A therapeutic being tested for nonalcoholic steatohepatitis (NASH) and liver fibrosis showed statistically significant improvement versus placebo on two primary endpoints in a one-year, Phase 2b trial, developer Sagimet Biosciences announced Monday. 

The pill, denifanstat (TVB-2640), demonstrated a consistent effect for both resolution of subjects’ NASH and fibrosis improvement at the 52-week mark in the study, which involved 168 NASH patients with stage 2 or 3 fibrosis. 

Statistical significance was achieved on multiple secondary endpoints, too, as assessed via liver biopsy and AI-assisted digital pathology.

“We believe these positive results represent a major advancement,” stated Sagimet CEO Dave Happel. Company shares traded at an all-time high following release of the news.

Happel added that the next step for his company involves holding an end-of-Phase 2 meeting with the Food and Drug Administration. After that, Sagimet hopes to start a Phase 3 program in the second half of the year.

Neutralizing NASH

Coming into 2024, NASH has been one of the hottest areas of drug development. 

The disease is caused by an overaccumulation of fat in the liver of those who drink little or no alcohol. This spring could see the approval of a first-ever treatment, Madrigal Pharma’s THR-beta agonist resmetirom, which has a March 14 FDA decision date.

Candidates from multiple other companies are in various stages. 

One is tirzepatide, the dual GLP1/GIP agonist which is the main ingredient in Eli Lilly’s mega blockbusters Mounjaro and Zepbound. The incretin-based therapeutic appears to be achieving both NASH resolution and fibrosis improvement in the drugmaker’s ongoing Phase 2b SYNGERY-NASH trial, which is expected to read out this quarter.

Elsewhere in the mid-stage NASH pipeline, assets include other THR-beta agonists like Terns Pharmaceuticals’ Phase 2a TERN-501 and Viking Therapeutics’ Phase 2b VK2809, as well as FGF-21 analogs such as 89bio’s pegozafermin and Akero Therapeutics’ efruxifermin, both in Phase 2b. 

Akero is also testing its FGF-21 analog in combination with Novo Nordisk’s GLP-1 semaglutide for possible synergistic effects in an ongoing Phase 2 NASH trial.

The breadth and depth of the NASH race is due in large part to the dearth of approved treatments and the large market size. In the U.S., the number of NASH cases is on the rise, expected to grow from 17.3 million cases in 2016 to 27 million by 2030, according to public health data cited by Sagimet. 

In addition, the rate of Americans with F3/F4 fibrosis or advanced liver cancer is likely to outpace that of other countries, growing from 21% of the 2016 NASH population to 29% of cases, a projected increase of 124%, the same projection indicates.

Developing denifanstat 

Sagimet’s once-daily pill is the only FASN inhibitor currently in clinical development for the treatment of NASH with related fibrosis. Its mechanism is designed to lower the three main drivers of NASH — fat accumulation, inflammation and fibrosis — by blocking fatty acid synthesis in the liver and a process called de-novo lipogenesis (DNL).

To assess the drug, the FASCINATE-2 trial looked at its ability to raise the NAFLD activity score (NAS) — a measure of the features of liver steatohepatitis — by two or more points. According to the topline data set, biopsy showed the two-point improvement in the NAS without worsening of fibrosis with denifanstat was statistically superior to placebo, 52% to 20%. 

When researchers looked at NASH resolution plus a two-point NAS improvement, without worsening of fibrosis, they observed a 36% improvement in the denifanstat group versus 13% on placebo. Besides showing a consistent effect for both NASH resolution and fibrosis improvement, the drug was well-tolerated.

“As in previous studies, there were no treatment-related serious adverse events and no deaths in this study,” reported Eduardo Martins, Sagimet’s chief medical officer, on a Monday investor call to review the data. “In short, the safety profile supports the further development of denifanstat in NASH patients.”

Meanwhile, denifanstat is being studied in multiple areas, including acne and solid tumors, both of which are in Phase 1 testing. 

Sagimet went public last July, with its IPO raising $96.4 million of gross proceeds. Cash and equivalents are expected to fund current operations into the first quarter of 2025.