Novel Intravenous Product Candidate 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. We believe SPR206 as a direct acting IV potentiator may effectively lead to LPS disruption.
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. In January 2020, Spero announced data from a Phase 1 clinical trial designed as a double-blind, placebo-controlled, ascending dose, multi-cohort study in healthy subjects. Preliminary Phase 1 clinical data suggests that SPR206 is well-tolerated at doses that are likely to be within a therapeutic range for target MDR Gram-negative bacterial infections and has a safety profile that Spero believes supports the further development of SPR206. In conjunction with its alliance partners, Spero plans to conduct a Phase 1 bronchoalveolar lavage (BAL) clinical trial assessing the penetration of SPR206 into the pulmonary compartment in the second half of 2020 as well as initiate a renal impairment study of SPR206.