Single Dose of CIDEB siRNA Normalizes Liver Fat in MASLD Through 36 Weeks

A single subcutaneous dose of CIDEBsiRNA (ALN-CIDEB), an investigational liver-targeted small interfering RNA (siRNA), reduced liver fat by 58% to 80% at Week 36 in adults with metabolic dysfunction-associated steatotic liver disease (MASLD), according to first-in-human trial results published in The New England Journal of Medicine.1 The data were presented simultaneously in an oral session at AASLD The Liver Meeting 2026, with liver fat normalizing in 62% of recipients.2

Jorg Taubel, MD, of Richmond Pharmacology in London, a co-lead author, discussed the findings in an interview with HCPLive. He noted current MASH therapies, resmetirom and semaglutide 2.4 mg, require ongoing administration and can be poorly tolerated, with the biggest downside being “they have to be given regularly, lifelong.”

How Did a Single Dose of CIDEB siRNA Affect Liver Fat?

CIDEBsiRNA is a GalNAc-conjugated siRNA designed to reduce hepatic expression of CIDEB, a gene in which rare loss-of-function variants have been linked to protection against steatotic liver disease. In an expanded genetic analysis of 1,243,365 participants, carriers of these variants had 22% lower liver fat by MRI proton density fat fraction (MRI-PDFF) and lower odds of MASLD or MASH (OR, 0.57; 95% CI, 0.46-0.71) and MASLD-related cirrhosis (OR, 0.57; 95% CI, 0.40-0.81) than noncarriers.1 Taubel said these findings prompted the hypothesis silencing CIDEB with an siRNA could offer a convenient, infrequently dosed therapy.

In part A of the double-blind, placebo-controlled trial, 40 adults with a body mass index of 30 to 40 and liver fat of at least 8.5% were randomized 3:1 to a single dose of CIDEBsiRNA (15, 60, 200, or 600 mg) or placebo and followed for 36 weeks.1

Mean liver fat reductions ranged from 49% to 72% at Week 6 and from 58% to 80% at Week 36, with similar reductions across dose levels. Overall, 93% (27/29) of recipients with Week 36 data had reductions exceeding 30%, a threshold previously linked to histologic improvement in MASH. Mean ALT levels declined across all doses, with directionally similar changes in AST.1

Is CIDEB siRNA Safe, and What Comes Next?

Adverse events occurred in 87% of CIDEBsiRNA recipients and 90% of placebo recipients, and most were mild or moderate. One serious, severe hyperglycemia event in the 200-mg group was not considered related to treatment; Regeneron reported the participant was later diagnosed with adult-onset type 1 diabetes. No recipients had ALT or AST elevations above 3 times the upper limit of normal, and there were no nausea or vomiting events, deaths, or discontinuations.1,2

“Small interfering RNA medicines are generally very well tolerated,” Taubel said.

He emphasized infrequent dosing may help address adherence challenges with current therapies, which many patients discontinue before deriving benefit. The authors noted the trial was not powered for statistical inference, and most participants did not have elevated liver enzymes or fibrosis at baseline, limiting generalizability to more advanced disease.1

“This has to be borne out in clinical trials, which are ongoing,” Taubel said.

Longer-term safety and histologic outcomes are being evaluated in part B of the trial and a phase 2b trial in MASH (NCT07631637), and Regeneron reported a phase 3 trial is recruiting.1,2

References:

1. Norton TD, Taubel J, Imperato GH, et al. A liver-targeted CIDEB siRNA in adults with MASLD. N Engl J Med. Published online November 8, 2026. doi:10.1056/NEJMc2612905

2. Regeneron Pharmaceuticals. CIDEBsiRNA normalizes liver fat and improves liver injury markers in MASLD patients, as highlighted at AASLD. GlobeNewswire. Published November 8, 2026. Accessed November 8, 2026. https://www.globenewswire.com/news-release/2026/11/08/3398021/0/en/cideb-sirna-normalizes-liver-fat-and-improves-liver-injury-markers-in-masld-patients-as-highlighted-at-aasld.html

3. Brooks A. FDA approves semaglutide (Wegovy) injection 2.4 mg for noncirrhotic MASH. HCPLive. Published August 15, 2025. Accessed November 8, 2026. https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash