GPR120

Study results identify NASH patients with Type 2 Diabetes as the key target population for Icosabutate therapy ICONA study assessed the safety, tolerability and efficacy of Icosabutate, a novel, dual FFAR1/FFAR4 (GPR40/GPR120) agonist in NASH patients with F1-F3 fibrosis. An increase in the proportion of patients achieving NASH resolution without worsening in fibrosis and a ≥2-point decrease in NAS was seen in the 600mg Icosabutate treated arm vs placebo (25.8% vs.11.9%, p=0.03), although the less stringent primary endpoint (not including NAS score) did not reach statistical significance in the overall study population. Significant treatment effect in diabetic NASH: In NASH patients with Type 2 diabetes (T2D), 600 mg Icosabutate significantly increased the proportion of patients achieving: NASH resolution without worsening of fibrosis (35.5% vs. 8.7% placebo, p=0.02) NASH resolution without worsening of fibrosis and ≥2-point decrease in NAS (35.5% vs. 4.3% placebo, p=0.007) ≥1-stage fibrosis improvement without worsening of NASH (19.4% vs. 0% placebo, p=0.02) Using AI technology, (qFibrosis, Histoindex) a 31% (p=0.03) treatment effect size was observed for regression of fibrosis stage in T2D patients treated with Icosabutate 600 mg. NorthSea will pursue a registrational development path for Icosabutate for the treatment of NASH patients with T2D. NorthSea to advance two additional clinical Phase 2 SEFA programs, i.e. SEFA-1024 for severe hypertriglyceridemia (SHTG) and SEFA-6179 for the orphan indication IFALD (Intestinal Failure Associated Liver Disease). AMSTERDAM--(BUSINESS WIRE)-- NorthSea Therapeutics B.V. (NST), a biotech company developing novel and innovative strategies for the treatment of non-alcoholic steatohepatitis (NASH) and other metabolic diseases, today announced that the results of the ICONA phase 2b study for the treatment of NASH, will be presented as an oral late-breaker at the AASLD Liver Meeting in Boston on November 13, 2023. The abstract, published today, describes that although the primary endpoint did not reach statistical significance, a significant increase in the proportion of patients achieving a more stringent endpoint, NASH resolution without worsening in fibrosis and a ≥2-point decrease in NAS, was seen in the 600 mg Icosabutate treated arm versus placebo (25.8% vs. 11.9%, p=0.03). A significant treatment effect size (31.2% placebo adjusted, p=0.007) was observed for the same endpoint in T2D patients. Based on the highly favorable response (both histological and non-invasive biomarkers) to therapy in T2D patients, NorthSea will pursue a registrational development path for Icosabutate in NASH patients with T2D. Professor Stephen Harrison, MD, consulting CMO, commented: “The high prevalence of NASH in patients with diabetes is well established. What is less well known is that subjects with both diabetes and NASH have a high prevalence of underlying significant liver fibrosis. Thus, there is a clear need for safe, well tolerated and efficacious therapies in this patient population that target both inflammation and fibrosis. Icosabutate’s mechanism of action, targeting FFAR1 and FFAR4, which regulate insulin secretion, insulin resistance and hepatic inflammation, provide biological rationale for the observed effects in diabetic patients. Overall, these study findings are highly promising with respect to the potential for Icosabutate as a backbone oral therapy for diabetic NASH.” Details of the ICONA Phase 2b data Two hundred and eighty patients were randomized in the ICONA trial, of which 178 per protocol patients met the histologic criteria (F1-3, NAS ≥ 4, ballooning ≥1, inflammation ≥1) based on a 3-member independent panel read. Patients were randomized 1:1:1 to receive once-daily, oral Icosabutate 300mg, Icosabutate 600mg or placebo for 52 weeks. The primary objective was to establish the proportion of patients with NASH resolution without worsening of fibrosis. Secondary objectives evaluated fibrosis improvement, as well as changes in markers of liver injury, inflammation, glycemic control, atherogenic lipids and safety and tolerability of Icosabutate. A subgroup analysis was performed in patients with T2D which comprised ~50% of the total population. The largest treatment effect was observed in patients with T2D, with 35.5% (p=0.007 vs. placebo) of T2D patients treated with Icosabutate 600 mg achieving NASH resolution and ≥2 point decrease in NAS compared to 4% in placebo-treated patients. For fibrosis improvement without worsening in NASH, 28.6% (p=0.005) and 19.4% (p=0.02) of T2D patients achieved a ≥1-stage improvement in the 300mg and 600mg arms respectively, versus none in placebo. A dose response in fibrosis stage regression (qFibrosis) was observed using AI technology (Histoindex) with a treatment effect size (placebo adjusted) in T2D patients of 13.7% (p=0.32) and 