First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections

Abstract

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.

In vitroactivity andin vivoefficacy against non-tuberculous mycobacteria of SPR719, the active moiety of the novel oral benzimidazole prodrug SPR720

“…Current therapeutics remain challenging because of the long treatment duration and poor tolerability, with many patients left with residual lung dysfunction (15,17) or failing to respond to treatment, relapsing, or developing macrolide resistance (18). SPR720 is a novel aminobenzimidazole antimicrobial phosphate prodrug that prevents bacterial growth by inhibiting bacterial DNA gyrase (19,20) and is orally bioavailable in humans (21). Specifically, SPR719 targets ATPase located on the bacterial gyrase B subunit of the heterotetrameric gyrase protein, a mechanism that is distinct from fluoroquinolones and other currently marketed antibiotics, so it is unlikely for SPR719 to show cross-resistance with any standard-of-care agents due to alteration of the target enzyme.…”

Advances in Key Drug Target Identification and New Drug Development for Tuberculosis

“…A randomized, double-blind, placebo-controlled, phase I clinical trial evaluated the safety, drug resistance, and pharmacokinetics of SPR720. The results showed that SPR720 was well tolerated orally, and the most common adverse events were mild to moderate gastrointestinal reactions and headache, which were shown to be dosedependent (ClinicalTrials.gov Identifier: NCT03796910) [78]. Besides, active compounds with aromatic skeleton structures were identified through high-throughput screening, and they showed desirable gyrB inhibitory and anti-Mtb activities in vitro (Figure 2(c)) [79][80][81] and then religating the seal.…”

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus

“…Recently, a novel benzimidazole (SPR719, Fig. 1A ) entered early clinical development for mycobacterial lung diseases ( 19 ). Benzimidazoles target the ATPase domain of the DNA gyrase complex, located on its B subunits and required to drive the catalytic cycle ( 20 ), distinct from the fluoroquinolone binding site.…”