Providing Solutions for Diseases with Unmet Medical Need

Aeglea is built on the concept of developing next generation engineered human enzymes to target and degrade metabolites in the blood, providing potential therapies for the treatment of diseases with unmet medical need.

Amino acids have generally been elusive as drug targets due to the lack of direct product candidates based on the human genome. By using our breakthrough bioengineering approach, we can engineer human enzymes with therapeutic potential across a number of areas of great medical need beginning with:

RARE GENETIC DISEASES (OR INBORN ERRORS OF METABOLISM)

CANCER

Currently we have multiple drug candidates in development. Each targets a different amino acid for potentially life-changing benefit.

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Arginine Modulator | Preclinical Candidates | Publications

Next Generation Enzyme Therapeutics

Our innovative approach of developing enzyme solutions to treat diseases with unmet medical need achieved its origins in the laboratory of Professor George Georgiou at the University Texas at Austin. Our in-house team of protein engineers develops next generation enzyme therapeutics by either enhancing the catalytic properties of existing enzymes or generating enzymes with novel activity from alternative human enzyme scaffolds. Examples of metabolites that are targeted using our novel enzymes include:

Because amino acids are critical to cell function, our engineered human enzymes have the potential to be applied to a variety of diseases including:

Inborn errors of metabolism: Treating excesses in amino acids through targeted degradation using engineered human enzymes. Our most advanced rare genetic disease focus is on Arginase 1 Deficiency.

Cancer: Coupling amino acid depletion therapy to capitalize on the abnormal metabolism of tumor cells, with a diagnostic strategy to identify patients who may benefit from such targeted cancer therapy.

Unlike microbial enzymes, engineered human enzymes may not be recognized as foreign by the body and may be less likely to elicit an immune response — potentially providing more tolerable, more flexible treatment options for patients.

Pegzilarginase: Modulation of Arginine Levels

Our lead product candidate, Pegzilarginase (AEB1102), is derived from human Arginase 1. Engineered modifications, which include the substitution of cobalt for the manganese cofactor and PEGylation, gives Pegzilarginase both increased catalytic activity and serum stability compared to native human Arginase 1, making it potentially suitable as a therapeutic for the degradation of arginine.

Pegzilarginase has a potential immunogenicity advantage over microbial enzymes with arginine degrading activity. The Pegzilarginase amino acid sequence is derived from the native human amino acid sequence. We believe the human immune system will be less likely to mount an immune response since it will not recognize Pegzilarginase as a foreign molecule. This is in contrast to microbial enzymes that are commonly seen as foreign by the human immune system.

Hyperargininemia Resulting from Arginase 1 Deficiency:

Arginase 1 Deficiency is a rare genetic disorder caused by a mutation in the Arginase 1 gene that leads to the inability to degrade arginine. This results in excessively high levels of arginine in the blood, referred to as hyperargininemia. Arginase 1 Deficiency is a urea cycle disorder with a reported incidence of 1:350,000 to 1:1,000,000 live births. Patients with this disease are predisposed to neurologic symptoms including cognitive deficits, seizures and spasticity, loss of ambulation, and severe intellectual disability.

High levels of blood arginine are believed to be the key driver of the clinical manifestations that develop in patients with Arginase 1 Deficiency. Although the medical literature suggests that disease progression can be slowed with strict adherence to dietary protein restriction, there is no approved therapeutic agent that addresses the cause of Arginase 1 Deficiency. Pegzilarginase is intended to replace the Arginase 1 missing in patients and lower blood arginine levels, which is anticipated to slow or halt the progression of disease.

Selective Arginine Deprivation for Cancer:

Arginine is synthesized in a three-step process using the enzymes ornithine transcarbamylase (OTC), argininosuccinate synthase (ASS), and argininosuccinate lyase (ASL). In many tumor cells, one or more of these enzymes is “silenced,” which in turn disables the synthesis of intracellular arginine in the tumor cells. To survive, these tumor cells depend on extracellular arginine uptake for survival, making them potentially vulnerable to selective cell killing by arginine depletion with Pegzilarginase. Preclinical and clinical data suggests the importance of arginine depletion in patients with a variety of tumor types.

