatohepatitis (NASH).

“Management of NASH is an unmet clinical need,” said the researchers. “Patients with significant (moderate) or advanced hepatic fibrosis are at increased risk of cirrhosis, which justifies the need for pharmacotherapy in patients with NASH and advanced fibrosis.”

The study comprised 247 patients (mean age 54 years, 58 percent female) with biopsy-proven, noncirrhotic NASH with severe disease activity (mean SAF-A*** score 3.3, 73 percent had NAS^# ≥6 indicating high disease activity). Of these, three-quarters had moderate/advanced fibrosis. Participants were randomized 1:1:1 to receive lanifibranor 1,200 or 800 mg or placebo QD for 24 weeks. [N Engl J Med 2021;385:1547-1558]

At 6 months, compared with the placebo arm, the percentage of participants with a reduction of ≥2 points in the SAF-A score without worsening of fibrosis was significantly higher in the lanifibranor 1,200-mg arm (55 percent vs 33 percent; risk ratio [RR], 1.7; p=0.007), but not in the lanifibranor 800-mg arm (48 percent vs 33 percent; RR, 1.5; p=0.07).

The fraction of patients who achieved NASH resolution without worsening of fibrosis was also greater in the lanifibranor 1,200-mg (49 percent) and 800-mg arms (39 percent) vs the placebo arm (22 percent). Comparisons between the lanifibranor and placebo arms yielded RRs of 2.2 and 1.7 for the respective 1,200- and 800-mg doses.

There were also more lanifibranor vs placebo recipients who had improvement in fibrosis stage of ≥1 without worsening of NASH (48 percent vs 29 percent; RR, 1.7 [lanifibranor 1,200 mg vs placebo] and 34 percent vs 29 percent; RR, 1.2 [lanifibranor 800 mg vs placebo]), and NASH resolution plus improvement in fibrosis stage of ≥1 – a composite secondary endpoint that is unique to this trial (35 percent vs 9 percent; RR, 4.0 and 25 percent vs 9 percent; RR, 2.6, respectively).

“Although regression of fibrosis can be indirectly accomplished with long-term therapy to control disease activity, the combination of therapy to control disease activity and fibrogenesis, the goals of which are reflected in the composite [secondary] endpoint … could have a stronger and faster effect on disease progression,” explained the researchers.

 

Favourable safety

The most common adverse events (AEs) with both lanifibranor doses were diarrhoea (22 percent), fatigue (17 percent), nausea (18 percent), weight gain (18 percent), and peripheral oedema (14 percent).

The researchers attributed the weight gain to improved adipose tissue function, as reflected by the increases in serum adiponectin level with both lanifibranor 1,200 and 800 mg (17.12 and 11.95 μg/ml, respectively). “Lanifibranor induced a histologic improvement despite this weight gain, which could be explained by the role of adipose tissue dysfunction rather than overweight per se in the pathophysiology of NASH, and by a shift from visceral to metabolically healthy subcutaneous adipose tissue, a finding that was noted with other PPARγ agonists.”

Four of the peripheral oedema cases were deemed lanifibranor-related, with one being severe. Nonetheless, the patient with the severe case recovered after drug discontinuation for 12 days, without reoccurrence after treatment resumption.

Overall, most AEs with lanifibranor were mild-to-moderate in severity, and discontinuation rates were low (4 percent and 5 percent in the respective lanifibranor 1,200- and 800-mg arms).

 

Targeting multiple pathways

“The complex pathophysiology of NASH may require targeting multiple pathways rather than a single pathway for successful treatment,” said the researchers. “The ability of lanifibranor to simultaneously improve pathways driving insulin resistance, reduce hepatic inflammation, and improve fibrotic response suggests an effective multitargeted mechanism of action.”

“These findings support further assessment of lanifibranor in phase III trials,” the researchers concluded. Future phase III trials of longer duration with larger cohorts shall provide more in-depth evaluations of the long-term efficacy and safety of lanifibranor in in this setting.

 

An invaluable opportunity

“NASH … has superseded hepatitis C as the main cause of cirrhosis and main reason for liver transplantation,” said Dr Guadalupe Garcia‑Tsao from the Yale University School of Medicine, New Haven, Connecticut, US, in an editorial. [N Engl J Med 2021;385:1615-1617]

“Contrary to hepatitis C [which is] caused by a single aetiologic agent, NASH is a multifactorial, complex metabolic disorder that forms part of a systemic disease. Therefore, finding therapies (other than weight loss), identifying the target population, and defining response to therapy represent important challenges in NASH,” Garcia-Tsao continued.

“The availability of new therapies that are effective in ameliorating the histologic features in NASH as shown [in this trial] represents an invaluable opportunity,” she added.