Results from the proof-of-concept phase 1b/2a clinical trial in NASH demonstrate the promise of BIO89-100 for the treatment of NASH. Results showed robust reductions in liver fat with a significant percentage of patients seeing clinically meaningful responses. Further, robust results were observed on key liver markers relevant in NASH. Strong efficacy and favorable tolerability were observed with weekly and every two-week dosing.
Specifically, the data showed statistically significant reductions in liver fat of up to 70% versus placebo with 43% of patients at the highest dose achieving normal liver fat of <5%. Up to 88% and 71% of BIO89-100 subjects achieved responses of ≥30% and ≥50% liver fat reduction, respectively. BIO89-100 demonstrated significant benefit in markers of liver injury and fibrosis, with up to 44% reduction in alanine aminotransferase (ALT) and up to 27% reduction in Pro-C3. Significant improvements were seen in key lipid markers – triglycerides, non-HDL, and LDL.
Overall, BIO89-100 has a favorable safety and tolerability profile. It was well tolerated across all dose ranges with few treatment related adverse events that occurred in ≥10% of subjects. Very low frequency of gastrointestinal events was observed with a similar profile to placebo.
A proof-of-concept phase 1b/2a clinical trial in NASH recently reported positive results and a phase 2 trial in SHTG is ongoing.
FGF21 is an endogenous metabolic hormone with broad effects regulating energy expenditure and glucose and lipid metabolism. FGF21 has been shown to reduce liver fat by increasing fatty acid oxidation, reducing the formation of new fat in the liver (de novo lipogenesis) and reducing systemic levels of triglycerides (fat). FGF21 agents have shown benefits in reducing fibrosis in the liver. This effect is mediated through two potential pathways. First, by improving metabolic regulation, it reduces ongoing liver injury, thus giving the liver time to heal. Second, FGF21 generates an on-target effect to increase adiponectin, a hormone released from adipose tissue that can, among other functions, suppress the development and progression of liver fibrosis. In addition to its effects on the liver, FGF21 has been shown to reduce systemic levels of lipids (triglycerides and LDL cholesterol) as well as improve glycemic control.
Hypertriglyceridemia is characterized by elevated levels of triglycerides (a type of non-cholesterol fat). When levels of triglycerides are severely elevated (≥500 mg/dL), the condition is known as SHTG and is associated with an increased risk of NAFLD, NASH, and cardiovascular diseases, as well as acute pancreatitis. It is estimated that there are up to 4 million patients in the US with triglyceride levels ≥500 mg/dL. Of these patients, it is estimated that up to 56% have excessive liver fat and up to 70% have elevated cholesterol or type 2 diabetes. This patient population is expected to increase due to the triple epidemic of obesity, metabolic syndrome, and Type 2 diabetes. A large portion of these patients are unable to achieve treatment goals with existing therapies. In third-party studies, up to 50% of treated SHTG patients were unable to reduce their triglyceride levels to <500 mg/dL despite using certain approved drugs. Further, while these therapies may decrease triglyceride levels, they generally do not have broader beneficial metabolic benefits.