Single- and Multiple-Ascending-Dose Study of the Safety, Tolerability, and Pharmacokinetics of the Polymyxin Derivative SPR206

Abstract

Carbapenem-resistant Acinetobacter baumannii and Enterobacterales are identified as urgent threats, and multidrug-resistant (MDR) Pseudomonas aeruginosa and extended-spectrum beta-lactamases (ESBL)-producing pathogens are identified as a serious threat by the Centers for Disease Control and Prevention (CDC). SPR206 is a novel polymyxin derivative with potent in vitro and in vivo activity against A. baumannii , P. aeruginosa , and multiple clinically important species of Enterobacterales, including multidrug- and extensively drug-resistant strains. This was a first-in-human (FIH) double-blind, placebo-controlled, single- and multiple ascending dose study of the safety, tolerability, and pharmacokinetics (PK) of SPR206 in 94 healthy subjects. Following IV administration (1 h infusion) at single doses of 10 mg to 400 mg and multiple doses of 25 mg to 150 mg q8h for 7 days and 100 mg q8h for 14 days, SPR206 was generally safe and generally well tolerated. While the incidence of adverse events increased with dose, most were of mild severity. Systemic exposure (C max and AUC) to SPR206 was approximately dose proportional, time to peak concentrations ranged from 1.1 to 1.3 hours, and half-life ranged from 2.4 to 4.1 hours. No appreciable accumulation occurred with repeated dosing of SPR206 and trough concentrations suggest that steady state was achieved by Day 2. Urinary excretion of unchanged SPR206 was dose dependent across single- (SAD) and multiple ascending dose (MAD) cohorts, and the percentage of dose excreted as SPR206 was up to >50%. Importantly, no evidence of nephrotoxicity was observed over 14 days of 100 mg q8h dosing of SPR206; a dosing regimen anticipated to exceed requirements for clinical efficacy.

Efficacy and In Vitro Activity of Novel Antibiotics for Infections With Carbapenem-Resistant Gram-Negative Pathogens

“…Non-clinical toxicology studies in mice, rats and non-human primates have found that SPR206 has a lower risk for kidney toxicity than colistin and polymyxin B ( Brown et al., 2019 ; Zhang et al., 2020 ). A double-blind placebo-controlled single and multiple-ascending-dose study of the safety, tolerability, and pharmacokinetics of SPR206 was conducted on 94 healthy subjects, and SPR206 was generally safe and well-tolerated ( Bruss et al., 2021 ).…”

A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens

“…There have been efforts to address their pharmacological liabilities with the development of new polymyxin analogs derived from polymyxin B and colistin 8 , 17 – 22 , 32 – 34 . While many novel polymyxin B and colistin derivatives have been generated using this approach, very few have entered clinical evaluation 19 , 35 . The polymyxin B analog SPR206 has successfully completed a Phase 1 study of both single- and multipleascending dose cohorts 35 .…”

“…While many novel polymyxin B and colistin derivatives have been generated using this approach, very few have entered clinical evaluation 19 , 35 . The polymyxin B analog SPR206 has successfully completed a Phase 1 study of both single- and multipleascending dose cohorts 35 . While no nephrotoxicity was observed at up to 100 mg q8h in the multiple-ascending dose cohort, neurotoxicity at single doses exceeding 200 mg was observed 35 .…”

“…The polymyxin B analog SPR206 has successfully completed a Phase 1 study of both single- and multipleascending dose cohorts 35 . While no nephrotoxicity was observed at up to 100 mg q8h in the multiple-ascending dose cohort, neurotoxicity at single doses exceeding 200 mg was observed 35 . These drug development efforts have primarily focused on modification of the N-terminus of the polymyxin B and colistin scaffold with very limited exploration of the remaining lipopeptide scaffold, especially the cyclic ring 19 , 21 .…”

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

“…It has thus a potential broad-spectrum of activity ( Brown et al., 2019 ). Data from a phase I clinical trial were recently published with no evidence of nephrotoxicity and supporting further development of SPR206 ( Bruss et al., 2021 ). Two additional phase I trials ( Figure 4B ) were also completed in December 2021: a bronchoalveolar lavage clinical trial assessing SPR206 penetration into the lungs, and a renal failure study.…”