Preclinical Candidates

AEB4104 Program – Homocyst(e)inase: Targeting homocysteine for classical homocystinuria

Classical homocystinuria is a rare disease resulting from the hereditary genetic deficiency in cystathionine beta synthase. It has been estimated to impact up to 1 in 344,000 people worldwide, however, its prevalence is significantly higher in some countries. The most common medical conditions associated with classical homocystinuria are cardiovascular complications including an increased risk of blood clots.  Other symptoms include skeletal abnormalities, dislocation of the lens in the eye, and development and learning defects.

Currently available treatments for classical homocystinuria include high doses of vitamin B6 and betaine (N,N,N-trimethylglycine), the latter reducing homocysteine levels.  Although these treatments are effective for some patients, responses fluctuate significantly due to the variations in the genetic mutation driving the disease.  As a result, there exists an opportunity to develop a therapy that addresses the need of all patients by reducing blood homocystine levels back to the normal range.

AEB4104 is the lead enzyme in our discovery program to develop an engineered human enzyme designed to treat homocystinuria. We anticipate that enzyme replacement therapy with AEB4104 will degrade homocysteine and the oxidized form  homocystine, returning blood levels to the normal physiological range. Normalization of homocystine/homocysteine levels may halt or slow the progression of the symptoms of the disease in these patients.

AEB3103 Program – Cyst(e)inase: Targeting cysteine/cystine and oxidative stress for oncology

Reactive oxygen species (ROS) have been widely reported in the scientific and clinical research literature to be produced in high amounts in tumors. To withstand this oxidative stress by ROS tumors have enhanced antioxidant mechanisms that depend on the amino acid cysteine/cystine. Reducing the amount of available cysteine/cystine from outside the cell decreases the availability of antioxidants such as glutathione, increasing ROS-related damage to cancer cells and leading to cancer cell death.

AEB3103, our lead enzyme in this program, is a novel engineered human enzyme that targets and degrades the amino acid cysteine/cystine (cystine is the oxidized form of cysteine). Our initial preclinical efficacy testing demonstrated a statistically significant depletion of glutathione and significantly increased levels of ROS in solid tumor and hematologic cancer cells. AEB3103 treatment did not have an effect on appetite or body weight loss. This is expected since normal cells have the ability to synthesize cysteine and thus are able to maintain their ROS-protective ability even upon depletion of extracellular cysteine/cystine. We believe Cyst(e)inase, provides us with the opportunity to target a vulnerability of cancer that has been recognized for over 60 years, but not yet exploited for therapeutic benefit. We plan to continue our preclinical development efforts for AEB3103 and, if appropriate, proceed to IND-enabling studies with a development candidate from this program.

AEB2109 Program – Methioninase: Targeting the methionine dependence of Cancer

The dependence of tumors on the essential amino acid methionine for survival has been described extensively in the medical literature, with the demand of some tumors for methionine far exceeding that of normal tissues. Methionine supports several metabolic pathways that promote tumor growth and ultimately forms the rationale for using methionine starvation to target tumor cells. Over 40 years of research on tumor methionine dependence has helped develop the rationale for targeting methionine tumor metabolism in cancer treatment.

AEB2109, our lead enzyme in this program, is an engineered human enzyme degrades the amino acid methionine.  An engineered human methionine-degrading enzyme represents a unique therapeutic opportunity. Earlier work from our enzyme-engineering program has been presented in the scientific literature describing activity in an animal tumor model.  AEB2109 provides us with the opportunity to exploit a tumor vulnerability that has been recognized for over 40 years. We plan to continue our preclinical development efforts for AEB2109 and, if appropriate, proceed to IND-enabling studies.

Scientific Publications and Presentations

Sharing data and discoveries is a cornerstone of scientific and medical research. For your convenience and information, we have compiled relevant materials here.