AV-006/ARX-1796 is a proprietary prodrug of Avibactam®, a beta-lactamase inhibitor which FDA approved in 2015 as a component of the intravenous-only antibiotic AvyCaz®. Avibactam’s United States composition of matter patent expires in early 2022, with Hatch-Waxman extensions to January 2026. Only 7% of FDA-approved IV avibactam is absorbed orally, making it unsuitable for oral administration, since to be a useful drug at least 30% of the administered active ingredient should be absorbed into the bloodstream. In Arixa’s first-in-human clinical trial and based on comparison to historical IV avibactam pharmacokinetics, the absolute bioavailability (%F) of AV-006/ARX-1796 as measured by blood avibactam appears to be ~80% at the oral dose that delivers exposures similar to the approved IV dose (which is a 2-hour infusion of 500 mg of avibactam). Importantly, in contrast to other oral BLI programs that we are aware of whose active ingredients are agents unapproved by FDA, AV-006/ARX-1796 delivers the exact FDA-approved avibactam molecule into the bloodstream. Our prodrugs are protected by a broad composition of matter patent through at least 2038.
Beta-lactamase inhibitors, or “BLIs”, restore the effectiveness of beta lactam antibiotics such as penicillins, cephalosporins, carbapenems and monobactam antibiotics, which together comprise approximately 55% of all intravenous antibiotic prescriptions in the United States. BLIs work by protecting the companion beta-lactam antibiotic from being destroyed by a family of more than 2000 enzymes which bacteria manufacture to defend themselves from antibiotics. The only orally absorbed beta-lactamase inhibitor ever marketed was approved by FDA in 1984 as a component of Augmentin®, which had peak sales of $2.1 billion/year. Avibactam, the compound we are making oral, is a third-generation beta-lactamase inhibitor whose spectrum is far superior to the previous generations of beta-lactamase inhibitors, including the oral one in Augmentin. We are pairing our lead prodrug with the cephalosporin antibiotic ceftibuten. As shown in the MIC study below avibactam restores ceftibuten’s effectiveness against resistant pathogens and the combination compares favorably with other oral antibiotics that we are aware of that are in development.
MIC Study & Microbiology
When paired with an appropriate oral beta-lactam antibiotic, avibactam restores the antibiotic’s effectiveness, as shown by the MIC data presented below, for which a number of antibiotics on the market or in development were tested by IHMA against a panel of recent clinical isolates. Arixa color coded the table, using CLSI breakpoints when available (green – susceptible, yellow – intermediate, red – resistant). Breakpoints for combinations of avibactam or clavulanic acid with approved cephalosporins have not been established, and the Company is using CLSI breakpoints of the approved cephalosporin. Sulopenem and tebipenem breakpoints have not been established, and the Company’s estimates use published human serum PK and MIC data for provisional breakpoints.