On November 8, 2016 Aeglea BioTherapeutics, Inc. (NASDAQ:AGLE), a biotechnology company committed to developing enzyme-based therapeutics in the field of amino acid metabolism to treat genetic rare diseases and cancer, reported findings from a preclinical study demonstrating that its lead product candidate, AEB1102, an engineered human arginase I enzyme designed to degrade the amino acid arginine in blood, exhibited enhanced inhibition of tumor growth in a mouse model in combination with immunotherapy checkpoint inhibitors (Press release, Aeglea BioTherapeutics, NOV 8, 2016, View Source [SID1234516424]). The study data will be presented by Scott Rowlinson, Ph.D., vice president of research at Aeglea, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 2016 Annual Meeting in Maryland on Friday, November 11 from 12:15 p.m. – 1:30 p.m. ET (Abstract #275). Schedule your 30 min Free 1stOncology Demo! Many tumors are predicted to be dependent on arginine for survival. AEB1102 is designed to degrade arginine and deprive tumor cells of this essential nutrient, therefore targeting a tumor growth pathway that cannot otherwise be blocked by small molecule or antibody-based approaches. However, the role of arginine in the tumor microenvironment is paradoxical since tumor associated myeloid-derived suppressor cells (MDSC) degrade arginine (via expression of arginase) to inhibit proliferation of anti-tumor-infiltrating lymphocytes. Based on this observed role of MDSC, AEB1102 would not be expected to complement the anti-tumor efficacy of immuno-oncology checkpoint inhibitors. Despite this, the results showed that, compared to immunotherapy or AEB1102 monotherapy, a combination treatment of AEB1102 with PD-1 pathway inhibitors decreased tumor size and increased survival in preclinical mouse models.
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"The results of these preclinical studies are encouraging as they not only reinforce previous data supporting the use of AEB1102 as a monotherapy targeting a metabolic vulnerability of cancer, but open the door for potential broader use in combination with immunotherapies. We believe combination therapies will be a key part of unlocking the full potential of cancer treatments," said David G. Lowe, Ph.D., co-founder, president and chief executive officer of Aeglea. "We are making exciting progress with the development of AEB1102 and look forward to continuing to investigate its use as a potential monotherapy and combination therapy for people with cancer."
Results of Preclinical Study
In vivo treatment of a colon cancer mouse model (CT26) with AEB1102 showed an increased life span with AEB1102 monotherapy compared to the untreated control group (46%, p<0.001). CT26 mice dosed with standard monotherapy using antibodies targeting PD-1 and PD-L1 increased life span by 0% (p=0.5) and 29% (p=0.002), respectively. Most notably, combination therapy of AEB1102 with PD-1 or PD-L1 inhibitors resulted in increased life spans compared to either AEB1102 or immunotherapy monotherapy. Treatment with AEB1102 in combination with PD-1 or PD-L1 inhibitors increased life span by 67% (p<0.001) in both cases. The improved response is currently believed to be the result of AEB1102 directly inhibiting tumor growth through depletion of arginine levels as well as potentially further sensitizing tumors to immunotherapy treatment. These findings suggest that combining AEB1102 with PD-1 or PD-L1 inhibitors may have the potential to further improve outcomes in cancer patients.
About AEB1102
AEB1102 is an engineered human arginase I enzyme designed to degrade the amino acid arginine. Aeglea is developing AEB1102 to treat two extremes of arginine metabolism, including arginine excess in patients with Arginase I deficiency, as well as some cancers which have been shown to have a metabolic dependency on arginine. In patients with Arginase I deficiency, AEB1102 is intended for use as enzyme replacement therapy to restore the function of arginase I in patients and return elevated blood arginine levels to the normal physiological range. Aeglea is currently conducting a Phase 1 trial in cancer patients with advanced solid tumors to evaluate the safety and tolerability of AEB1102. Data from this trial demonstrated that AEB1102 has the ability to reduce blood arginine levels, providing initial human proof of mechanism.