On March 9, 2023 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 the publication of data evaluating Annamycin’s performance as an anthracycline designed to avoid the cardiotoxicity typically associated with currently prescribed anthracyclines (Press release, Moleculin, MAR 9, 2023, View Source [SID1234628379]). The manuscript titled, "Anthracycline-induced cardiotoxicity – are we about to clear this hurdle?1," was published in the peer-reviewed European Journal of Cancer
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The published manuscript discusses clinically evaluated doxorubicin analogs that were developed as potentially non-cardiotoxic anticancer agents and includes Annamycin. The anthracycline family of drugs (i.e., doxorubicin, daunorubicin, epirubicin, idarubicin) has significantly contributed to marked improvements of overall survival (OS) during the last few decades and represents one of the most potent cytostatic drugs for cancer treatment across various histologies (5-year overall survival of 80
Despite the major impact of anthracyclines on overall survival in the treatment of a wide spectrum of solid tumors and hematologic malignancies, the development of life-threatening cardiotoxicity still remains a huge challenge for physicians treating cancer patients. Annamycin has consistently demonstrated little to no cardiotoxicity to date and we continue to be highly encouraged by its potential. The discussion throughout this manuscript further demonstrates that the development of non-cardiotoxic anthracyclines is not only feasible, but an elegant and much-needed approach to eliminate this potentially life-threatening adverse event in patients with cancer," commented Walter Klemp, Chairman and CEO of Moleculin. "We look forward to continuing to advance the development of Annamycin with the goal of offering a non-cardiotoxic treatment option for patients
Key Highlights
An initial key modification leading to the design of Annamycin was the replacement of a basic amine at the C-3’ position with a hydroxy group, which was shown to significantly reduce cardiotoxicity when compared with doxorubicin. Removal of the basic amine from doxorubicin not only decreased cardiotoxicity, but also led to increased activity against multidrug resistant (MDR-1) tumors
In addition to the C-3’ hydroxylation, Annamycin incorporates several important structural modifications, including demethoxylation at C-4, epimerization at C-4’, and for the first time in this class of agents, an iodine atom was introduced at C-2’ position
L-ANN (Annamycin) has been shown to be a consistently more potent inducer of apoptosis in vitro than doxorubicin and more efficacious in vivo (in animal models) against MDR-1 tumors
Separate in vitro studies documented L-ANN as a potent TOPO-II inhibitor
Another critical property differentiating L-ANN from doxorubicin is its organotropism. This indicates that there is a high uptake of L-ANN in several organs, including the lungs, which significantly exceeds that of doxorubicin
An incremental increase was noted for L-ANN and in two animal studies the Cmax of L-ANN in lungs was > 30-fold greater than that of doxorubicin. With weekly intravenous doses of 5.2 mg/kg L-ANN for 6 weeks or 3.1 mg/kg and 4.2 mg/kg L-ANN for 10 weeks, the cardiotoxicity of L-ANN was less than equitoxic doses of doxorubicin
The design and development of novel, potentially non-cardiotoxic anthracyclines that are already under clinical evaluation suggests that the approach based on structural modification leading to elimination of drug interactions with cardiotoxic pathways/targets may be a valid and highly promising approach. These promising results suggest that the identification of non-cardiotoxic, clinically effective anthracycline-based anticancer agent is a real possibility
The authors of the article include Dr. Wolfram Dempke (Moleculin’s European Chief Medical Officer), Dr. Sandra Silberman (Moleculin’s Chief Medical Officer – New Products) and Dr. Waldemar Priebe (Moleculin’s Chair – Scientific Advisory Board
Annamycin is the Company’s next-generation anthracycline that has been designed to be non-cardiotoxic and has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin (a commonly prescribed anthracycline), as well as demonstrating the ability to avoid the multidrug resistance mechanisms that typically limit the efficacy of doxorubicin and other currently prescribed anthracyclines. Annamycin is currently in development for the treatment of relapsed or refractory AML and STS lung metastases and the Company believes it may have the potential to treat additional indications.