31% (p=0.03) in the 300mg and 600mg treatment arms respectively. Icosabutate markedly improved all markers of liver injury, inflammation, fibrosis, glycemic control (placebo corrected ~1% decrease in HbA1c in T2D patients with ≥6.5% at baseline), atherogenic lipids and hsCRP in a dose-dependent manner (Table 1). Both doses of Icosabutate were well tolerated. Change in markers of liver injury, inflammation and fibrosis in T2D patients1 Change from baseline Placebo (n=35) ICO 300mg (n=40) ICO 600mg (n=39) Relative change (%) in ALT -9.6 -33§§§ -42§§§ Relative change (%) in AST -16 -18§ -38§§§ Change in Enhanced Liver Fibrosis (ELF) Score (LS mean) -0.04 -0.06 -0.48§§§ Change in mean in Pro-C3 (ug/L) -2.86 -7.96§§§ -10.24§§§ Change in mean hsCRP (mg/L) 1.4 -1.1 -2.55* Change in HbA1c in T2D patients with ≥6.5% at baseline LS mean change from baseline Placebo (n=27) ICO 300mg (n=27) ICO 600mg (n=26) Change in HbA1c (%) absolute 0.35 -0.75* -0.61* Table 1. *p<0.05; §p<0.05, §§§p<0.001 vs baseline. 1All T2D subjects with baseline and 52 wk biopsies Arun Sanyal, Interim-Chair of the Division of Gastroenterology, Hepatology and Nutrition at VCU/VCU Health, added: “As is implied by the novel nomenclature, MASH (metabolic dysfunction associated steatohepatitis), metabolic dysfunction is an upstream driver of liver disease. The ability of Icosabutate to improve multiple markers of metabolic dysfunction, including insulin resistance, glycemic control, systemic inflammation and oxidative stress, are thus aligned with the improvements in histology and could potentially meet a key unmet need in MASH patients with type 2 diabetes”. Rob de Ree, CEO at NorthSea Therapeutics, said: “The ICONA trial is the first time that patients with NASH have been treated with Icosabutate. The significant improvements shown across both biomarker and histology parameters for patients with type 2 diabetes is important and, in our view, holds great promise. We believe that this data allows us to make a strong argument in favour of further clinical development of Icosabutate in Type 2 diabetes. The findings also validate the potential of targeting FFAR as a therapeutic approach for the treatment of diabetic NASH, either as monotherapy or in combination with other drugs in clinical development. We look forward to advancing Icosabutate as a safe, oral therapy for the treatment of diabetic NASH. In the meantime, we are pushing forward with the development of our other SEFA programmes.” Notes to Editors About NorthSea Therapeutics NorthSea Therapeutics B.V.(NST) is a Dutch biotech company focused on developing structurally engineered fatty acids (‘SEFAs’) for the treatment of NASH and other metabolic disorders. NST licensed the rights to its lead compound icosabutate and a library of SEFAs from Pronova BioPharma Norge AS, who developed Lovaza® (US brand, branded Omacor® in Europe), a blockbuster cardiometabolic drug. Icosabutate has been found safe and well tolerated in two prior phase 2 clinical studies for treatment of hypertriglyceridemia and mixed dyslipidemia and is currently in clinical development for NASH. Two additional SEFAs are in clinical development: SEFA-1024 has been developed for SHTG and now has entered Phase 2a; SEFA-6179, which completed a phase 1 study in Q4-2022, is being developed for the orphan indication IFALD (Intestinal Failure Associated Liver Disease). NST is headquartered in the Netherlands with a presence in Norway and the US and is supported by Ysios Capital, Forbion Growth, Forbion Ventures, Novo Holdings, BGV, NSV, venBio Partners and Sofinnova investments. Find out more about us online at: . SEFA-1024 SEFA-1024 is an oral, highly lipophilic SEFA for the treatment of severe hypertriglyceridemia that is designed to target the gut-liver axis and to concurrently improve plasma lipids and glycemic control. NST has concluded a Phase 1 clinical trial with single and multiple ascending doses and a drug-to-drug interaction study of SEFA-1024 in healthy volunteers with an excellent safety pro encouraging early signs of improvements in atherogenic lipids and lipoproteins. A Phase 2 proof-of-concept study started in H2 2023. SEFA-6179 NST is also developing SEFA-6179 – a novel, oral, fully synthetic medium chain fatty acid analogue – for the treatment of intestinal failure-associated liver disease, (IFALD), an orphan liver disease affecting individuals on prolonged parenteral nutrition. The unique pharmacologic properties of SEFA-6179 facilitate intestinal uptake, which is critical for ensuring optimal drug absorption in patients with intestinal failure and short bowel syndrome and has demonstrated strong anti-inflammatory and anti-cholestatic effect in pre-clinical parenteral nutrition induced liver injury models. A phase 1 single and multiple ascending dose study has been successfully completed. SEFA-6179 has advanced into Phase 2 in H2 2023.

