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).
Abnormal fat deposits in the liver.
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
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.