Nash

A Life-Threatening Liver Disease

NASH (non-alcoholic steatohepatitis) is a serious form of NAFLD (non-alcoholic fatty liver disease). NASH is closely linked to the obesity and diabetes epidemics seen around the world. The progressive damage to the liver associated with NASH closely resembles damage caused by excessive alcohol consumption or viral infections. However, NASH is driven primarily by chronically excessive intake of calories.

NASH is characterized by an excessive accumulation of fat in the liver that causes stress and injury to liver cells, leading to inflammation and fibrosis, which can progress to cirrhosis, liver failure, cancer and eventually death.

A Growing Health Epidemic


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An estimated 17 million Americans have NASH

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The US NASH patient population is expected to grow over 50% to 27 million by 2030

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The number of NASH patients with advanced-stage fibrosis and cirrhosis is predicted to grow to 8 million in the US by 2030, an increase of approximately 140% from 2015

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NASH is a leading cause of liver transplantation in the US and Europe

METABOLIC DRIVERS OF NASH

Step 1 - Illustration of the effects of a NASH disease state, and caloric overburdening in liver

METABOLIC DRIVERS OF NASH

NASH is a complex disease that is influenced by multiple biological pathways. Scientific evidence points to five core processes that underlie its progression:

  1. Caloric overburdening in liver
  2. Excessive liver fat, fat oxidation and oxidative stress
  3. Liver cell stress, injury, death
  4. Inflammation
  5. Fibrosis
Step 2 - Illustration of excess liver fat, fat oxidation and oxidative stress

METABOLIC DRIVERS OF NASH

Fat in the liver comes from dietary fat, fatty acids released from adipose tissue and the synthesis of new fat (de novo lipogenesis). When the intake of calories chronically exceeds the body’s demand for energy, the body adapts its metabolism to limit energy uptake into organs such as muscle and adipose tissue that normally use and store large amounts of energy. This limitation results in excess energy being redirected to the liver, which effectively acts as a “trash can” for unwanted energy.

Step 3 - Illustration of liver cell stress

METABOLIC DRIVERS OF NASH

The largest source of liver fat in NASH patients is fatty acids released from adipose tissue, which accounts for nearly half of liver fat on average. Lipolysis, the release of fatty acids from adipose tissue, is normally inhibited by the effect of insulin on adipose tissue. However, resistance to insulin causes higher rates of lipolysis and less dietary fat being taken up by adipose tissue and muscle. This leads to an excess of calories entering the liver.

Step 4 - Illustration of inflammation

METABOLIC DRIVERS OF NASH

The high flux of calories into the liver leads to increased secretion of fat manifested as very low density lipoproteins (VLDL), and to hypertriglyceridemia. Elevated LDL cholesterol and apolipoprotein B (ApoB) are also characteristic of the dyslipidemia associated with NASH, and underlie the increased risk of cardiovascular disease, such as angina, heart attack and stroke.

Step 5 - Illustration of fibrosis

METABOLIC DRIVERS OF NASH

As more and more calories flow into the liver, fat accumulates to levels associated with lipotoxicity, while the rates of fat oxidation exceed demand for energy, leading to oxidative stress. Lipotoxicity and oxidative stress lead to hepatocyte injury and trigger cell death pathways. Dying hepatocytes release signals that activate inflammatory and fibrotic cells resident in the liver. In severe cases, this can lead to cirrhosis.

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

NASH pathogenesis is driven by hepatocyte stress and cell death (apoptosis), which acts as the bridge between (a) upstream oxidative stress and lipotoxicity arising from caloric overburdening of the liver and (b) the downstream consequences of inflammation and fibrosis.

Step 1 - Illustration of NASH pathogenesis

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

As a result of excess calories being redirected to the liver, the energy overload causes fat accumulation, lipotoxicity, and oxidative stress within hepatocytes.

Step 2 - Illustration of the result of excess calories being redirected to the liver

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

Fat accumulation and subsequent lipotoxocity drive hepatocyte stress, which causes hepatocyte injury and induces apoptosis. High rates of fat oxidation in the liver leads to formation of highly reactive molecules, known as free radicals, which cause oxidative stress. Oxidative stress causes mitochondrial stress, DNA and protein damage, and formation of lipid peroxides, all of which disrupt cellular processes and homeostasis, thereby further increasing hepatocyte stress, injury and apoptosis.

Step 3 - Illustration of apoptosis

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

Dying hepatocytes, characterized by ballooning, release danger-associated signaling molecules that activate liver-resident immune surveillance cells, called Kupffer cells. Once activated, Kupffer cells release pro-inflammatory molecules that attract other immune cells to amplify inflammation in the liver. One of these pro-inflammatory molecules directly stimulates hepatocyte apoptosis, establishing a vicious cycle of inflammation and hepatocyte death.

Step 4 - Illustration of apoptosis resulting in inflammation

A CLOSER LOOK: DOWNSTREAM INFLAMMATION AND FIBROSIS

Pro-inflammatory molecules also induce other liver-resident cells, known as hepatic stellate cells, to differentiate into collagen-producing myofibroblasts. Chronically high levels of collagen secretion leads to fibrosis of the liver, with scarring so severe in cirrhosis that it reduces the blood supply to hepatocytes, starving them of oxygen and nutrients, resulting in liver failure.

Step 5 - Illustration of increased inflammation resulting in increased fibrogenesis and cirrhosis

Finding a Treatment for NASH

There are no FDA-approved therapies for NASH. Many current investigational treatments aim to reduce inflammation and fibrosis but have demonstrated little improvement in addressing the underlying metabolic drivers of disease. In addition, some investigational treatments do not improve dyslipidemia— including hypercholesterolemia and hypertriglyceridemia—which underlies NASH patients’ susceptibility to cardiovascular disease.

We believe our Phase 2 clinical-stage candidate, AKR-001, is a powerful new therapy that has the potential to reverse the underlying metabolic dysregulation of the liver, protect against hepatocyte stress, and suppress downstream inflammation and fibrosis, with the ultimate goal of resolving NASH and restoring a healthy liver.

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