Regeneron’s CIDEBsiRNA reduced liver fat by up to 80% through week 36 after a single dose in adults with MASLD, supporting further clinical development.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
A single subcutaneous dose of Regeneron’s investigational CIDEB siRNA reduced liver fat by up to 80% in adults with metabolic dysfunction-associated steatotic liver disease (MASLD), with reductions sustained through week 36. The first-in-human findings were published in The New England Journal of Medicine on November 8, 2026, and presented at the American Association for the Study of Liver Diseases (AASLD) The Liver Meeting 2026. The results provide early clinical evidence for a genetics-led RNA interference (RNAi) approach targeting hepatic lipid accumulation, although its effects on liver fibrosis and clinical outcomes remain unestablished.
Human Genetics Provides the Therapeutic Rationale
The programme builds on discoveries by the Regeneron Genetics Center, which identified rare genetic variants in CIDEB associated with protection against steatotic liver disease. CIDEB encodes a structural protein involved in hepatic lipid-droplet biology. Individuals carrying protective loss-of-function variants have been associated with lower liver fat and reduced liver disease risk.
CIDEBsiRNA, previously known as ALN-CIDEB, is designed to reproduce this protective effect by reducing hepatic CIDEB messenger RNA expression through RNA interference. Regeneron collaborated with Alnylam Pharmaceuticals to develop the investigational siRNA. Regeneron holds exclusive development and commercialization rights, while Alnylam is eligible for development milestones and tiered royalties of up to 20%.
First-in-Human Study Evaluates Single-Dose Administration
The findings come from Part A of an ongoing randomized, double-blind, placebo-controlled Phase 1/2 study (NCT06836609). The reported analysis included 40 adults with MASLD, randomized 3:1 to receive a single subcutaneous dose of CIDEB siRNA at 15, 60, 200 or 600 mg, or placebo. Participants were followed for 36 weeks.
Safety and tolerability constituted the primary study objective, while changes in liver fat measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and liver injury markers were secondary endpoints.
Liver Fat Reduction Reaches 80% at Week 36
CIDEBsiRNA produced dose-dependent reductions in liver fat, reaching 49% to 72% at week 6 and deepening to 58% to 80% by week 36. These figures represent relative reductions from baseline measured by MRI-PDFF. The placebo group recorded a mean 2.9% decrease at week 36.
62% of CIDEB siRNA recipients achieved liver fat levels below 5%, compared with none in the placebo group. Additionally, 93% experienced at least a 30% reduction in liver fat, a threshold previously associated with histological MASH resolution.
Liver injury markers also improved. Mean alanine aminotransferase (ALT) levels declined across all dose groups, with directionally similar changes in aspartate aminotransferase (AST). These improvements appeared early and persisted through week 36.
Safety Profile and Potential for Less Frequent Dosing
Overall adverse-event rates were similar between CIDEB siRNA and placebo recipients, at 87% and 90%, respectively. Most events were mild or moderate. One severe serious event of hyperglycemia occurred in a treated participant but was not attributed to the study drug; it was subsequently associated with a diagnosis of adult-onset type 1 diabetes.
No participants discontinued treatment, and no nausea or vomiting events were reported in the CIDEB siRNA groups. Although these observations provide an encouraging early tolerability signal, larger studies will be needed to characterize the safety profile.
The persistence of liver-fat reductions through 36 weeks has also raised the possibility of twice-yearly administration. Lead investigator Jörg Täubel identified this as a potential dosing strategy, although the appropriate long-term dosing interval remains to be established.
Regeneron has cited historical trials in which approved MASH therapies achieved mean liver-fat reductions of approximately 47% to 57% at around one year. However, differences in study populations, treatment duration and trial design prevent direct comparisons or conclusions about comparative efficacy.
Phase 2b Study Moves Evaluation Towards Fibrotic MASH
Regeneron has initiated a Phase 2b study (NCT07631637) in approximately 360 patients with biopsy-confirmed F2-F3 fibrotic MASH. The 52-week randomized trial compares two CIDEB siRNA dose levels with placebo.
The primary endpoint is percentage change in liver fat measured by MRI-PDFF at week 52. Key secondary endpoints include MASH resolution without worsening fibrosis and fibrosis improvement without worsening MASH. The company expects final data in 2029.
Clinical Interpretation
The findings establish an encouraging early pharmacodynamic signal for a genetics-guided RNAi approach to metabolic liver disease. The magnitude and durability of liver-fat reduction following a single administration, together with improvements in liver injury markers, support further clinical development.
However, MRI-PDFF reductions do not independently establish MASH resolution, fibrosis regression or reduced liver-related complications. The initial study involved a small MASLD population and was primarily designed to assess safety and tolerability. Its results therefore cannot establish clinical benefit in patients with fibrotic MASH.
The Phase 2b study represents the next important test: whether sustained suppression of hepatic CIDEB translates into histological improvement. Until those findings emerge, the potential for durable disease modification and infrequent dosing remains promising but unproven.
CIDEBsiRNA remains investigational, and its safety and efficacy have not been established by any regulatory authority.
References
CIDEBsiRNA Normalizes Liver Fat and Improves Liver Injury Markers in MASLD Patients, Regeneron Pharmaceuticals, November 8, 2026.
Norton TD, et al. A Liver-Targeted CIDEB siRNA in Adults with MASLD. New England Journal of Medicine. 2026. doi:10.1056/NEJMc2612905
Alnylam Collaborator Regeneron Advances CIDEBsiRNA with Promising First-in-Human Results in Patients with MASLD, Alnylam Pharmaceuticals, November 10, 2026.
A Study to Evaluate ALN-CIDEB in Adult Participants with Metabolic Dysfunction-Associated Steatotic Liver Disease or With Metabolic Dysfunction-Associated Steatohepatitis (MASLD/MASH), ClinicalTrials.gov ID NCT06836609
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.