Advancing into clinical development for multiple indications

Pipeline

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

Pegozafermin was engineered using a proprietary glycoPEGylation technology to prolong the biological activity of FGF21 while maintaining the efficacy of native FGF21. FGF21 is an endogenous metabolic hormone that regulates energy expenditure and glucose and lipid metabolism. Pegozafermin has the potential to be the best-in-class FGF21 analog based on the current clinical profile which delivers a compelling risk-benefit profile with the tolerability and dosing convenience necessary for adoption and compliance.

Because pegozafermin improves liver pathology and addresses underlying metabolic issues, we are studying it in non-alcoholic steatohepatitis (NASH). Recent 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.

Given the potential of pegozafermin to meaningfully reduce triglycerides, we are also developing pegozafermin 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 pegozafermin 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 pegozafermin could make it a highly differentiated new therapy for this condition.

Learn more about the pegozafermin trials here

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 pegozafermin 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 hese 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

Pegozafermin Led to Significant Metabolic Benefits, in Addition to Robust Beneficial Effects on the Liver, in an Open label Cohort of a Phase 1b/2a Study in Subjects with Nonalcoholic Steatohepatitis (NASH)

N. Alkhouri, R. Loomba, J.P. Frias, L. Morrow, S. Feng, L. Tseng, G.D. Agollah, W.R. Charlton, H. Mansbach, M. Margalit, and S. Harrison. Poster presented at the EASL International Liver Congress, June 22-26, 2022.

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Pegozafermin Led to Improved Liver Histology, Liver-related Non-invasive Tests and Metabolic Profile, With Favorable Safety and Tolerability, in an Open label Cohort of a Phase 1b/2a Study in Subjects With Nonalcoholic Steatohepatitis

R. Loomba, N. Alkhouri, D. Lazas, P. Bedossa, L. Morrow, S. Feng, L. Tseng, G.D. Agollah, W.R. Charlton, H. Mansbach, M. Margalit, and S. Harrison. Poster presented at the EASL International Liver Congress, June 22-26, 2022.

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Pharmacokinetics (PK) and Pharmacodynamics (PD) of BIO89-100, a Novel GlycoPEGylated FGF21, in Nonalcoholic Steatohepatitis (NASH) Patients with Compensated Cirrhosis

N. Alkhouri, R.W. Charlton, H. Mansbach, M. Margalit, K. Balic, and L. Tseng. Poster presented at the EASL International Liver Congress, June 22-26, 2022.

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Pegozafermin Treatment Ameliorates a Subclinical Increase in Spleen Volume, That Is Associated With a Worsening Metabolic Profile, in Non-cirrhotic NASH in Correlation With Change in Liver Fat and Inflammatory Markers in a Phase 1b/2a, Placebo-Controlled, Double-Blind Proof of Concept Study

J.P. Frias, L. Johansson, R.W. Charlton, S. Feng, G.D. Agollah, H. Mansbach, and M. Margalit. Poster presented at ENDO 2022, June 11-14, 2022.

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Treatment With BIO89-100 Led to Decreased Spleen Volume that was Correlated with Relative Change in Liver Fat Volume, CK 18 and Platelet count in a Phase 1b/2a, Placebo controlled, Double blind, NASH Proof of Concept Study

R. Loomba, L. Johansson, R. W. Charlton, G.D. Agollah, H. Mansbach, M. Margalit. Presented at The Liver Meeting AASLD, November 12-15, 2021.

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Population Pharmacokinetics (PK) and Pharmacodynamics (PD) of BIO89-100, a Novel GlycoPEGylated FGF21, in a Phase 1b/2a POC Study in Nonalcoholic Steatohepatitis (NASH)

L. Tseng, R.W. Charlton, M. Margalit, H. Mansbach, R.M. Savic. Presented at The Liver Meeting AASLD, November 12-15, 2021.

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BIO89-100 Demonstrated Robust Reductions in Liver Fat, Improved Metabolic Parameters, 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.

J.P. Frias, G. Ortiz-Lasanta, C. Hartsfield, L. Tseng, R.W. Charlton, H. Mansbach, M. Margalit, R.Loomba. Presented at the 16th Annual Cardiometabolic Health Congress, October 14-17, 2021 (National Harbor, MD).

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Prevalence of Nonalcoholic Fatty Liver Disease in Patients With Severe Hypertriglyceridemia (SHTG)–Initial Baseline Data From an Ongoing Phase 2 Study

D.L. Bhatt, J.J.P Kastelein, T. Parli, R.W. Charlton, C.L. Hartsfield, S.Feng, H. Mansbach, H. Bays. Presented at the 16th Annual Cardiometabolic Health Congress, October 14-17, 2021 (National Harbor, MD).

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Prevalence of NAFLD in Subjects with Severe Hypertriglyceridemia: Initial Baseline Data from an Ongoing Phase 2 Study

H. Bays, J. Kastelein, T. Parli, W. Charlton, H. Mansbach, S. Feng, C. Hartsfield and M. Miller. Presented at the National Lipid Association Scientific Sessions, September 24-26, 2021.

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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

J.P. Frias, E.J. Lawitz, G. Ortiz-Lasanta, B.B. Franey, L. Morrow, C. Chen, L. Tseng, RW W. Charlton, H. Mansbach, M. Margalit, R. Loomba. Poster presented at ENDO 2021, March 20-23, 2021.

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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.

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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.

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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).

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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).

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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.
View Poster >
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.
View Poster >
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).
View Poster >
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).
View Poster >