PMID- 34491803
OWN - NLM
STAT- MEDLINE
DCOM- 20211102
LR  - 20211102
IS  - 1098-6596 (Electronic)
IS  - 0066-4804 (Print)
IS  - 0066-4804 (Linking)
VI  - 65
IP  - 11
DP  - 2021 Oct 18
TI  - First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of 
      SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial 
      Infections.
PG  - e0120821
LID - 10.1128/AAC.01208-21 [doi]
LID - e01208-21
AB  - 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 T(max) ranged from 2.8 to 8.0 h 
      across cohorts, and the t(1/2) 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 AUC(0-24) 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.).
FAU - Talley, Angela K
AU  - Talley AK
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Thurston, Archie
AU  - Thurston A
AD  - ADME Solutions, Inc., San Diego, California, USA.
FAU - Moore, Grayson
AU  - Moore G
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Gupta, Vipul K
AU  - Gupta VK
AUID- ORCID: 0000-0002-8093-5126
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Satterfield, Myriah
AU  - Satterfield M
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Manyak, Erika
AU  - Manyak E
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Stokes, Suzanne
AU  - Stokes S
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
FAU - Dane, Aaron
AU  - Dane A
AD  - DaneStat Consulting, Macclesfield, United Kingdom.
FAU - Melnick, David
AU  - Melnick D
AUID- ORCID: 0000-0002-4687-6361
AD  - Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT03796910
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20210907
PL  - United States
TA  - Antimicrob Agents Chemother
JT  - Antimicrobial agents and chemotherapy
JID - 0315061
RN  - 0 (DNA, Bacterial)
RN  - 0 (Topoisomerase II Inhibitors)
RN  - EC 5.99.1.3 (DNA Gyrase)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Area Under Curve
MH  - DNA Gyrase/genetics
MH  - DNA, Bacterial
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Humans
MH  - Mice
MH  - *Mycobacterium
MH  - *Mycobacterium Infections, Nontuberculous/drug therapy
MH  - Topoisomerase II Inhibitors
PMC - PMC8525492
OTO - NOTNLM
OT  - DNA gyrase inhibitor
OT  - Mycobacterium avium complex
OT  - Mycobacterium tuberculosis
OT  - SPR720
OT  - aminobenzimidazole
OT  - nontuberculous mycobacteria
OT  - pharmacokinetics
EDAT- 2021/09/08 06:00
MHDA- 2021/11/03 06:00
PMCR- 2021/10/18
CRDT- 2021/09/07 17:15
PHST- 2021/09/08 06:00 [pubmed]
PHST- 2021/11/03 06:00 [medline]
PHST- 2021/09/07 17:15 [entrez]
PHST- 2021/10/18 00:00 [pmc-release]
AID - 01208-21 [pii]
AID - aac.01208-21 [pii]
AID - 10.1128/AAC.01208-21 [doi]
PST - ppublish
SO  - Antimicrob Agents Chemother. 2021 Oct 18;65(11):e0120821. doi: 
      10.1128/AAC.01208-21. Epub 2021 Sep 7.