Why GLP-1 Monoagonism Falls Short in NASH

GLP-1 receptor agonists reduce hepatic lipid accumulation, improve insulin sensitivity, and suppress appetite — but clinical evidence shows that GLP-1 monoagonism alone is insufficient for consistent NASH resolution. Liraglutide, a once-daily GLP-1R agonist, was associated with NASH remission in clinical trials but achieved only 5.5% mean weight loss — meaningfully below the approximately 10% threshold hypothesized for optimal NASH resolution. This single data point, cited across multiple patent backgrounds from Shanghai Benemae Pharmaceutical Corporation and Spitfire Pharma LLC, has become the canonical justification for escalating to dual and triple receptor approaches.

NASH — non-alcoholic steatohepatitis — is characterized by three co-occurring hepatic pathologies: steatosis (lipid accumulation), lobular inflammation, and hepatocyte ballooning with fibrosis. Disease progression is staged F0 through F4, with F3–F4 (bridging fibrosis and cirrhosis) representing the highest-risk patient population and the primary unmet clinical need. The GLP-1 receptor (GLP-1R), expressed on pancreatic β-cells and neurons, activates Gαs-coupled signaling to drive cAMP accumulation, insulin secretion, appetite suppression, and hepatic lipid reduction — making it a logical anchor for NASH therapeutics. However, the disease’s multifactorial nature means that a single receptor axis rarely addresses all pathological drivers simultaneously.

Two structural classes of GLP-1R monoagonists are documented in the retrieved patent dataset. Peptide-based agents — analogues of native GLP-1 — are evidenced at clinical stage, with liraglutide serving as the reference compound. Small molecule oral GLP-1R agonists represent a newer modality: Pfizer holds active Russian patents (2021–2022) on non-peptide heterocyclic GLP-1R agonist compounds suitable for oral administration, while Gilead Sciences holds multiple active Japanese patents and a WO filing on polyheterocyclic carboxy-benzimidazole GLP-1R modulating compounds explicitly described as useful for NASH, obesity, and type 2 diabetes. Gasherbrum Bio, Inc. also holds IL-jurisdiction patents on heterocyclic GLP-1 agonists. The oral administration route addresses a key barrier for existing peptide agents — primarily subcutaneous injection — and may expand patient access if these compounds advance clinically.

According to WHO, NAFLD affects approximately 25% of the global adult population, making the development of effective therapies an urgent public health priority. The scale of unmet need is a direct driver of the patent activity analyzed here.

The GLP-1/Glucagon Dual Agonist Landscape: The Most Crowded Patent Space

GLP-1/glucagon receptor (GLP-1R/GCGR) dual agonism is the most densely populated modality in the retrieved patent dataset, with filings from Hanmi Pharmaceutical, Boehringer Ingelheim, Spitfire Pharma, Merck & Co., AstraZeneca, and Eli Lilly. The core rationale is mechanistically distinct from monoagonism: GCGR co-activation drives hepatic fatty acid oxidation and energy expenditure beyond what GLP-1R alone achieves, providing critical weight loss advantages for NASH patients.

“GCGR co-activation drives hepatic fatty acid oxidation and energy expenditure beyond what GLP-1R alone achieves — and multiple assignees have independently filed IP to capture this advantage in NASH.”

Hanmi Pharmaceutical Co., Ltd. holds the most extensive IP position in this space within the dataset, with filings across JP (2 filings, 2021), AR (2017), CR (2017), and BR (2024) jurisdictions. Their long-acting GLP-1/glucagon receptor dual agonist conjugates incorporate immunoglobulin Fc regions and non-peptidyl polymers to extend half-life — a design explicitly aimed at reducing the weight gain side effects associated with conventional NASH therapeutics. Preclinical data included in Hanmi’s filings demonstrate reduction of hepatic triglycerides and blood cholesterol in high-trans-fat diet-induced obese mouse models.

Boehringer Ingelheim International GmbH filed patents in MX (2022) and BR (2022) on long-acting glucagon analogues with dual GLP-1/glucagon receptor agonist activity, explicitly covering NAFLD, NAFL, NASH, and NAFLD-associated liver fibrosis and cirrhosis as indications. Spitfire Pharma LLC holds IL and WO filings (2021–2022) and an active JP patent (2023) on GLP-1R/GCGR dual agonist peptides (SEQ ID NOS. 1–27) conjugated to non-ionic glycolipid surfactants, with formulation optimized for once-weekly administration. Merck & Co. (MSD) holds a CN filing (2020) on long-acting GCG/GLP-1 receptor co-agonist peptides for NAFLD, NASH, and obesity.

