icosabutate (NST-4016) / Abbott, NorthSea Therap - LARVOL DELTA

DECREASED SERUM CONCENTRATIONS OF PRO-INFLAMMATORY OXYLIPINS IN MASH PATIENTS TREATED WITH ICOSABUTATE (ICONA STUDY) (AASLD 2025) - P2 | "Treatment with icosabutate for 52 weeks was associated with markedly lower serum concentrations of multiple MASH associated oxylipins, in particular HETEs and oxPLs. These findings in patients confirm hepatic changes observed in pre-clinical MASH models, indicating that icosabutate is potently reducing both enzymatic (LOX/COX/CYP450) and non-enzymatic (oxidative stress) oxidation of PUFAs in MASH patients. Reductions in oxylipins, in particular oxPLs for which a causal role has been established in pre-clinical MASH models, may underlie the improvements in fibrosis observed in patients treated with icosabutate."

Clinical • Fibrosis • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

NorthSea Therapeutics Announces Publication of Positive Results from Phase 2b ICONA Clinical Trial of Icosabutate in Biopsy-Confirmed F1-F3 MASH in Journal of Hepatology (Businesswire) - P2b | N=180 | ICONA (NCT04052516) | Sponsor: NorthSea Therapeutics B.V. | "49.2% (p=0.02 vs placebo) of 600 mg treated patients achieving a ≥1-stage improvement in fibrosis versus 25.7% of placebo treated patients as assessed by qFibrosis (Histoindex). 32.7% (p=0.004 vs placebo) of F3-F4 patients treated with 600 mg icosabutate achieved ≥1-stage improvement in fibrosis without worsening of MASH versus 9.6% of placebo treated patients as assessed by AIM-MASH (Path-AI)...30.8% (p=0.036 vs placebo) and 28.3% (p=0.065 vs placebo) of F2-F3 patients treated with icosabutate 300 and 600 mg respectively achieving a ≥1-stage improvement in fibrosis versus 13% of placebo treated patients. 28.6% (p=0.003 vs placebo) and 21.2% (p=0.013 vs placebo) of Type 2 diabetic patients treated with icosabutate 300 and 600 mg respectively achieving a ≥1-stage improvement in fibrosis versus 0% of placebo treated patients."

P2b data • Metabolic Dysfunction-Associated Steatohepatitis

ICONA: A Phase 2b Study of Icosabutate in Fatty Liver Disease (clinicaltrials.gov) - P2 | N=280 | Completed | Sponsor: NorthSea Therapeutics B.V. | Phase classification: P2b ➔ P2

Phase classification • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

A phase IIb randomised-controlled trial of the FFAR1/FFAR4 agonist icosabutate in MASH. (PubMed, J Hepatol) - P2b | "Although the primary endpoint was not met, treatment with icosabutate demonstrated encouraging fibrosis (as measured by both conventional and AI-assisted digital pathology) and non-invasive biomarker data, supporting further development in MASH patients."

Journal • P2b data • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus

MASH 2B TRIALS- A SYSTEMATIC REVIEW (AASLD 2024) - "These include PPAR agonists, SGLT-2 inhibitors, GLP-1 inhibitors, and the recently approved Resmetirom...The Harmony trial with efruxifermin showed significant fibrosis improvement, while the Enliven trial with pegozafermin also demonstrated significant fibrosis reduction at higher doses...Alpine 2/3 and Alpine 4 trials with aldafermin showed mixed results, with significant fibrosis improvement only in specific doses. The TANDEM trial, comparing Tropifexor and Cenicriviroc, focused on safety and efficacy, showing ALT, AST, and GGT reductions... RCTs in NASH treatment showed mixed outcomes. Lanifibranor and icosabutate showed promise, especially in T2D patients. FGF21 analogues like efruxifermin improved fibrosis, while FGF19 trials had variable results."

