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

Angela K Talley, Archie Thurston, Grayson Moore, Vipul K Gupta, Myriah Satterfield, Erika Manyak, Suzanne Stokes, Aaron Dane, David Melnick, Angela K Talley, Archie Thurston, Grayson Moore, Vipul K Gupta, Myriah Satterfield, Erika Manyak, Suzanne Stokes, Aaron Dane, David Melnick

Abstract

SPR720 (phosphate prodrug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for nontuberculous 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 to 2,000 mg or repeat total daily doses ranging from 500 to 1,500 mg for 7 or 14 days. SPR720 was well tolerated at daily doses of up to 1,000 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 AEs were reported. The median SPR719 Tmax ranged from 2.8 to 8.0 h across cohorts, and the t1/2 ranged from 2.9 to 4.5 h 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 AUC0-24 was comparable between days 7 and 14. The 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. (This study has been registered at ClinicalTrials.gov under registration no. NCT03796910.).

Keywords: DNA gyrase inhibitor; Mycobacterium avium complex; Mycobacterium tuberculosis; SPR720; aminobenzimidazole; nontuberculous mycobacteria; pharmacokinetics.

Figures

FIG 1
FIG 1
Geometric mean plasma SPR719 concentration-time curves following single ascending doses (SAD) of SPR720 (A) and SP720 of 1,000 mg during fed and fasting states (B).
FIG 2
FIG 2
Geometric mean plasma SPR719 concentration-time curves following multiple ascending doses (MAD) of SPR720 on days 1, 7, and 14.
FIG 3
FIG 3
Study design. Subjects in SAD cohort 4, part 2, were dosed in the fed state; all others were fasting. BID, twice daily; MAD, multiple ascending dose; PK, pharmacokinetic; SAD, single ascending dose; SMG, safety monitoring group; QD, once daily.

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Source: PubMed

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