AstraZeneca AB takes a distinct approach, referencing cotadutide — a balanced GLP-1R/GCGR dual agonist peptide — as the incretin-axis partner in a combination strategy with PNPLA3 antisense oligonucleotides. The AstraZeneca filings describe additive efficacy in humanized PNPLA3-I148M knock-in mice on NASH-inducing diets, constituting IND-enabling preclinical evidence for a precision medicine approach to NASH that layers genetic risk stratification onto incretin receptor agonism. Eli Lilly holds an active JP patent noting synergistic effects when a glucagon receptor agonist is combined with GLP-1R or GIP-GLP-1 co-agonists for weight loss and body composition in obesity, NAFLD, and NASH.

Triple-Receptor Strategies and GLP-1/GIP Approaches: Emerging Signals

The triple-receptor approach — simultaneously targeting GCGR, GLP-1R, and GIPR — represents the most mechanistically ambitious strategy in the dataset, and Hanmi Pharmaceutical holds the most explicit filing in this space. Hanmi’s active JP patent (2022) covers compositions containing a glucagon derivative co-administered with tirzepatide, Eli Lilly’s marketed GLP-1/GIP dual agonist, creating a de facto triple-receptor regimen. Preclinical data in the filing demonstrate significantly reduced NAFLD Activity Score (NAS), decreased collagen expression (a fibrosis marker), improved fat mass, improved blood lipids, improved insulin sensitivity, and increased UCP-1 and PGC-1α gene expression in mice — constituting in vivo proof-of-concept for the triple-receptor strategy.

GLP-1/GIP dual agonism is also evidenced as a standalone NASH strategy. Jnana Therapeutics Inc. filed a WO patent (2025) disclosing co-administration of an SLC6A19 inhibitor with a dual GLP-1/GIP agonist for NAFLD/NASH, diabetic nephropathy, and chronic kidney disease. Inventiva filed TW-jurisdiction patents (2025) on combinations of lanifibranor — a pan-PPAR agonist in late-stage clinical development for NASH — with both a GLP-1/GIP dual receptor agonist and a GLP-1/glucagon dual receptor agonist, representing two distinct bispecific complement strategies for liver disease.

A distinct GLP-1/GLP-2 dual agonist modality is also present in the dataset. Zealand Pharma A/S holds an active SG patent (2019) on acylated GLP-1/GLP-2 dual agonists, and OcellusMetagen Co. filed a CN patent (2023) on a bispecific fusion protein containing a GLP-1 analogue fused to an antibody Fc region dimerized with a GLP-2 analogue Fc fusion — designed to address NASH through complementary metabolic and intestinal trophic mechanisms.

As documented by NIH, NASH-related liver disease is projected to become the leading indication for liver transplantation in the United States within the coming decade, underscoring the urgency of developing therapies that address fibrosis — the endpoint most clearly targeted by triple-receptor approaches in the retrieved filings.

Combination Partners: ACC, FASN, PNPLA3, and Beyond

Beyond receptor-level polypharmacology, the dominant patent strategy in the GLP-1 NASH dataset pairs GLP-1R agonists with inhibitors of hepatic metabolic enzymes and genetic risk targets. Pfizer Inc. anchors this space with a geographically broad portfolio covering combinations of a benzodioxol-class GLP-1R agonist with ACC inhibitors, DGAT2 inhibitors, KHK inhibitors, and FXR agonists — filed across JP (2020), CA (2020, 2024), AR (2021), TW (2021), CN (2021), and EP (2025).

The ACC inhibitor described in Pfizer’s filings — 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid — is a selective inhibitor targeting acetyl-CoA carboxylase 1/2, blocking de novo lipogenesis, promoting fatty acid oxidation, suppressing Th17-mediated inflammation, and reducing stellate cell fibrosis. These mechanisms are posited to complement GLP-1R-mediated pathways rather than duplicate them, providing the scientific rationale for combination IP protection.

Sagimet Biosciences Inc. filed WO and TW patents (2025) on FASN inhibitor combined with GLP-1 agonist, with preclinical data showing reduction of AST, ALT, liver triglycerides, cholesterol, steatosis, inflammation, hepatocyte ballooning, and fibrosis — and reversal of established MASH after 44 weeks of high-fat/fructose/cholesterol diet before treatment initiation. This represents an advanced established-disease preclinical model and constitutes the most recently filed NASH-specific GLP-1 combination in the dataset.

AstraZeneca AB holds WO, AU (2024), BR (2024), MX (2024), and US (2025) pending filings on PNPLA3 antisense oligonucleotide combined with a GLP-1R/GCGR agonist. The PNPLA3 I148M variant is a well-characterized genetic risk allele for NASH; AstraZeneca’s use of genetically humanized PNPLA3-I148M mouse model data positions genetic risk stratification as a companion diagnostic concept for this combination. According to EMA guidance on companion diagnostics, this type of biomarker-stratified development approach can support accelerated regulatory pathways for combination therapies in genetically defined patient subpopulations.