Dive Brief:Novo Nordisk is adding to its recent string of obesity-related dealmaking, announcing Wednesday it has agreed to pay 15 million euros, or about $16 million, to buy Embark Biotech, a startup it helped found from a research center at the University of Copenhagen.Per deal terms, Embark shareholders could receive up to 456 million euros in additional payments based on achievement of certain development, regulatory and commercial goals. The startups staff will continue their research under a new company called Embark Laboratories.Fueled by quickly growing sales of its weight-loss drug Wegovy and diabetes therapy Ozempic, Novo has secured a leading position in obesity treatment, which could be worth tens of billions of dollars in annual sales. The Danish firm is looking to strengthen its hold through dealmaking, with the latest acquisition coming three weeks after the announced buyout of Canadian biotechnology company Inversago Pharma.Dive Insight:Embark got its start at the Novo Nordisk Foundation Center for Basic Metabolic Research, where research conducted by Zach Gerhart-Hines, Jakob Bondo Hansen and Thue Schwartz gained seed backing from Novo Holdings and a collaboration with Novo Nordisk itself.Gerhart-Hines and Schwartz have published research on two proteins, FFAR4 and GPR3, that regulate energy expenditure and the breakdown of fatty tissue. In announcing the deal, Embark cited a novel target that suppresses appetite, increases energy expenditure and enhances insulin sensitivity.In previous disclosures, Embark said it had identified a peptide drug for cardiovascular and metabolic disease and a small molecule energy expenditure activator that it was investigating for obesity.Novo set a new standard in obesity treatment when it repurposed its daily blood-sugar-lowering injection Victoza into a weight-loss drug called Saxenda. A weekly diabetes treatment Ozempic followed, which it sells in weight-loss as Wegovy, although Ozempic is widely used off-label to treat overweight people.These drugs regulate blood sugar by activating a hormone called GLP-1. Eli Lilly is looking to dethrone Novo with Mounjaro, a dual-acting injection that activates GLP-1 and another target called GIP. Mounjaro has been approved in diabetes and could be launched soon for weight loss.In response, Novo is beefing up its diabetes and weight-loss pipeline, where it has around nine novel projects in clinical trials.With the Inversago and Embark deals, Novo will add up to five experimental drugs in diabetes, obesity and metabolic diseases. '

Former Pfizer Internal Medicine CSO joins the Board as an independent board member AMSTERDAM--(BUSINESS WIRE)-- NorthSea Therapeutics B.V. (‘NST’), a biotech company developing novel and innovative strategies for the treatment of non-alcoholic steatohepatitis (NASH) and other metabolic diseases, today announces the appointment of Morris J. Birnbaum as an independent board member. Morris J. Birnbaum, MD, PhD, after a successful academic career studying insulin action and the regulation of metabolism, joined Pfizer in 2014 initially as the Chief Scientific Officer of the internal medicine research unit. During his years at Pfizer Morris built a vast experience in discovery and early-stage clinical development for metabolic diseases. A full biography is in the notes to editors. NorthSea Therapeutics has three SEFAs (Structurally Engineered Fatty Acids, a new class of drugs) in clinical development: icosabutate is in phase 2b (ICONA, top line readout in H1-23) and is being developed for NASH. SEFA-1024 is being developed for SHTG (Severe Hypertriglyceridemia). A phase 1 study was successfully completed in Q4-22. A phase 1 study was also successfully completed in Q4-22 for SEFA-6179, a third SEFA being developed for IFALD (Intestinal Failure associated Liver Disease). Both SEFA-1024 and SEFA-6179 will advance to phase 2 in 2023. Rob de Ree, NST’s CEO commented: “With the appointment of Morris we are adding a global healthcare professional to our board. Given his relevant background in pharma, his leadership and insights in both early and late-stage clinical development in the metabolic space will be very valuable to our clinical development programs.” Morris Birnbaum added: “NST has developed a fascinating development