Close-up of a scientist working in a lab to develop innovative therapies to treat liver and cardiometabolic diseases. Close-up of a scientist working in a lab to develop innovative therapies to treat liver and cardiometabolic diseases.

Powerful Science to Develop Potential Options for the Treatment of Liver and Cardiometabolic Diseases

We are focused on developing and delivering innovative therapies for the treatment of liver and cardiometabolic diseases. Our lead candidate, pegozafermin, is currently being developed for the treatment of MASH and SHTG.

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

MASH is a severe and progressive liver disease accompanied by multiple metabolic abnormalities.

MASH is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) defined by liver inflammation and injury. The disease progresses over time, resulting in increased fat accumulation in the liver and, in many cases, permanent scarring of the liver.

NASH-NAFLD - Nonalcoholic Steatohepatitis and fatty liver disease

MASH is a severe and progressive liver disease accompanied by multiple metabolic abnormalities.

MASH is a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) defined by liver inflammation and injury. The disease progresses over time, resulting in increased fat accumulation in the liver and, in many cases, permanent scarring of the liver.

Stages of NASH, a severe and progressive liver disease accompanied by multiple metabolic abnormalities.
NASH - Nonalcoholic Steatohepatitis

Advanced stages of MASH are associated with poor clinical outcomes.

MASH progression can result in cirrhosis, liver failure, liver cancer, and death. In fact, MASH is the second leading cause of liver transplant among all adults, and it is expected to become the dominant cause for liver transplant in coming years. In addition, MASH predicts risk of cardiovascular events, and the presence of MASH increases the risk of cardiovascular disease above that of MASLD.

MASH impacts extra-hepatic organs and is associated with multiple diseases.

The majority of patients with MASH have been diagnosed with other cardiometabolic comorbidities:

Graphic showing of people with NASH, 83% have high triglycerides
Graphic showing of people with NASH, 82% obesity
Graphic showing of people with NASH, 71% metabolic syndrome
Graphic showing of people with NASH, 44% type 2 diabetes

The occurrence of comorbidities increases with progression from MASLD to MASH.

MASH prevalence is rising rapidly due to the increasing epidemic of obesity and metabolic syndrome.

In the US, approximately 25% of the population will develop MASLD, with 20-25% of those patients progressing to MASH. The prevalence of MASH in the US is predicted to increase 63% from 16.5 million cases in 2015 to 27.0 million cases in 2030, with similar rates across Europe.

MASH is usually undetected with patients often remaining asymptomatic until late stages of disease, when consequences to the liver and the rest of the body are more severe.

MASH develops through fat accumulation in the liver which often leads to insulin resistance. These two factors can result in increased inflammation and cellular injury within the liver. The inflammation then promotes the secretion of excess collagen, causing the fibrosis, or scarring, of the liver.

Graphic showing ~20% of people with MASH with advanced fibrosis progress to cirrhosis in 2 years.

Current treatment options for MASH are limited and significant unmet need remains for this growing population of patients.

The primary treatment goal for MASH is to reduce fibrosis in the liver, which we believe to be a major predictor of poor clinical outcomes. Therapies that can positively impact liver disease as well as common co-morbidities could be beneficial to patients with metabolic disease. Our treatment goals for MASH are to reduce liver fibrosis, decrease liver inflammation and liver fat, while improving other metabolic disturbances that affect many patients living with MASH.

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Severe Hypertriglyceridemia (SHTG)

SHTG is a rare metabolic disorder that can arise from multiple factors with severe consequences throughout the body.

SHTG is a lipid abnormality defined by severely elevated triglyceride (TG) levels, with fasting TG levels ≥500 mg/dL. SHTG can result from environmental factors, such as poor diet, and, less frequently, genetic conditions, such as familial chylomicronemia, that cause an imbalance between TG production and breakdown. Persistent elevation of TG levels can ultimately result in abnormal fat deposition in organs throughout the body, including the liver, pancreas, heart, and muscle, potentially leading to lipotoxicity and insulin resistance.

SHTG increases the risk for severe diseases and plays a key role in the onset and progression of multiple comorbidities with potentially life-threatening consequences.

The risk for severe diseases like acute pancreatitis and atherosclerotic cardiovascular disease (ASCVD) increases as TG levels increase. Both acute pancreatitis and ASCVD have life-threatening consequences and can lead to organ failure and death.

The majority of patients with SHTG have been diagnosed with liver or cardiometabolic comorbidities:

Graphic showing of people with SHTG, 100% have fatty liver diseasee
Graphic showing of people with SHTG, 80% metabolic syndrome
Graphic showing of people with SHTG, 64% obesity
Graphic showing of people with SHTG, 75% diabetes
Graphic showing higher triglyceride levels are associated with higher incidence of pancreatitis. Incidence of pancreatitis per 1000 person-years chart

*Patients with TG levels ≥2000 mg/dL.

While SHTG is a rare disease, its prevalence is expected to rise in coming years, emphasizing the need for effective treatment options that improve outcomes for patients.

SHTG currently affects ~2% of the US population, but the number of patients with SHTG is expected to rise due to the increasing prevalence of obesity and diabetes. Over the next decade, nearly 3.4 million ASCVD events, such as heart attack or stroke, are expected to occur among patients with elevated TG levels, highlighting the need for treatments that can reduce TG levels and provide broad metabolic benefits for patients.

SHTG is an asymptomatic condition with an urgent need for treatments that can effectively reduce TG levels and restore the balance in lipid metabolism.

SHTG is an asymptomatic disorder that often goes untreated, with only 20% of patients currently on medication, including statins, fibrates, and fish oils. These SHTG treatment options can help reduce TG levels, but they often have tolerability issues and are often insufficient for improving liver and cardiometabolic comorbidities, which is the goal of treatment for SHTG.

Graphic showing only 20% of people with SHTG are on medication.

Insulin resistance both contributes to and is a consequence of SHTG.

Insulin resistance leads to the secretion of free fatty acids and, over time, inflammation. Low-grade inflammation caused by SHTG may lead to the release of free fatty acids in the pancreas. This, in turn, leads to a cycle of continuing inflammation and, ultimately, acute pancreatitis events. At the same time, elevated TGs in circulation ultimately lead to a more atherogenic lipid profile resulting in increased arterial inflammation and plaque formation, promoting the progression of ASCVD.

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References

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