R & D

Our R&D is singularly focused on developing medicines to reverse the escalating NASH epidemic. NASH is a disease involving the whole body, requiring treatment of the imbalanced metabolism, as well as acting directly on the liver. This approach addresses not only the underlying metabolic causes but also the downstream pathological pathways leading to liver cirrhosis, liver failure and death.

The Science of NASH

Metabolic Drivers of NASH

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

Caloric overburdening of the liver

Excessive liver fat, fat oxidation and oxidative stress

Liver cell stress, injury, death

Inflammation

Fibrosis
Fat in the liver comes from dietary fat, fatty acids released from adipose tissue, and the synthesis of new fat by the liver. 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 trashcan for unwanted energy.
The largest source of liver fat in NASH patients is fatty acids released from adipose tissue, which accounts for nearly half of the flow of fat through the liver. Lipolysis, the release of fatty acids from adipose tissue, is normally inhibited by the effect of insulin. However, resistance to insulin causes higher rates of lipolysis and less dietary fat uptake by adipose tissue and muscle. This leads to an excess of calories entering the liver.
The high flux of calories into the liver leads to secretion of fat as very low density lipoproteins (VLDL) into the bloodstream. This results in elevated triglycerides, and is associated with elevated LDL-cholesterol and apolipoprotein B (ApoB) in NASH patients. This dyslipidemia underlies the increased risk of cardiovascular disease such as angina, heart attack and stroke.
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 causing 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.

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Metabolic drivers of NASH

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

Caloric overburdening in the liver
Excessive liver fat, fat oxidation and oxidative stress
Liver cell stress, injury, death
Inflammation
Fibrosis

Excess intake of calories drives fat storage in liver

Fat in the liver comes from dietary fat, fatty acids released from adipose tissue and the syntheses 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… [rest of content missing from flat.]

Insulin resistance exacerbates liver fat

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 uptake by adipose tissue and muscle. This leads to an excess of calories entering the liver.

Excess fat in liver drives increase in blood fatty acids

Oxidative stress due to excess fat causes cell death and fibrosis

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

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.
As a result of excess calories being redirected to the liver, the energy overload causes fat accumulations, lipotoxicity and oxidative stress within hepatocytes.
Fat accumulation and subsequent lipotoxicity drive hepatocyte stress, which causes hepatocyte injury and induces apoptosis. High rates of fat oxidation in the liver lead 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, which add to hepatocyte stress, injury and apoptosis.
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 induces hepatocyte apoptosis, establishing a vicious cycle of inflammation and hepatocyte death.
The resulting pro-inflammatory environment induces other liver-resident cells, known as hepatic stellate cells, to differentiate into collagen-depositing myofibroblasts. Chronically high levels of collagen synthesis lead 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, ultimately resulting in liver failure.

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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.

Excess calories drive fat accumulation and toxicity in liver cells

This drives apoptosis

Fat accumulation and subsequent lipotoxcity drive hepatocyte stress, which causes hepatocyte injury and induces apoptosis. High rates of fat oxidation in the liver lead 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.

Dying liver cells trigger more inflammation

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.

Inflammation leads to fibrosis and potentially cirrhosis

Finding a Treatment for NASH

There are currently no FDA-approved therapies for NASH. Many investigational treatments aim to reduce inflammation and fibrosis, but have demonstrated little improvement in addressing the underlying metabolic drivers of the 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.

We recently announced key results from our ongoing Phase 2a trial, the BALANCED study. Specifically, we reported that, after 12 weeks of treatment, patients in each of the three groups treated with AKR-001 had statistically significant reductions in liver fat and a liver enzyme called ALT, compared to placebo. The results observed for the top two dose groups are among the most robust results publicly reported across NASH trials.