On April 10, 2024 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting hard-to-treat tumors and viruses, reported positive preclinical data regarding the Company’s next-generation anthracycline, Annamycin, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 5-10, 2024 in San Diego, CA (Press release, Moleculin, APR 10, 2024, View Source [SID1234641983]).
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The poster titled, Non-cardiotoxic Properties of Annamycin, a Clinically Evaluated Anthracycline and Potent Topoisomerase 2β Poison, was presented in the "Late-Breaking Research: Experimental and Molecular Therapeutics 2" session held on Monday, April 8th. The presented poster outlined results from the assessment and comparison of the potency of doxorubicin (a commonly prescribed anthracycline) and Annamycin, Moleculin’s next-generation anthracycline, against topoisomerase II-alpha and II-beta and determine their impact on physiology of human cardiomyocytes demonstrating no pathologic changes in mice hearts following chronic in vivo exposure.
"Cardiotoxicity continues to be a significant side effect limiting the clinical use of anthracyclines, despite anthracyclines representing some of the most important treatments available for AML and Advanced STS. These data, documenting lack of cardiotoxicity of Annamycin and aligned with the data demonstrated to date in our ongoing clinical trials, bolster our confidence in Annamycin potential to offer patients a safe and effective treatment option. Interestingly, the presented data demonstrates that Annamycin appears to be a significantly more potent inhibitor of topoisomerase II-beta than doxorubicin providing validation for additional studies to reevaluate the role of topoisomerase II-beta in anthracycline induced cardiotoxicity," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin.
"Additionally, with our recently issued patent, which covers composition of matter protection across all indications, we have the potential to expand the development of Annamycin into greater patient populations in indications where cardiotoxicity remains a significant unmet need. We remain highly encouraged by Annamycin and committed to advancing its development," concluded Mr. Klemp.
As part of the presented data, the potency of Annamycin and doxorubicin to inhibit topoisomerase II was tested in DNA relaxation assays using recombinant topoisomerase II-alpha and II-beta with kinetoplast as the DNA substrate. Annamycin and doxorubicin cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models.
Key Data Highlights:
Annamycin demonstrated to be a more potent topoisomerase II-alpha and II-beta poison than doxorubicin.
In contrast to doxorubicin:
Annamycin does not affect viability of established culture of human iPSCc cardiomyocytes (tested up to 1.5 μM)
Annamycin does not affect contractility or the electric potential of the cardiomyocytes
Rat cardiomyocytes (H9c2) appear to be resistant to ANN while sensitive to DOX
Annamycin is well tolerated by the animals even at schedules exceeding the therapeutic dosage while ex vivo pathology examination of the mice confirmed no toxicity to the heart/myocardium.
These data are clearly aligned with the lack of drug-related cardiotoxic events in Annamycin-treated patients in ongoing clinical trials
The role of topoisomerase II-beta in cardiotoxicity of anthracyclines should be further investigated
A video on the comparison of cardiotoxic effects of Annamycin and doxorubicin on human cardiomyocytes can be accessed here
The Company also announced that the United States Patent and Trademark Office (USPTO) formally issued U.S. Patent number 11,951,118 titled, "Preparation of Preliposomal Annamycin Lyophilizate" (the ‘118 patent’) to Moleculin and The University of Texas System Board of Regents.
Annamycin is currently being evaluated in ongoing clinical trials for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases. For more information about the ongoing trials, please visit clinicaltrialsregister.eu: EudraCT 2020-005493-10 or clinicaltrials.gov: NCT05319587; and clinicaltrials.gov: NCT04887298, respectively.