NorthSea Therapeutics to present ICONA Phase 2b data as an oral late-breaker session at the 2023 AASLD Liver Meeting

−  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).

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.