Review • Fatigue • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Pain • Solid Tumor • Type 2 Diabetes Mellitus • FGF19 • FGF21

Effects of icosabutate, a dual free fatty acid receptor-1 and -4 agonist, on elevated noninvasive markers of liver injury, fibrosis and glycemic control in type 2 diabetic MASH patients and F1-F3 fibrosis (EASL-ILC 2024) - "Once-daily, oral therapy with 600 mg ICO induces pronounced reductions in multiple elevated markers of liver injury and fibrosis in T2D MASH patients. Furthermore, a simultaneous decrease in ALT and ELF score may help identify histological responders to ICO therapy."

Clinical • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus

ICOSABUTATE IN NASH/MASH WITH FIBROSIS: RESULTS FROM A RANDOMISED, MULTICENTRE, DOUBLE-BLIND, PLACEBO CONTROLLED, PHASE 2b TRIAL (ICONA) (AASLD 2023) - "Icosabutate improves histology, multiple non-invasive markers of liver injury/inflammation/fibrosis, glucose, and lipid metabolism in patients with F1-F3 fibrosis due to NASH/ MASH. The enhanced results in subjects with T2D support further development in this patient population, with potential for attenuation of both liver related and CV outcomes."

Clinical • Late-breaking abstract • P2b data • Diabetes • Fibrosis • Hepatology • Hypoglycemia • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Non-alcoholic Steatohepatitis • Type 2 Diabetes Mellitus • ARRB1 • CRP

[VIRTUAL] Decline in NASH and atherosclerosis-associated oxidised phospholipids and 7-ketocholesterol in response to icosabutate therapy (EASL-ILC-I 2020) - P1 | "Icosabutate effectively reduces pro-inflammatory oxidised lipids in both liver and plasma. Marked decreases in hepatic oxPLs were observed in mice despite icosabutate’s resistance to membrane incorporation whilst decreases in plasma 7-KC exceeded the decreases in plasma LDL-C in humans. These findings support the therapeutic potential of icosabutate for the treatment of both NASH and atherosclerosis via a reduction in pathology-associated oxidised lipids."

Atherosclerosis • Cardiovascular • Dyslipidemia • Hepatology • Non-alcoholic Steatohepatitis

[VIRTUAL] Icosabutate, a novel structurally engineered fatty acid, significantly reduces relevant markers of NASH and fibrosis in 16 weeks: interim analysis results of the ICONA trial (EASL-ILC 2021) - "Treatment of NASH patients with ICO forn16 weeks had a dose-dependent improvement in multiple relevant biologic pathways, with broad and potent effects on markers of liver injury, inflammation and fibrogenesis along with improvements in glycemic control and atherogenic lipids. These data, combined with a favorable safety profile to date, support a potential for impacting liver histology at 52 weeks as well as improving common comorbid conditions seen in NASH patients."

Late-breaking abstract • Cardiovascular • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis • MRI

[VIRTUAL] Icosabutate, a novel structurally engineered fatty acid, significantly reduces relevant markers of NASH and fibrosis in 16 weeks: interim analysis results of the ICONA trial (EASL-ILC 2021) - "Arun Sanyal of the Virginia Commonwealth University, Richmond in the U.S. noted that treatment of NASH patients with ICO for 16 weeks had a dose-dependent improvement in multiple relevant biologic pathways, with broad and potent effects on markers of liver injury, inflammation and fibrogenesis along with improvements in glycemic control and atherogenic lipids. Sanyal concluded that these data, combined with a favourable safety profile to date, support a potential for impacting liver histology at 52 weeks as well as improving common comorbid conditions seen in NASH patients."

