BIO89-100 Demonstrated Robust Reductions in Liver Fat and Liver Fat Volume (LFV) by MRI-PDFF, Favorable Tolerability and Potential for Weekly (QW) or Every 2 Weeks (Q2W) Dosing in a Phase 1b/2a Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study in NASH

Background: FGF21 is an endogenous hormone that regulates carbohydrate, lipid and energy metabolism. FGF21 analogs improve liver and metabolic abnormalities in non-alcoholic steatohepatitis (NASH). BIO89-100 is a long-acting glycoPEGylated FGF21, with promising tolerability and pharmacodynamic effects and potential for QW or Q2W dosing. Methods: This Phase 1b/2a trial enrolled 81 subjects with liver fat ≥10% by MRI-PDFF and either biopsy-confirmed NASH (BC-NASH) or phenotypic NASH (PNASH: central obesity with either type 2 diabetes mellitus or with evidence of liver injury by ALT or FibroScan vibration controlled transient elastography score above defined thresholds). Subjects were randomized to 12 weeks of treatment at one of 6 doses (3, 9, 18 or 27mg weekly [QW]; 18 or 36mg Q2W) or placebo. Key endpoints were safety, tolerability, pharmacokinetics, change in liver fat content as measured by MRI-PDFF and liver and metabolic markers. Results: Baseline characteristics were generally similar between pooled BIO89-100 v. pooled placebo groups, and between BC-NASH v. PNASH subjects. At week 13, all BIO89-100 dose groups showed significant relative reductions up to 70% (placebo adjusted p<0.001) in MRI-PDFF. Up to 88% of BIO89-100 subjects achieved ≥30% MRI-PDFF reduction v. baseline (p<0.001). Decreased liver fat was accompanied by decreased LFV of up to 305 mL or 65% from baseline (p<0.001). Significant decreases in ALT vs. placebo were observed with BIO9-100, maximal with 27 mg QW (30 U/L decrease from baseline, p<0.001) and prominent in the subgroup (n=17) with baseline ALT>45 U/L (35 U/L decrease from baseline, p<0.05). Metabolic benefits of BIO89-100 included a favorable effect on lipids with significant improvements in triglycerides (TG; up to 28% reduction in overall population, up to 49% in the subgroup [n=15] with baseline TG≥200 mg/mL); non-HDL cholesterol and LDL-C (up to 15% and 16%) and increased adiponectin (up to 61%). There were no deaths or related serious adverse events; one BIO89-100 treated subject discontinued due to a related adverse event (localized skin rash). Mild increased appetite (15.9% in pooled BIO89-100) was the most common treatment-related AE. The frequency of gastrointestinal (GI) AEs compared favorably to placebo; diarrhea (BIO89-100 12.7%, placebo 22.2%) and nausea (BIO89-100 7.9%, placebo 16.7%) were the only GI AEs in ≥5% BIO89-100-treated subjects. There were no hypersensitivity reactions or adverse effects on blood pressure or heart rate. Conclusion: In subjects with NASH, BIO89-100 led to significant and clinically meaningful reductions in liver fat and LFV assessed by MRI-PDFF with concurrent metabolic benefits. These effects were observed with both QW and Q2W dosing, with a good safety and tolerability profile. A Phase 2b study in NASH is planned and there is an ongoing proof of concept study in patients with severe hypertriglyceridemia.