IV Antibiotics Potentiator Platform for Treating MDR Gram-Negative Infections in the Hospital
There has been a significant decrease in the number of novel IV antibiotics in development and approved over the past 40 years for the treatment of Gram-negative infections. The physiology of Gram-negative bacteria – specifically the make-up of the outer-membrane of these bacteria – is one of the primary roadblocks hindering innovation.
While Gram-positive bacteria possess a single phospholipid cell membrane, Gram-negative bacteria have a phospholipid inner membrane (akin to the Gram-positive membrane), plus an outer membrane bilayer composed primarily of phospholipid at the inner surface and lipopolysaccharide (LPS) at the outer leaflet. It is this layer of highly polar, negatively charged LPS that excludes many excellent target-based inhibitors, including a trove of clinically useful Gram-positive antibiotics from entering Gram-negative bacteria to do their work.
Unfortunately, a distinct incongruence between chemical properties required for Gram-negative penetration (both membranes), and that imposed by many of the known (and novel) bacterial targets, means that simple (or complex) medicinal chemistry tactics have not been able to provide a solution. Spero Therapeutics believes its IV Potentiator Platform approach (SPR206 & SPR741) to LPS disruption will be the solution.
SPR206 is an IV direct-acting antibiotic within the potentiator platform that has shown antibiotic activity against MDR Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, Acinetobacterbaumannii and Pseudomonas aeruginosa in preclinical studies. SPR206 completed non-clinical, IND-enabling studies supporting its advancement as a clinical candidate designed to treat MDR and extensively drug-resistant (XDR) bacterial strains. Based on microbiological and in vivo testing, Spero believes that SPR206 has the potential to offer a broad-spectrum of activity, including against extensively drug-resistant (XDR) bacterial strains, together with improved safety and tolerability compared with other molecules in its class. Spero initiated a Phase 1 clinical trial of SPR206 in December 2018, designed as a double-blind, placebo-controlled, ascending dose, multi-cohort study in healthy subjects.
SPR741 is an IV product that does not have any significant antimicrobial activity on its own. However, when combined with an antibiotic, SPR741 has demonstrated the ability to expand the spectrum and potency of the co-administered antibiotic against Gram-negative bacteria, including organisms identified by the CDC and WHO as urgent and serious threats. SPR741 has demonstrated the ability to expand the spectrum and enhance the potency of more than two dozen existing antibiotics and enabled expanded utility against resistant Gram-negative pathogens. SPR741 has completed Phase 1a and 1b trials highlighting its tolerability and pharmacokinetic profile.