portfolio with three programmes already in the clinic and all holding great potential for significant medical impact. I am delighted to be joining the Board and will be keen to assist the leadership team as the programmes advance towards approval.” -Ends- Notes to editors About Morris J. Birnbaum Morris J. Birnbaum, M.D., Ph.D. is a physician scientist who has led research teams investigating fundamental problems in metabolic regulation and their relevance to chronic disease in both academic and pharmaceutical settings. After a lengthy academic career, in 2014, Dr. Birnbaum moved to Pfizer Inc in Cambridge, MA as Chief Scientific Officer of the Internal Medicine Research Unit, where he was responsible for the discovery and early clinical development of drugs designed to treat metabolic diseases such as diabetes, obesity, heart failure and cachexia. Under his leadership, Pfizer has brought seven novel potential medicines into clinical development. Dr. Birnbaum earned a PhD and a MD from Brown University and completed an Internal Medicine residency at Barnes Hospital at Washington University in St. Louis followed by postdoctoral training at the University of California, San Francisco, and Sloan-Kettering Institute in New York. Dr. Birnbaum has held faculty positions at Harvard Medical School, the Perelman School of Medicine at the University of Pennsylvania, and the Howard Hughes Medical Institute. He currently is on the Editorial Boards of Science Signaling and Cell Metabolism. About NASH NASH is a chronic liver disease characterized by liver inflammation and fibrosis and represents a more advanced stage of non-alcoholic fatty liver disease (NAFLD). It is frequently found in association with obesity and type 2 diabetes and is driven by multiple factors, including the formation of toxic lipid species in the liver, inducing liver inflammation. Further disease progression leads to advanced liver fibrosis and cirrhosis with a high risk of liver failure, hepatocellular cancer and the need for liver transplantation. An estimated 15–30% of the adult population in developed countries have NAFLD, 10-15% of whom may advance to NASH, representing at least ~15–30 million patients in the 6 major markets. About Icosabutate. Icosabutate, NorthSea Therapeutic’s lead candidate, is an orally administered, structurally engineered, liver-targeted eicosapentaenoic acid derivative. The structural modifications result in high hepatic concentrations of non-esterified icosabutate that in turn optimise targeting of fatty acid receptors of key relevance to NASH, including FFAR4. Preclinical data have demonstrated its therapeutic potential for treating fibrosing NASH and, of relevance to NASH patients, significant improvements in atherogenic lipids, glycemic control and inflammation have been shown in clinical studies. The potential to target both NASH and its associated comorbidities coupled with a favorable safety pro oral administration support icosabutate as a potential as backbone therapy for a broad range of patients with NASH. About NorthSea Therapeutics NorthSea Therapeutics B.V.(NST) is a Dutch biotech company focused on developing structurally engineered fatty acids (‘SEFAs’) for the treatment of NASH and other metabolic disorders. NST licensed the rights to its lead compound icosabutate and a library of SEFAs from Pronova BioPharma Norge AS, who developed Lovaza® (US brand, branded Omacor® in Europe), a blockbuster cardiovascular drug. Icosabutate has been found safe and effective in two prior phase 2 clinical studies for treatment of hypertriglyceridemia and mixed dyslipidemia and is currently in clinical development for NASH. The icosabutate phase 2b ICONA NASH trial is scheduled to readout in the first half of 2023. Two additional SEFAs are in clinical development; SEFA-1024 completed in Q4-2022, a phase 1 study and is developed for SHTG, and SEFA-6179, completed a phase 1 study in Q4-2022, is being developed for the orphan indication IFALD, (Intestinal Failure Associated Liver Disease). NST is headquartered in the Netherlands with a presence in Norway and the US and is supported by Ysios Capital, Forbion Growth, Forbion Ventures, Novo Seeds, BGV, NSV, venBio Partners and Sofinnova investments. 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