Advancing into clinical development for multiple indications

Pipeline

BIO89-100 is an ideal candidate for liver and cardio-metabolic diseases

BIO89-100 was engineered using a proprietary glycoPEGylation technology to prolong the biological activity of native FGF21 while maintaining the efficacy of native FGF21. FGF21 is an endogenous metabolic hormone that regulates energy expenditure and glucose and lipid metabolism. BIO89-100 has the potential to be the best-in-class FGF21 analog based on the current clinical profile which delivers a compelling risk-benefit profile in this chronic, progressive, and generally asymptomatic liver disease. BIO89-100 achieves this by improving liver pathology and addressing the underlying metabolic issues while balancing it with the tolerability and dosing convenience necessary for adoption and compliance.

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.

Given the potential of BIO89-100 to meaningfully reduce triglycerides, we are developing BIO89-100 for the treatment of severe hypertriglyceridemia (SHTG). SHTG is defined as patients with triglycerides ≥500 mg/dL. While currently approved SHTG therapies decrease triglyceride levels, they have limitations. The early data suggest that BIO89-100 could offer robust and durable reductions in triglycerides as well as address other metabolic issues common in patients with SHTG including reducing hepatic fat which is found in a majority of these patients. These broad effects of BIO89-100 could make it a highly differentiated new therapy for this condition.

A proof-of-concept phase 1b/2a clinical trial in NASH recently reported positive results and a phase 2 trial in SHTG is ongoing.

Learn more about the BIO89-100 trials at clinicaltrials.gov

What makes FGF21 such a promising target?

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.

FGF21 therapies such as BIO89-100 have a number of diverse beneficial biological effects, including effects on the liver, fat, muscle, and more

NASH: A serious liver condition for which there are currently no therapies

NASH is a severe form of non-alcoholic fatty liver disease (NAFLD) characterized by inflammation and fibrosis (scarring) in the liver that can progress to cirrhosis, liver failure, and liver cancer. The prevalence of NAFLD, which affects approximately 25% of the global population, and NASH, which develops in approximately 20% to 25% of NAFLD patients, is growing and is driven primarily by the worldwide obesity epidemic. Patients with NASH frequently have other significant metabolic co-morbidities such as obesity, high blood sugar, elevated cholesterol and triglycerides, and systemic hypertension (a constellation commonly referred to as metabolic syndrome), and these further contribute to the risk of cardiovascular disease.
The number of NASH cases in the US is projected to expand from 16.5 million in 2015 to 27 million in 2030, with similar prevalence growth expected in Europe. Diet and exercise are currently the standard of care for NAFLD and NASH, but adherence is poor, and there remains a high unmet need in the treatment of NASH.
Prevalence and liver-related mortality rate by fibrosis stage
It is estimated that 20% to 25% of NAFLD patients progress to NASH. Of those with NASH, cirrhosis develops in approximately 20%, and 45% of patients with cirrhosis progress to decompensated cirrhosis, which results in permanent liver damage that can lead to liver failure. In addition, it is estimated that 8% of patients with advanced fibrosis will develop liver cancer.
Mechanisms underlying development and progression of NASH
The critical pathophysiologic mechanisms underlying development and progression of NASH include (1) reduced ability to handle lipids, (2) increased insulin resistance, (3) injury to liver cells and (4) development and progression of liver fibrosis in response to liver injury.

Severe Hypertriglyceridemia (SHTG): An important and prevalent lipid abnormality

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.

Posters

Bio89-100 Demonstrated Robust Reductions in Liver MRI-PDFF, Favorable Tolerability and Potential for every 2 Weeks Dosing in a Phase 1b/2a Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study in NASH
R. Loomba, E. J. Lawitz, B.B. Franey, L. Morrow, C. Chen, L. Tseng, H. Mansbach, M. Margalit. Poster presented at the Liver Meeting Digital Experience AASLD, November 13-16, 2020.
BIO89-100, a novel glycoPEGylatedFibroblast Growth Factor 21 (FGF21) analog activates FGF receptors (FGFR) 1c, 2c and 3c but not FGFR4 in L6 cells transfected with the four different human FGFRs and beta-Klotho (KLB)
M. Rosenstock, A. Pierce, A. Di Marco, G. Auciello, A. Bresciani, H. Mansbach, M.Margalit. Poster presented at the Liver Meeting Digital Experience AASLD, November 13-16, 2020.
BIO89-100, a Novel Glycopegylated FGF21 Analogue, Demonstrates Robust Reduction in Serum Lipids and Long Half-life in a Phase 1 Randomized, Controlled Single Ascending Dose Trial in Healthy Subjects
R. Loomba, H. Mansbach, L. Tseng, C. Chen, M. Rosenstock, G. Atiee and M. Margalit. Poster presented at the American Association for the Study of Liver Diseases (AASLD) Meeting, November 8-12, 2019 (Boston, MA).
Weekly Subcutaneous Administration of BIO89-100, a Novel GlycoPEGylated-Fibroblast Growth Factor21 (FGF21) Analogue, Inhibits Sweetness Preference in Obese Cynomolgus Monkeys
M. Rosenstock, Y. Liu, H. Mansbach and M. Margalit. Poster presented at the American Association for the Study of Liver Diseases (AASLD) Meeting, November 8-12, 2019 (Boston, MA).