Aldafermin reduces liver fat in phase 2 study

Aldafermin significantly reduced liver fat content and liver damage in a phase 2 study of a 24-week treatment course, Dr Stephen Harrison, Visiting Professor of Hepatology at the University of Oxford, told the Digital International Liver Congress last month.

Aldafermin is being developed as a treatment for non-alcoholic steatohepatitis (NASH), liver damage and inflammation caused by liver fat accumulation (non-alcoholic fatty liver disease, NAFLD).

Aldafermin is an analogue of FGF19 (fibroblast growth factor), a gut hormone that regulates bile acid metabolism and fat storage in the liver. FGF19 levels are lower in people with NAFLD and insulin resistance, while activation of the FGF19 pathway has been shown to lead to improvements in insulin sensitivity and liver fat content (steatosis).

Aldafermin reduces bile acid production, limiting liver injury, and improves insulin sensitivity. It also reduces production of fatty acids and lipids that lead to fat deposition in the liver.

Preliminary studies showed that 12 weeks of treatment with aldafermin reduced liver fat. The phase 2 placebo-controlled trial evaluated the effect of 24 weeks of aldafermin treatment on liver fat content in people with biopsy-proven NASH and stage F3 or F4 fibrosis.

Three cohorts of the phase 2 trial have reported previously on the outcomes of 12-week treatment courses of various doses. The final study cohort, presented at the Digital International Liver Congress, randomised participants to 1mg of aldafermin by subcutaneous injection or placebo injection for 24 weeks.

Liver fat content was assessed by MRI scan at baseline, weeks 6, 12 and 24, and again 6 weeks after completion of treatment. Participants also underwent liver biopsy at baseline and week 24.

The 1mg study cohort recruited 78 participants, randomised 2:1 to aldafermin or placebo. The study population had a median age of 54 years, was evenly balanced between men and women and had a high body mass index (35 kg/m²) and body weight (100kg). Sixty per cent had diabetes.

Liver fat content measured by MRI-PDFF, was 18%, and the NAFLD activity score was 5.7, indicating moderate NAFLD activity. Approximately half the aldafermin group and one-third of the placebo group had F3 fibrosis.

After 24 weeks, liver fat content had fallen by 39% in the aldafermin group (from 18% to 10%) compared to 13% (19% to 15%) in the placebo group. Sixty-eight per cent in the aldafermin group experienced an absolute liver fat reduction of at least 5% compared to 24% in the placebo group (p < 0.001) and 66% in the aldafermin group experienced a reduction of at least 30% compared to 19% in the placebo group (p = 0.004).

Twenty-two per cent of the aldafermin group experienced a fibrosis improvement of at least one stage and a resolution of NASH, defined as reduced inflammation and lack of ballooning of liver cells, compared to none in the placebo group (p = 0.015).

Assessing changes in each component of the NAFLD Activity Score (NAS) (liver fat accumulation, ballooning of liver cells and lobular inflammation), the study found that 62% of the aldafermin group experienced an NAS score reduction of at least two points without any worsening of fibrosis, compared to 9% of the placebo group (p < 0.001).

Aldafermin treatment was also associated with a significant reduction in ALT (liver enzyme associated with inflammation and liver damage). ALT levels fell by an average of 49% in the aldafermin group compared to 6% in the placebo group (p < 0.001).

Study treatment was well tolerated and aldafermin recipients did not report a high rate of any adverse event during the study. One participant in the placebo group withdrew due to a serious adverse event.

The greater duration of aldafermin treatment in this cohort of the phase 2 study was associated with a higher frequency of fibrosis improvement compared to 12-week treatment courses of doses varying from 0.3mg to 6mg. Drug developer NGM Biopharmaceuticals is awaiting results of a study of a 24-week treatment course of a 3mg aldafermin dose to determine if a higher dose should proceed to phase 3 studies.