Advancing into clinical development for multiple indications

Pipeline

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

BIO89-100, engineered using a proprietary glycoPEGylation technology to prolong the biological activity of native FGF21, is a metabolic hormone that regulates energy expenditure and glucose and lipid metabolism. We believe BIO89-100 may be a differentiated FGF21 therapy, based on its robust and durable biological effects and favorable tolerability profile, as well its potential for a longer dosing interval. Combining these characteristics with the ability to address the key liver pathologies in NASH, as well as the underlying metabolic dysregulation in NASH patients, BIO89-100 has the potential to become a mainstay of NASH therapy.

In a Phase 1a clinical trial in healthy volunteers, BIO89-100 demonstrated a favorable tolerability profile as well as robust and durable biological effects on key lipid parameters after a single dose. In the study, the pharmacokinetic profile of BIO89-100 was generally dose-proportional with a half-life of 55-100 hours. Furthermore, at single doses of 9.1 mg and higher, BIO89-100 demonstrated significant improvements versus baseline in key lipid parameters measured at 8 and 15 days. The mean changes versus baseline included reductions in triglycerides (up to 51%) and LDL-C (up to 37%) and an increase in HDL-C (up to 36%). These data, together with data from pre-clinical studies done with BIO89-100, support weekly or every two weeks subcutaneous dosing. This longer dosing interval could provide significant value to patients who are typically asymptomatic from their liver disease and will require chronic therapy.

Given the potential of BIO89-100 to meaningfully reduce triglycerides, we also intend to develop 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. To the extent that we can show in subsequent human clinical trials that BIO89-100 significantly decreases both triglyceride and LDL-C levels and improves other metabolic parameters, we believe that BIO89-100 could be a differentiated therapy in this indication.

A phase 1b/2a trial in NASH is ongoing, and a phase 2 trial in SHTG is planned.

Learn more about the NASH trial at clinicaltrials.gov

What makes FGF21 such a promising target?

FGF21 is a metabolic hormone that regulates energy expenditure and glucose and lipid metabolism. It has been clinically shown to reduce liver fat (steatosis). It is also thought to exert effects on liver fibrosis through two 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 hepatic fibrosis.

FGF21 therapies such as BIO89-100 have a number of diverse biological effects, including effects on the liver, adipose tissue, 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 in the liver that can progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). 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, hyperglycemia, dyslipidemia, 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 a high unmet need in the treatment of NASH remains.
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 HCC.
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 hepatocytes, and (4) development and progression of liver fibrosis in response to hepatocyte injury.

SHTG: An important and prevalent lipid abnormality

Hypertriglyceridemia is characterized by elevated levels of triglycerides (a type of lipid). 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 2.5 million to 4 million patients in the US with triglyceride levels ≥500 mg/dL. Of these patients, it is estimated that 42% have dyslipidemia and 27% have 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 metabolic benefits.

Scientific Publications

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).