Vonafexor induces improvements in liver fat content, kidney function in NASH

Vonafexor induced a strong reduction in liver fat content and improvements in biochemical and imaging markers of liver inflammation and kidney function, according to a presenter at The Liver Meeting Digital Experience.

“The primary endpoint of hepatic fat decrease was met at week 12 in patients with presumed fibrosis treated with bone effects or 100 mg and 200 mg,” Stephen A. Harrison, MD, medical director at Pinnacle Clinical Research in San Antonio, Texas, said during the presentation.

“There were consistent improvements of the noninvasive fibro inflammatory markers. Potentially there's some clinical benefit found on renal function with [glomerular filtration rate (GFR)] improvement with this mechanism.

“The dual effect seen in the study of both liver function improvement noninvasively and the renal improvement that was seen support further clinical and pathophysiological investigations in this population,” Harrison added.

Vonafexor vs. placebo

Harrison, also honorary chair at the University of Oxford, and colleagues randomly assigned 96 patients with phenotype stage 2 or 3 fibrosis NASH to receive either daily oral placebo (PBO, n = 32) or vonafexor 100 mg (n = 31) or 200 mg (n = 33) for 12 weeks. Patients also had an absolute liver fat content of 10% or greater and liver stiffness by transient elastography 8.5 kPa or greater or previous biopsy-proven NASH.

At week 12 patients given vonafexor saw a statistically significant reduction in absolute liver fat content (–6.3% with 100 mg, –5.5% with 200 mg, and –2.3% with placebo; P < .001). Harrison noted a greater than 5% absolute liver fat content reduction was achieved in 58% of patients in the 100 mg group compared with 22% in the placebo group.

Results showed 50% of vonafexor-treated patients compared with 13% of placebo patients achieved relative liver fat content reduction of 30% or greater. Patients who were treated with vonafexor achieved a significant 26% mean reduction in alanine aminotransferase compared with 13% for placebo. Vonafexor-treated patients achieved a rapid and sustained 42% mean reduction in gamma-glutamyl transferase (P <.001).

Liver, renal improvements

Harrison noted the liver fibro-inflammation marker corrected T1, decreased by 81 msec in patients treated with 100 mg vonafexor vs. 10 msec in the placebo group (P < .001). The vonafexor 100 mg group had a significant mean improvement in estimated GFR [5.6 mL/min/1.73 m²]; whereas the placebo group had a decrease in eGFR [–2.8 mL/min/1.73 m²].

Also, 76% of patients who received vonafexor had an eGFR increase less than 0.1 mL/min/1.73 m² over the 12-week treatment period, whereas 66% of patients who received placebo had a decrease in kidney function. Investigators observed a 34% increase in low density lipid cholesterol (LDL-C). LDL-C levels normalized to 70 mg/dL after statin dose adjustment.

“When we look at body weight and waist circumference, we see both doses having impact on body weight and a reduction in waist circumference relative to placebo at week 12, but no differences between the two doses of vonafexor,” Harrison said.

According to Harrison, 9% of patients discontinued treatment with vonafexor 100 mg due to pruritus. Harrison and colleagues did not report any alanine aminotransferase increases of grade 2 or higher. There were five severe adverse event reports, however they were non-drug related.