Novel siRNA Therapeutic Cuts Liver Fat in MASLD, Early Trial Shows

One dose of a novel small interfering RNA (siRNA) therapy — CIDEB^siRNA (also known as ALN-CIDEB) — led to normal liver fat content and lower alanine aminotransferase (ALT) levels in most patients with metabolic dysfunction-associated steatotic liver disease (MASLD) in a placebo-controlled phase I trial.
Among 40 patients with MASLD, 62% of those randomized to a single subcutaneous shot of one of four doses of CIDEB^siRNA had normalized liver fat (less than 5%) after 36 weeks. Nearly all (93%) reached the 30% relative reduction in liver fat linked to histological improvement in MASLD.
None of the study’s placebo patients reached normalized liver fat levels by 36 weeks, and only 10% saw a 30% relative reduction in liver fat, reported Jörg Täubel, MD, of Richmond Pharmacology in London, at the American Association for the Study of Liver Diseases‘ annual Liver Meeting in Denver.
All four CIDEB^siRNA doses led to greater declines than with placebo in mean liver fat percentages from baseline to 36 weeks:

• 15 mg: -57.8% change
• 60 mg: -59.3% change
• 200 mg: -65.2% change
• 600 mg: -80.3% change
• Placebo: -2.9% change

Mean serum ALT levels among all CIDEB^siRNA patients fell 32% from baseline to week 12, while the placebo group saw a 5% increase. By week 36, those in the 600-mg group saw their ALT levels drop 36.5% from baseline, compared with a 6.6% increase in the placebo group.
Results were simultaneously published in the New England Journal of Medicine.
“We know that if we manage to reduce the amount of fat in the liver, this correlates very favorably with clinical outcomes,” Täubel said in a presentation at the meeting. “What is particularly striking in these results is that we actually normalized liver fat in four out of five participants by week 24.”
Because the results go well beyond a 6-month period, “this lends itself for a therapeutic that only needs to be given once every 6 months or so,” Täubel noted.
Despite the positive results, “this is a first-in-human study,” he cautioned, “so of course the data we can derive are limited.” The trial wasn’t powered for statistical inference, and most study participants didn’t have baseline elevated liver enzyme levels or fibrosis. Lack of those baseline data could limit the study’s generalizability to those with more advanced MASLD, such as patients with metabolic dysfunction-associated steatohepatitis (MASH).

Up to 85 million U.S. adults have MASLD, but no drugs are specifically indicated for the disease. Management includes lifestyle changes such as diet, exercise, and weight loss. An estimated 25% to 30% of those with MASLD will go on to develop MASH, which can lead to liver fibrosis and dysfunction and raise the risk for transplant and hepatocellular carcinoma.
CIDEB^siRNA targets the mRNA coded by liver cells’ CIDEB gene, which helps control the size of liver fat droplets. People with loss-of-function CIDEB gene mutations have lower risks of MASLD, MASH, and cirrhosis.
Participants in the study had MASLD with a body mass index (BMI) of 30-40 and liver fat content of at least 8.5%. Mean patient age was 40.4 years, 78% were male, 58% were white, 30% were Asian, and 25% had type 2 diabetes. Mean BMI was 34.2, mean liver fat measured by MRI proton density fat fraction was 14.3%, and mean serum ALT was 43 U/L.
Treatment-emergent adverse event rates were similar between the CIDEB^siRNA and placebo groups, at 87% and 90%, respectively. Adverse events related to the study drug happened in 10% of the CIDEB^siRNA patients and none of the placebo patients.
The most common adverse event was upper respiratory tract infection, in 20% for both groups. Type 2 diabetes worsened in 10% of both groups, and aspartate aminotransferase levels rose in 7% of the treatment group and 10% of the placebo group.
CIDEB^siRNA has moved into a phase II trial for MASH and a phase III trial for MASLD.