AKR-001

A Metabolic and Anti-Fibrotic Solution

AKR-001 is an analog of the naturally-occurring hormone FGF21, comprised of an engineered version of the human polypeptide sequence of FGF21 fused to the Fc domain of human immunoglobulin (IgG1). AKR-001 is uniquely designed to deliver sustained signaling through FGF21’s receptors, thereby addressing the underlying drivers of NASH (non-alcoholic steatohepatitis), and in turn reducing liver fat, and directly reducing inflammation and fibrosis of the liver.

Current investigational NASH therapies are typically classified as either metabolic OR anti-fibrotic. AKR-001 is Both.

METABOLIC

AKR-001 redirects calories away from the liver, restores lipid metabolism in the liver to a healthy state, and protects against hepatocyte stress and death.

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ANTI-FIBROTIC

AKR-001 directly suppresses downstream inflammation and fibrosis.

Harnessing an Endogenous Hormone

Image of AKR-001 Image of AKR-001 docked to Beta-Klotho

Harnessing an Endogenous Hormone

FGF21 is an endogenous hormone that acts systemically to regulate whole-body metabolism and locally to alleviate cellular stress, making it a compelling therapeutic target. While FGF21’s short half-life of under two hours limits its therapeutic potential, AKR-001 has been engineered to enhance its biological activity by extending half-life to over 3 days for once-weekly subcutaneous administration.

Specifically, AKR-001 incorporates two amino acid substitutions, at positions 171 and 180 in the FGF21 sequence, to prevent degradation of FGF21 at the C-terminus, which is essential for receptor binding. Half-life is further extended by fusing FGF21 to the Fc domain of human IgG1. AKR-001 also incorporates a third amino acid substitution at position 98 in the FGF21 sequence, to improve pharmaceutical stability.

Docked to β-Klotho

FGF21 signals through a co-receptor complex of β-Klotho and an FGF receptor (FGFR); β-Klotho acts to trap FGF21 on the cell surface, bringing FGF21 close to the FGFR through which it signals. AKR-001’s targeted amino acid substitutions increase binding affinity for β-Klotho and enable AKR-001 to signal through the FGF receptors.

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Balanced Receptor Potency

AKR-001 reproduces the balanced potency of native FGF21, activating three cell-surface receptors known as FGFR1c (the most highly-expressed FGFR in adipose tissue), and FGFR2c and FGFR3c (FGFRs expressed in liver), which appear responsible for FGF21’s combined metabolic and anti-fibrotic effects. By acting on different tissues, AKR-001 targets all sources of liver fat: dietary fat, de novo lipogenesis in liver and adipose tissue lipolysis. With nearly half of liver fat in NASH patients coming from adipose tissue, intervening in both adipose and liver is likely to maximize the reduction of liver fat.

AKR-001 also reproduces native FGF21’s weak potency at another FGF receptor known as FGFR4, whose activation does not appear to contribute to improving the metabolic health of the liver, but is associated with higher LDL-C.

Flow chart of how AKR-001 activates various cell surface receptors.

Leveraging Whole-Body Metabolism to Restore Liver Health

Illustration of AKR-001 treatment state. Illustration of NASH disease state.

Leveraging Whole-Body Metabolism to Restore Liver Health

We believe intervening in the core processes underlying NASH pathogenesis is the most effective way to restore liver health. By improving insulin sensitivity, AKR-001 leverages whole-body metabolism to redirect calories away from the liver to fatty tissue and muscle throughout the body. Consequently, AKR-001 reduces fat deposited in the liver and decreases the rate of fat oxidation by the liver, which reduces lipotoxicity and oxidative stress, mitigates inflammatory response, and inhibits fibrosis. Unlike other interventions that improve insulin sensitivity, AKR-001 does not appear to be associated with body weight gain. The marked improvement in lipoproteins observed with AKR-001 treatment has the potential to reduce cardiovascular disease, which is the leading cause of death among NASH patients.

View NASH State

We believe intervening in the core processes underlying NASH pathogenesis is the most effective way to restore liver health. By improving insulin sensitivity, AKR-001 leverages whole-body metabolism to redirect calories away from the liver to fatty tissue and muscle throughout the body. Consequently, AKR-001 reduces fat deposited in the liver and decreases the rate of fat oxidation by the liver, which reduces lipotoxicity and oxidative stress, mitigates inflammatory response, and inhibits fibrosis. Unlike other interventions that improve insulin sensitivity, AKR-001 does not appear to be associated with body weight gain. The marked improvement in lipoproteins observed with AKR-001 treatment has the potential to reduce cardiovascular disease, which is the leading cause of death among NASH patients.

Treatment with AKR-001

Suppression of Downstream Inflammation and Fibrosis

Suppression of Downstream Inflammation and Fibrosis

AKR-001 also acts directly to alleviate hepatocyte stress and to reduce inflammation and fibrosis of the liver.

AKR-001 protects hepatocytes against cellular stress by ensuring that proteins appropriate to the needs of cells are produced at the right time and in the right amounts, including proteins associated with protection against oxidative stress, degradation of damaged proteins and regulation of cell death pathways. AKR-001 also appears to directly inhibit the activation of pro-inflammatory Kupffer cells and the differentiation of hepatic stellate cells into collagen-forming myofibroblasts, which are responsible for inflammation and fibrosis associated with NASH.

View NASH State

AKR-001 also acts directly to alleviate hepatocyte stress and to reduce inflammation and fibrosis of the liver.

AKR-001 protects hepatocytes against cellular stress by ensuring that proteins appropriate to the needs of cells are produced at the right time and in the right amounts, including proteins associated with protection against oxidative stress, degradation of damaged proteins and regulation of cell death pathways. AKR-001 also appears to directly inhibit the activation of pro-inflammatory Kupffer cells and the differentiation of hepatic stellate cells into collagen-forming myofibroblasts, which are responsible for inflammation and fibrosis associated with NASH.

Treatment with AKR-001

Illustration of AKR-001 treatment state. Illustration of NASH disease state.

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