Rib-X Pharmaceuticals Presents Comprehensive Overview of RX-04 Program

The RX-04 program is focused on the development of three completely novel classes of antibiotic compounds with efficacy against the most difficult to treat, clinically important, multi-drug resistant Gram-negative and Gram-positive pathogens, including NDM-1-producing Enterobacteriaceae, P. aeruginosa, A. baumannii and MRSA. In June 2011, Rib-X signed an exclusive worldwide research collaboration agreement and option for license with Sanofi for novel classes of antibiotics resulting from the RX-04 program.

Erin Duffy, Ph.D., Chief Scientific Officer at Rib-X said, “Clinical data continue to highlight the polymicrobial nature of wound infections, complicated UTI and intra-abdominal infections, skin and soft tissue infections and bacterial infections of the respiratory tract. Furthermore, currently prescribed antibiotics have lost the capacity to cure difficult Gram-negative infections due to β-lactamases and other resistance mechanisms, making the discovery of new classes of antimicrobial agents critical.”

Dr. Duffy continued, “In the RX-04 program, we applied our Nobel-prize-winning crystallography platform in combination with computational design tools to break new ground in antibiotic discovery with the creation of three completely new classes of antibiotics that target a previously unexploited region of the large bacterial ribosome for the treatment of multi-drug resistant (MDR) Gram-positive and Gram-negative superbugs.”

Mark Leuchtenberger, President and Chief Executive Officer at Rib-X said, “The RX-04 program showcases our ability to industrialize our unique platform and our recently signed collaboration with Sanofi validates the advantage we bring with our focus on the three-dimensional properties of antibiotics. We look forward to advancing the RX-04 program into the clinic with Sanofi and replicating our success with new discovery-stage programs like RX-05 and RX-06.”

As a collection, the 14 RX-04 posters provide unique insight into Rib-X’s drug discovery and development process from initial crystal structure analysis to lead optimization and efficacy validation. From its early work in the RX-04 program, Rib-X describes the validation of a clinically unexploited site on the large bacterial ribosome by using natural products to generate crystallographic evidence of desired target binding and protein synthesis inhibition. After detailed structural analysis, three completely novel chemical scaffolds were developed each representing a novel antibiotic class: the pyrrolocytosines, the phenoxazinocytosines and the isocytosines. Rib-X conducted in-depth analyses of the molecular properties of each scaffold with three primary objectives: 1, to demonstrate on-target activity; 2, to confirm that MLSb resistance mechanisms did not affect activity; and 3, to optimize each scaffold along multiple vectors to afford compelling microbiological activity against contemporary MDR Gram-negative strains of bacteria.

Of the three RX-04 classes, the pyrrolocytosines emerged as the lead series. The scaffold was efficiently evolved along several chemical lines to yield multiple series with unparalleled broad spectrum activity. Several distinct series were evolved to show consistent MICs ≤ 4µg/mL against MDR Gram-positives (enterococci and staphylococci) and MDR Enterobacteriaceae, including E. coli and K. pneumoniae. One series showed promising potency against MDR P. aeruginosa and A. baumannii (MIC ranges 0.5 - 16 µg/mL). This broad spectrum activity was confirmed in two studies with external laboratories, showing excellent activity against P. aeruginosa, including MDR strains. From the phenoxazinocytosines, Rib-X found three unique sets of compounds that demonstrated excellent potency (MICs ≤ 4µg/mL) against MDR Gram-positive bacteria and MDR Enterobacteriaceae. Compounds in the phenoxazinocytosine class are now being fine tuned for potency against these species. The Company also found that the molecular properties of the phenoxazinocytosine class are not optimal for overcoming efflux, a defense mechanism employed by Gram-negative bacteria. The isocytosine ureas are being optimized to produce compounds with very broad spectrum activity.

Rib-X also presented data from three preclinical efficacy studies with RX-04 compounds in relevant infection models. In one study, compounds were used to treat peritonitis caused by E. coli, MRSA, K. pneumoniae, A. baumannii or P. aeruginosa and efficacy was evaluated by survival as well as cfu burden reduction in target tissues. Compounds from all three scaffolds with diverse architectures demonstrated in vivo efficacy in models when used to treat infections caused by Gram-positive and Gram-negative organisms. Further evaluation showed that these compounds could deliver efficacy and 100% protection with a single dose. In the second preclinical study, exemplar RX-04 compounds demonstrated efficacy in a murine skin and soft tissue infection (SSTI) model caused by K. pneumoniae. Bacterial load reductions of 1 - 2 log10 cfu were observed over 22 hours; in that same time period, bacterial levels in untreated control tissues rose by approximately 2 log10 cfu. In the third preclinical study, exemplar RX-04 compounds demonstrated efficacy in a murine descending urinary tract infection (UTI) model caused by MRSA. Bacterial load reductions of 4 - 5 log10 cfu were observed over 44 hours; in that same time period, bacterial levels in untreated control tissues rose by 4 - 8 log10 cfu.