Regeneron’s CIDEBsiRNA Phase‑1/2 Trial Shows 24% Liver Fat Drop in NAFLD Patients

Regeneron Pharmaceuticals Reports Promising Phase‑1/2 Results for CIDEBsiRNA, a Liver‑Targeted Therapeutic

Regeneron Pharmaceuticals disclosed the first interim data from a phase‑1/2, double‑blind, placebo‑controlled study evaluating CIDEBsiRNA, a liver‑selective small‑interfering RNA (siRNA) designed to emulate the protective effect of naturally occurring loss‑of‑function variants in the CIDEB gene. The data were presented at the 2026 American Association for the Study of Liver Diseases (AASLD) Annual Meeting and subsequently published in the New England Journal of Medicine.

Scientific Rationale

The CIDEB gene encodes a protein that facilitates the formation of triacylglycerol droplets within hepatocytes, a process that predisposes to hepatic steatosis. Genetic studies have identified rare loss‑of‑function alleles that confer resistance to non‑alcoholic fatty liver disease (NAFLD) and metabolic dysfunction‑associated steatohepatitis (MASH). CIDEBsiRNA exploits this mechanism by delivering a chemically stabilized siRNA conjugated to N-acetylgalactosamine (GalNAc), thereby enabling selective uptake through the asialoglycoprotein receptor on hepatocytes. Upon intracellular entry, the RNA-induced silencing complex (RISC) incorporates the antisense strand, leading to sequence‑specific cleavage of CIDEB mRNA and a consequent reduction in protein expression.

Preclinical data in murine models of diet‑induced steatosis demonstrated a dose‑dependent decrease in hepatic triglyceride content and an attenuation of inflammatory markers. These findings established a clear pharmacodynamic signal that informed the dosing strategy in the human study.

Study Design and Cohort

• Population: 52 adults aged 18–70 with metabolic dysfunction‑associated steatotic liver disease (MASH) confirmed by magnetic resonance imaging–proton density fat fraction (MRI‑PDFF) and elevated alanine aminotransferase (ALT) levels.
• Intervention: A single subcutaneous dose of CIDEBsiRNA (10 mg) or matching placebo administered under blinded conditions.
• Duration: 36 weeks of observation, with primary assessments at baseline, 12, 24, and 36 weeks.
• Endpoints:
• Primary: Change in hepatic fat fraction (% by MRI‑PDFF) from baseline to week 36.
• Secondary: ALT normalization, liver stiffness by transient elastography, and safety endpoints.

Key Efficacy Findings

The magnitude of fat reduction surpassed what has been historically achieved with conventional lifestyle interventions or pharmacologic agents such as obeticholic acid and pioglitazone. Moreover, the majority of CIDEBsiRNA recipients attained hepatic fat content below the clinical threshold for steatosis, suggesting a clinically meaningful response.

Safety Profile

The safety data were reassuring:

• Adverse events (AEs): 15 % in the CIDEBsiRNA group vs. 12 % in placebo. Most AEs were mild or moderate (Grade 1–2), primarily consisting of injection‑site erythema and transient arthralgia.
• Serious adverse events (SAEs): None in either arm.
• Discontinuations: None attributable to AEs.
• Laboratory abnormalities: No clinically significant changes in renal or hematologic parameters.

This safety signal aligns with the known tolerability of GalNAc‑conjugated siRNAs in other therapeutic contexts (e.g., inclisiran, patisiran).

Implications for Dosing and Regulatory Pathways

Regeneron interprets the durable pharmacodynamic effect and favorable safety profile as supportive of a biannual dosing schedule, mirroring the dosing paradigm of approved siRNA therapies. A reduced dosing frequency could enhance patient adherence and streamline post‑approval pharmacovigilance.

From a regulatory standpoint, the data bolster the investigational new drug (IND) dossier for subsequent phase‑2a and phase‑2b studies. The company anticipates engaging the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) early to align on endpoints, particularly imaging‑based quantification of hepatic fat and fibrosis, and to discuss potential for accelerated approval pathways if phase‑3 studies demonstrate sustained benefit.

Next‑Generation Development Pipeline

Regeneron is concurrently pursuing other genetics‑driven candidates for steatotic liver diseases, including:

• SLC27A5‑targeting siRNA: Designed to enhance bile acid synthesis and improve lipid export.
• PNPLA3‑editing CRISPR‑Cas9 therapeutics: Aimed at correcting the risk allele prevalent in diverse populations.

The diversification of the pipeline reflects a strategy to leverage genomic insights across the spectrum of hepatic metabolic disorders.

Investor Engagement and Strategic Outlook

The company will hold a virtual investor event as part of its “Regeneron Roundtable” series, scheduled for the first week of December 2026. The agenda will cover:

• Detailed review of CIDEBsiRNA phase‑2 data projections.
• Updates on cardiometabolic pipeline assets, including GLP‑1 receptor agonist candidates.
• Discussion of potential combination strategies with existing NAFLD therapeutics (e.g., glucagon‑like peptide‑1 analogues).
• Q&A on regulatory strategy and commercial prospects.

Stakeholders are expected to gain insight into the translational roadmap, risk–benefit calculus, and projected timelines for regulatory submission.

Conclusion

Regeneron’s phase‑1/2 data for CIDEBsiRNA provide compelling evidence that a single, subcutaneous dose can produce significant, sustained reductions in hepatic steatosis and liver injury biomarkers with a tolerable safety profile. These findings support a progression to larger, long‑duration trials that will address fibrosis progression and clinical outcomes. While the results are encouraging, the therapeutic remains early in development; confirmation in phase‑3 trials will be essential to substantiate efficacy claims and secure regulatory approval. The forthcoming investor event will serve as a platform to disseminate further progress and refine strategic plans for the steatotic liver disease portfolio.