Late-breaking abstract • Cardiovascular • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis

[VIRTUAL] Anti-inflammatory and anti-fibrotic effects of icosabutate as mono- or combination therapy with a GLP-1 receptor agonist, a FXR agonist or an ACC inhibitor in a dietary mouse model of progressive fibrosis (EASL-ILC 2021) - P2b | "To assess if additional anti-inflammatory and/or anti- fibrotic effects could be achieved via combination therapy, a comparison of ICOSA, firsocostat [FIR, a liver-targeted acetyl- coenzyme A carboxylase (ACC 1/2) inhibitor], semaglutide [SEMA, an injectable glucagon-like 1 (GLP-1) receptor agonist] or obeticholic acid [OCA, a farnesoid-X receptor agonist] as monotherapy was performed in a choline-deficient, L-amino acid defined high-fat dietary (CDAA-HFD) mouse model. As monotherapy, ICOSA is a more potent anti-inflam- matory/anti-fibrotic compound than SEMA, OCA or FIR in a dietary mouse model of advanced fibrosis. The ability of SEMA to induce weight loss amplified the beneficial effects of ICOSA on inflammation and fibrosis and provides an attractive combination option for the treatment of fibrosing NASH in humans."

Combination therapy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis

A structurally engineered fatty acid, icosabutate, rapidly normalises elevated plasma ALT and gamma-glutamyl transferase (GGT) concentrations in a study population at high risk of NAFLD/NASH (EASL-ILC 2019) - P1, P2; "Oral icosabutate (600mg) rapidly reduces both plasma ALT and GGT within 1-2 weeks, with >80% of subjects achieving normal levels within 12 weeks. Absolute decreases are comparable/superior to those that have been associated with histological responses in NASH intervention trials. An upcoming phase 2b trial with icosabutate will confirm whether reductions in liver enzyme in a study population with a high prevalence of NAFLD/NASH are also predictive of decreases in patients with biopsy confirmed NASH."

Clinical • Late-breaking abstract

ICONA: A Phase 2b Study of Icosabutate in Fatty Liver Disease (clinicaltrials.gov) - P2b | N=280 | Completed | Sponsor: NorthSea Therapeutics B.V. | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Non-alcoholic Steatohepatitis

Icosabutate: targeting metabolic and inflammatory pathways for the treatment of NASH. (PubMed, Expert Opin Investig Drugs) - "Ideally, candidate drugs for NASH and associated liver fibrosis should be pleiotropic in mechanism and work upstream on multiple drivers of NASH, including lipotoxic lipid species, oxidative stress, and key modulators of inflammation, liver cell injury and fibrosis. Icosabutate has demonstrated an ability to target these pathways in preclinical NASH models with interim data from the ICONA trial supporting, at least non-invasively, the clinical translation of the highly promising pre-clinical data."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Liver Failure • Non-alcoholic Steatohepatitis

A structurally engineered fatty acid, icosabutate, suppresses liver inflammation and fibrosis in NASH. (PubMed, J Hepatol) - "Icosabutate avoids hepatocyte accumulation and confers beneficial effects on hepatic oxidative stress, inflammation and fibrosis in mice. In conjunction with reductions in markers of liver injury in hyperlipidemic subjects, the findings suggest that structural engineering of LCn-3FAs offers a novel approach to the treatment of NASH."

Journal • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity

ICONA: A Phase 2b Study of Icosabutate in Fatty Liver Disease (clinicaltrials.gov) - P2b; N=280; Active, not recruiting; Sponsor: NorthSea Therapeutics B.V.; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Hepatology • Non-alcoholic Steatohepatitis • MRI

NorthSea Therapeutics Completes US$80 Million Series C Fundraising to Advance Clinical Programs in Metabolic Disorders (Businesswire) - "NorthSea Therapeutics B.V...today announces the close of a USD 80 million Series C financing round...The proceeds of the fundraising will be used to advance development of NST's pipeline of Structural Engineered Fatty Acids (SEFA) clinical-stage programs in NASH and other metabolic disorders, of which the Company currently has three in the clinic: Icosabutate, NST's lead product, recently completed enrolment of its phase 2b ICONA study in NASH, which reported strong interim results, as presented by NST's acting CMO, Professor Stephen Harrison at the EASL NALFD summit meeting..."

