Progress on prostate and breast with AEB3103

Aeglea BioTherapeutics finds product candidate effective in slowing cancer growth

Rachel Flehinger
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AUSTIN, Texas—Aeglea BioTherapeutics Inc. reported in an article published in the November issue of Nature Medicine that its product candidate AEB3103 shows significant suppression of tumor growth in both prostate and breast cancers. The product, one of Aeglea’s signature enzyme-based therapeutic options in the field of amino acid metabolism, appears to induce production of reactive oxygen species (ROS) and suppress tumor growth in mice.
“Preclinical findings showed that AEB3103 had a potent antitumor effect in multiple solid tumor models, including prostate and breast cancer, and was well tolerated for more than five months. This suggests AEB3103 could be a safe and effective alternative to experimental drugs targeting oxidative stress that are currently under clinical evaluation,” said study co-author Dr. George Georgiou, co-founder of Aeglea and the Laura Jennings Turner Chair in Engineering at the University of Texas at Austin. “As many other chemotherapeutic agents are also known to oxidatively stress cancer cells, we are looking forward to exploring AEB3103 in combination with ROS-inducing drugs as a potential cancer treatment.”
In preclinical trials, AEB3103 appeared to starve tumors of serum L-cystine and its oxidized form L-cystine, which are key ingredients for tumor growth. Cancerous tumor cells experience a high level of ROS, and thus require elevated levels of antioxidant compounds such as L-cystine in order to survive and thrive. Absorption of L-cystine is well documented as a significant enabler to cancer growth and has been the subject of enzymatic research. AEB3103 appears to be the first significant therapy to effectively reduce L-cystine absorption.
“These preclinical results suggest that the use of AEB3103 to deplete the amino acid L-cysteine has the potential to be a well-tolerated approach for treating tumors with high levels of ROS. The idea of targeting cancer with an enzyme that degrades L-cysteine was first proposed in 1961. Since then, the evidence that this is an important and unexploited vulnerability of cancer has been widely described but not effectively applied for therapeutic benefit,” said Dr. David G. Lowe, president and CEO of Aeglea. “Our results with AEB3103 also provide support for our broader cancer strategy of using well-established amino acid biology to target tumor metabolism.”
AEB3103, a biologically engineered enzyme, appears to significantly reduce L-cystine, which can slow ROS in tumorous cells, killing them by depriving them of this key antioxidant precursor. Reactive oxygen species are constantly generated and eliminated in the biological system and play important roles in a variety of normal biochemical functions and abnormal pathological processes. Growing evidence suggests that cancer cells exhibit increased ROS stress, due in part to disease-induced stimulation, increased metabolic activity, and mitochondrial malfunction. While the relationship between ROS and tumor growth has long been understood, efforts to block significant antioxidant processes that protect cancer cells have proven unsuccessful.
“In these preclinical studies, treatment with AEB3103 demonstrated significantly longer survival in a CLL animal model compared to treatment with the standard of care alone, indicating that AEB3103 has potential as a treatment for hematological malignancies as well as solid tumors,” said Dr. Peng Huang, co-author of the published paper and a professor in the Department of Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center in Houston.
“We are excited about the results that we have presented to date and hope to utilize this novel technology to benefit patients with cancer. This product candidate would require FDA approval, but as we are in the early stages of development, we feel it would be premature to discuss the timeline to approval. We are planning to conduct human trials in the future, potentially in 2018,” states Lowe.
In mid-January, Aeglea also announced the upcoming presentation of new clinical and research data in two presentations at the 2017 American College of Medical Genetics and Genomics Annual Clinical Genetics Meeting being held at in Phoenix, Arizona, in March.
Aeglea’s first presentation will include initial data from its Phase 1, open-label study of AEB1102 in two adult patients with arginase I deficiency. The results show that AEB1102 was well tolerated and effective at reducing arginine levels in the blood of both patients. Treatment with AEB1102 resulted in a dose-proportional decrease in plasma arginine levels of between 25 and 49 percent of pre-dose levels one week after dosing.
The company’s second presentation will include research data on newborn screening protocols. The research data demonstrated that arginase I deficiency can be screened with very high efficiency, which underscores the company’s belief that it is a potential candidate for future addition to the Recommended Uniform Screening Panel.

Rachel Flehinger

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