Novel fatty acid synthase inhibitor for NASH makes good in early trial

The small molecule fatty acid synthase (FASN) inhibitor TVB-2640 boasts a win in addressing the three key drivers of nonalcoholic steatohepatitis (NASH)—namely liver fat, fibrosis, and inflammation—in the phase II FASCINATE-1 trial presented during The Liver Meeting Digital Experience of the American Association for the Study of Liver Diseases (AASLD).

“TVB-2640 is an orally bioavailable, first-in-class FASN inhibitor. FASN is a key enzyme in the de novo lipogenesis (DNL) pathway that is responsible for the synthesis of excess fat and activation of fibrogenic and inflammatory mechanisms in the liver of patients with NASH,” said presenting author Dr Rohit Loomba from the University of California, San Diego in the US.

“The potent liver fat reduction, measured by an advanced magnetic resonance imaging (MRI) method called MRI-derived proton density fat fraction (PDFF), combined with the additional biomarkers demonstrates that TVB-2640 is positively impacting multiple pathological mechanisms causing liver damage in NASH patients,” Loomba continued.

He pointed out that MRI-PDFF response was an accurate and reliable biomarker, which was indicative of histological response and also had been shown to predict NASH resolution.

FASCINATE-1 randomized 99 patients to receive placebo or TVB‐2640 at 25 or 50 mg once daily for 12 weeks. Most patients had type 2 diabetes, and the mean liver fat content at baseline according to PDFF was 16.7 percent. All patients had evidence of liver fibrosis (magnetic resonance elastography [MRE] ≥2.5 kPa or liver biopsy F1‐F3)­. 

TVB‐2640 demonstrated a clear dose‐dependent effect on liver fat. Week-12 data showed a mean reduction of 9.6 percent in the 25-mg group (n=30; p=0.053) and of 28.2 percent in the 50-mg group (n=28; p=0.001) as opposed to a 4.5-percent increase in the placebo group (n=27). [AASLD 2020, abstract 67]

A PDFF response occurred in the majority of patients in the 50-mg group (61 percent vs 11 percent with placebo; p=0.001) and in 23 percent of the 25-mg group.

Patients who received TVB‐2640 also exhibited declines in alanine aminotransferase (ALT) levels, with a 20.4-percent reduction in the 50-mg group (p=0.001) and an even larger decrease in the subgroup of those with baseline ALT greater than the upper limit of normal. There also was a marked drop in low-density lipoprotein (LDL) cholesterol with the 50-mg regimen vs placebo.

Moreover, Loomba and his team noted parallel improvements in serum markers of fibrosis and inflammation. For example, in the 50-mg group, TIMP1 decreased by 18 percent (26-ng/mL reduction; p<0.05 vs placebo) while adiponectin increased by 24 percent (vs 8 percent with placebo).

“A novel marker of DNL, serum tripalmitin, was reduced in TVB‐2640-treated patients compared to placebo, confirming inhibition of FASN,” Loomba added.

The drug was well tolerated, with most adverse events (AEs) being mild in severity. None of the patients developed serious AEs. Treatment did not significantly alter plasma triglycerides, and neither did it induce biochemical or haematologic toxicity. 

“The treatment response seen in TVB-2640 treated subjects in this study along with the additional biomarkers increases our confidence to embark upon a larger phase II liver biopsy-based clinical trial in NASH patients with stage 2–3 fibrosis,” according to Loomba.