ARIXA PHARMACEUTICALS: Announces Publication of Seminal Paper Demonstrating First Oral Prodrug of Avibactam

Arixa Pharmaceuticals issued the following announcement on Nov. 12.

Arixa Pharmaceuticals™, Inc., a company dedicated to developing oral antibiotics for drug-resistant Gram-negative infections, today announced publication of a paper describing the chemistry of its oral prodrug of avibactam, a previously intravenous (IV)-only beta lactamase inhibitor (BLI). The article, entitled “Orally Absorbed Derivatives of the Beta-Lactamase Inhibitor Avibactam. Design of Novel Prodrugs of Sulfate Containing Drugs,” was published online in The Journal of Medicinal Chemistry (DOI: 10.1021/acs.jmedchem.8b01389) and was selected as an “ACS Editors’ Choice.” The lead author is Eric M. Gordon, Ph.D., Co-founder and Chief Scientific Officer of Arixa.

In addition, the Company was recently granted a broad composition of matter patent, patent No. 10,085,999, by the U.S. Patent and Trademark Office covering use of its prodrug chemistry to create oral prodrugs of avibactam, as well as relebactam, nacubactam and ETX2514, which share the same chemical scaffold. Arixa’s lead candidate, ARX-1796, a proprietary, orally-available prodrug of avibactam, is anticipated to enter into a Phase 1 study with data available in mid-2019.

ARX-1796 is the only oral BLI in development whose active ingredient is an FDA-approved compound, which the company believes substantially decreases its risk of successful development. It could eventually be the first oral BLI since clavulanic acid was approved in 1984 as part of the antibiotic Augmentin® (amoxicillin-clavulanic acid), once a $2.1 billion annual revenue generating medicine. Avibactam has much broader coverage than clavulanic acid against beta lactamase enzymes that bacteria make to defend themselves against antibiotics such as penicillins, cephalosporins and carbapenems.

“The conventional wisdom had been that synthesis of a non-alkylating orally-bioavailable prodrug of avibactam was not possible,” said Daniel H. Rich, Ph.D., Emeritus Ralph F. Hirschmann Professor of Medicinal and Organic Chemistry at the University of Wisconsin-Madison. “The authors of this paper demonstrated that it could be done. This novel orally-available form of a critically important beta-lactamase inhibitor is a stunning accomplishment in prodrug design and synthesis.”

Avibactam was approved by the U.S. Food and Drug Administration (FDA) in 2015 as the BLI in Avycaz®, an intravenous combination with a cephalosporin, ceftazidime, for the treatment of a number of indications caused by Gram-negative pathogens. Arixa’s invention opens the way for an orally-available avibactam to be part of a next-generation oral antibiotic combination for resistant infections, a critical unmet medical need.

“Common Gram-negative infections such as complicated urinary tract infections are becoming a major treatment challenge because of increasing rates of multidrug resistance,” said Jose Vazquez, M.D., Professor, Department of Medicine and Chief of Infectious Diseases at Medical College of Georgia at Augusta University. “There are a progressively larger number of patients who cannot be treated with oral antibiotics and we are forced to treat them with intravenous agents, which are costly, are associated with their own complications and require hospital admission. The option to administer an oral antibiotic containing avibactam to my patients with infections due to pathogens resistant to other oral agents, and thus avoiding intravenous administration and a hospital stay, would always be considered an important advance.”

“Beta-lactamase inhibitor combinations have become a mainstay of antimicrobial therapy, but clavulanic acid, approved by FDA in 1984, is the only inhibitor available to treat patients that is orally bioavailable,” said Karen Bush, Ph.D., an expert in beta-lactamase resistance and Professor of Practice, Biotechnology at Indiana University - Bloomington. “This paper describes prodrugs of the broad-spectrum inhibitor avibactam, providing the potential for an oral inhibitor combination that can be administered outside the hospital setting, with utility against multidrug-resistant pathogens.”

John Freund, M.D., Co-Founder and chief executive officer of Arixa added, “The most commercially successful antibiotics have been orally available compounds, such as Augmentin and Zithromax®, but there has not been a good, new oral antibiotic for antibiotic-resistant Gram-negative infections in years. Resistance to current agents has become a serious public health issue. We look forward to initiating our Phase 1 human clinical study of ARX-1796 and disclosing top-line data from the study in mid-2019.”

About ARX-1796

ARX-1796 is a proprietary oral prodrug of avibactam, the first of a new class of BLI’s known as diazabicyclooctanes, or “DBOs”, that offer much broader coverage against beta-lactamase enzymes than clavulanic acid or tazobactam, the previously-approved beta-lactamase inhibitors. Like other BLIs, Avibactam is designed to protect beta-lactam antibiotics such as penicillins, cephalosporins and carbapenems from being destroyed by beta-lactamase enzymes that bacteria produce to defend themselves. Unfortunately, very little of avibactam is absorbed orally, making it unsuitable for oral administration. Avibactam was approved by the FDA in 2015 as a component of the intravenous-only antibiotic AvyCaz® in combination with the cephalosporin antibiotic ceftazidime.

Arixa’s technology has produced several prodrugs of avibactam demonstrating oral absorption levels of 80% in monkeys and 100% in dogs. Importantly, unlike other programs in development to create novel oral beta-lactamase inhibitors, Arixa’s prodrugs have been shown to deliver a modern, FDA-approved active ingredient into the bloodstream.

Original source can be found here.

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