Additional combination strategies documented in the dataset include: North Sea Therapeutics and BASF AS filing overlapping JP patents on oxygenated structure-enriched unsaturated fatty acids combined with GLP-1R agonists, ACC inhibitors, and/or FXR agonists — with data from CDAA diet and STAM NASH models demonstrating GLP-1 combination superiority over GLP-1 alone; and Coherus Biosciences filing on combinations of a Formula (I) compound with SGLT-2 inhibitor and/or GLP-1 receptor agonist and/or metformin for NAFLD, describing synergistic effects. Shanghai Yinuo Pharmaceutical Co., Ltd. filed a CN patent (2025) on SSAO inhibitor combined with GLP-1R agonist, noting in the background that resmetirom (MGL-3196), a THR-β agonist, received FDA approval for NASH — the first approved agent in the field, contextualizing the regulatory landscape for NASH therapeutics.

A 2017 paper from Northeast Ohio Medical University retrieved in the dataset identifies bile acid-activated receptors FXR and TGR5 (GPBAR1) as metabolic integrators in NASH progression, providing pathway-level scientific context for the FXR agonist pairings documented in Pfizer’s and North Sea Therapeutics’ filings. The convergence of academic mechanistic work with commercial IP filing strategies reflects the maturity of the FXR axis as a validated NASH target, consistent with broader industry trends tracked by WIPO in its annual reporting on pharmaceutical innovation.

Assignee Landscape and What the Patent Geography Reveals

Patent activity strongly dominates over academic literature in this dataset, with only one standalone academic paper retrieved. The landscape is characterized by large pharmaceutical companies, mid-size biotechs, and an emerging Chinese biopharma tier — each with distinct IP strategies that reflect their underlying drug development assets.

Pfizer Inc. is the single most prolific assignee in this dataset, with at least 7 patent records spanning RU, JP, CA, AR, TW, CN, and EP jurisdictions. Activity is entirely IP-driven, reflecting a broad combination coverage strategy around a benzodioxol-class GLP-1R agonist molecule. Hanmi Pharmaceutical Co., Ltd. is second most prominent, with filings in JP (3 records), AR, CR, and BR, signaling a peptide engineering focus with long-acting Fc-conjugate technology. AstraZeneca AB holds a dual portfolio — PNPLA3 ASO + GLP-1/GCGR agonist combinations (WO, AU, BR, MX, US, TW) and, separately, earlier omega-3 fatty acid + SGLT-2 inhibitor combinations (JP, MX, CN, 2017–2020) — signaling a broad metabolic liver disease IP strategy.

Gilead Sciences, Inc. holds two active JP patents and a WO filing on small molecule GLP-1R modulators (polyheterocyclic and carboxy-benzimidazole scaffolds) with explicit NASH utility, consistent with Gilead’s documented strategic interest in NASH drug development. Sagimet Biosciences Inc. and Inventiva both filed in 2025, representing the newest entrants in the dataset and signaling active combination IP strategy building around their respective clinical assets (FASN inhibitor and lanifibranor, respectively).

Chinese-jurisdiction filers represent an emerging tier: Shanghai Benemae Pharmaceutical Corporation (WO, 2021), Shenzhen Tuwei Anchuang Technology Development Co., Ltd. (CN), OcellusMetagen Co. (CN, 2023), and Shanghai Yinuo Pharmaceutical Co., Ltd. (CN, 2025) collectively document a growing Chinese biopharma presence in GLP-1-NASH IP, predominantly in CN jurisdiction. The geographic concentration of these filings in CN — rather than WO or EP — may reflect domestic market prioritization or early-stage development status. Academic activity is limited in this dataset relative to commercial IP filings, with only one standalone academic paper retrieved (Northeast Ohio Medical University, 2017).

“The 2025 filing cohort — Sagimet Biosciences, Inventiva, Shanghai Yinuo — signals that the GLP-1 NASH combination patent space is still actively expanding, with new entrants building IP around clinical-stage assets as recently as the current year.”

The regulatory context for this patent activity is anchored by the FDA approval of resmetirom (MGL-3196), a THR-β agonist, as the first approved agent for NASH — a milestone noted in a 2025 Chinese patent filing background. This approval establishes a regulatory precedent for NASH drug approval and is likely to accelerate clinical development and IP filing activity across the GLP-1 pipeline. As FDA has signaled through its accelerated approval pathway for NASH, surrogate endpoints including NAS score and fibrosis stage are increasingly accepted for regulatory decision-making — endpoints that appear directly in the preclinical data claims of the Hanmi triple-receptor and Sagimet FASN combination filings reviewed here.