[VIRTUAL] Free Fatty Acid Receptors (FFARs) as Therapeutic Targets for Liver Disease (NASH Summit-US 2021) - "Reviewing the biology of FFARs and their relevance to metabolic liver disease Discussing recent advances in developing fatty acids as treatments for metabolic and liver diseases Presenting the icosabutate clinical program including the interim analysis results from the phase 2b ICONA trial in NASH"

Hepatology • Non-alcoholic Steatohepatitis

Icosabutate Latest Phase 2b Interim Data Show Significant Decreases in NASH and Fibrosis Biomarkers Independent of Fibrosis Stage and Disease Severity (Businesswire) - "Professor Stephen Harrison...said, 'These data demonstrate the potential for icosabutate to have a strong treatment effect across a broad range of patients. Based on preclinical and clinical data generated to date, along with the favorable safety profile, icosabutate has the potential to be the backbone for either mono- or combination therapy in NASH.'"

Media quote

[VIRTUAL] ICOSABUTATE, A NOVEL ORAL FREE FATTY ACID RECEPTOR 4 (FFAR4) AGONIST, SIGNIFICANTLY DECREASES BIOMARKERS OF NASH AND FIBROSIS INDEPENDENT OF DISEASE SEVERITY (AASLD 2021) - "Treatment of NASH patients with ICOSA has a potent dose-dependent improvement in key biomarkers of liver injury, inflammation and fibrogenesis. These data are supportive of a potential impact on liver histology at 52 weeks across a broad range of patients, independent of baseline fibrosis or inflammation. Based on the clinical data generated to date, along with a favorable safety and tolerability profile, ICOSA has the potential to be a backbone for either mono- or combination therapy in NASH ."

Biomarker • Dyslipidemia • Fibrosis • Hepatology • Immunology • Inflammation • Liver Failure • Non-alcoholic Steatohepatitis • CRP • MRI

ICONA: A Phase 2b Study of Icosabutate in Fatty Liver Disease (clinicaltrials.gov) - P2b; N=264; Recruiting; Sponsor: NorthSea Therapeutics B.V.; Trial completion date: Sep 2021 ➔ Jan 2023; Trial primary completion date: Jul 2021 ➔ Oct 2022

Clinical • Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis • MRI

Icosabutate, a novel structurally engineered fatty acid receptor agonist, significantly reduces relevant biomarkers of NASH and fibrosis in 16 weeks: Results of an interim analysis of the phase 2b ICONA trial (EASL-NAFLD 2021) - No abstract available.

Biomarker

Icosabutate reduces relevant markers, fibrosis in NASH (Healio) - "'This drug works on the interface of oxidative stress of which is inflammation fibrosis, and all of those downstream elements did show improvement while the steatosis did not really change,' Sanyal said. 'We are very encouraged by these initial findings, but of course the final proof will come when we have the histology data for the full trial at the end of 1 year.'"

Media quote

Arun Sanyal, EASL 2021: Icosabutate ICONA Trial Interim Analysis - "In Part 2, we speak with Prof. Arun Sanyal...about the interim analysis from the ICONA trial (NCT04052516) which is designed to investigate icosabutate as a potential therapeutic approach to address liver- and cardiovascular-related morbidity and mortality in patients with NASH."

Video

Advances in Nonalcoholic Fatty Liver Disease Unveiled at International Liver Congress (Managed Healthcare Executive) - "Arun Sanyal...noted that treatment of NASH patients with icosabutate for 16 weeks had a dose-dependent improvement in multiple relevant biologic pathways, with broad and potent effects on markers of liver injury, inflammation and fibrogenesis along with improvements in glycemic control and atherogenic lipids. 'Sanyal concluded that these data, combined with a favorable safety profile to date, support a potential for impacting liver histology at 52 weeks as well as improving common comorbid conditions seen in NASH patients,' said a press release from the organizers of the International Liver Congress meeting."

Media quote