RX-04

Description

 

Our most advanced preclinical program, the RX-04 program is focused on using a discrete, novel binding site within the ribosome to design and develop new classes of antibiotics to treat some of the most deadly and difficult-to-treat, multi-drug resistant Gram-positive and Gram-negative infections. Pathogens associated with these infections include E.coli, Klebsiella pneumoniae, Enterobacter species, Pseudomonas aeruginosa and Acinetobacter baumannii and MRSA. Using our proprietary drug discovery platform, we have developed three novel classes of antibiotics in less than three years that bind to this ribosome site, show high levels of antibacterial activity against a number of these pathogens, and show compelling efficacy in multiple animal models of infection.

 

Based on the preclinical data from the RX-04 program and on studies published in Antimicrobial Agents and Chemotherapy, we believe that RX-04 is the only drug development program that has produced compounds with demonstrated in vitro coverage of all of the following multi-drug resistant Gram-positive bacteria: Enterococci, Streptococci and Staphylococci, including MRSA; and multi-drug resistant and extremely drug resistant Gram-negative bacteria: Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and E. coli. These pathogens account for a majority of hospital-acquired infections, are associated with high rates of morbidity and mortality and are increasingly multi-drug resistant, meaning that they are resistant to more than three classes of antibiotics. Because the RX-04 compounds bind to a novel site on the ribosome that has never before been exploited by marketed antibiotics and because they have proprietary chemical characteristics distinct from all current classes of broad-spectrum or Gram-negative therapies, we have shown that their activity is unaffected by cross-resistance to current therapies, and we expect lower resistance development than current therapies. These compounds are also small molecules, thereby providing us with the potential to ultimately offer an IV-to-oral switch for maximum flexibility. Furthermore, in vitro preclinical studies have shown that these compounds have little propensity for drug-drug interactions, have demonstrated no cardiovascular toxicity in in vitro models, are not mutagenic and do not appear to have undesired pharmacological interactions. Based on these characteristics, we believe that the RX-04 program has significant potential to produce drug candidates that directly address the urgent public health threat caused by the most difficult to treat pathogens. 

 

Status

 

In June 2011, we entered into a collaboration and license agreement with Sanofi related to our RX-04 program. Under this agreement, Sanofi has the right to license an unlimited number of product candidates targeting a discrete binding site within the ribosome. We retain all rights pertaining to our proprietary drug discovery platform, including all other binding sites within the ribosome and all future programs, as well as to any RX-04 compound that Sanofi does not exercise its option to develop during the three-year term of the collaboration. We have received $22.0 million through March 31, 2012 in upfront and milestone payments under the collaboration, including the receipt of a payment of $3.0 million from Sanofi in January 2012 for the achievement of a research milestone. For each RX-04 product developed by Sanofi, we are eligible for up to $9.0 million in potential research milestone payments, up to $27.0 million in potential development milestone payments relating to initiation of Phase 1, 2 and 3 clinical trials, up to $50.0 million in potential regulatory milestone payments relating to approvals in various jurisdictions including the United States, the European Union and Japan, up to $100.0 million in potential commercial milestone payments, and tiered percentage royalties of up to 10% on sales from products commercialized under the agreement, if any. We also have the right under the collaboration to co-commercialize one RX-04 product of our choosing with Sanofi in the United States. We are currently collaborating with Sanofi on ongoing preclinical development and lead generation and, as part of a comprehensive safety assessment, we have just completed in vitro and in vivo profiling of the first cohort of leads from the RX-04 program that demonstrated strong potency and efficacy. These results have informed the next iteration of design and optimization. We expect the results of this optimization round to inform the selection of a lead compound in 2012 for toxicology studies followed by Phase 1 studies in humans.

 

Recent Data

 

At ECCMID 2011, data were presented supporting the efficacy of sample compounds from each of the three novel classes of protein synthesis inhibitors from the RX-04 program. The compounds were studied in vivo in two models of Gram-negative infection, Escherichia coli peritonitis and Klebsiella pneumoniae skin and soft tissue infection and in a Gram-positive infection model of methicillin-resistant Staphylococcus aureus (MRSA) kidney abscess. Bacterial burden reduction in all three models was exhibited with at least one compound and a number of compounds were highly effective in the two Gram-negative infection models. The design, optimization and activity of each of the three novel antibiotic classes, which yielded multiple series of compounds with broad spectrum activity, were presented. Each class evolved from a unique scaffold designed to target the large ribosomal subunit. The direct impact on protein synthesis inhibition, and thus ribosome maturation, was confirmed. In vitro activity was demonstrated against clinical isolates of particularly difficult to treat enteric pathogens containing extended spectrum beta-lactamases and KPC and NDM-1 carbapenemases.