First-Time-in-Human Study and Prediction of Early Bactericidal Activity for GSK3036656, a Potent Leucyl-tRNA Synthetase Inhibitor for Tuberculosis Treatment

Abstract

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0–τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0–14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.)

Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase inMycobacterium tuberculosis

“…New chemical scaffold with novel inhibition mechanism against Mtb is being actively sought. An oxaborole compound GSK3036656 that inhibits Mtb leucyl-tRNA synthetase is currently undergoing clinical trial (6).…”

Aminoacyl-tRNA Synthetases as Valuable Targets for Antimicrobial Drug Discovery

“…However, its development was halted in phase II clinical trials due to the rapid emergence of resistance [ 171 ]. Furthermore, a series of novel 3-aminomethyl-4-halogeno-benzoxaboroles were synthesized and preclinically evaluated by GSK as selective inhibitors against Mycobacterium tuberculosis LeuRS (Mtb-LeuRS) [ 172 ]. The promising lead compound GSK3036656 ( Figure 12 a) demonstrated a MIC value of 23.5 ng/mL against M. tuberculosis strain H37Rv and an IC 50 value of 58.8 ng/mL against Mtb-LeuRS in vitro.…”

“…The promising lead compound GSK3036656 ( Figure 12 a) demonstrated a MIC value of 23.5 ng/mL against M. tuberculosis strain H37Rv and an IC 50 value of 58.8 ng/mL against Mtb-LeuRS in vitro. In addition, this compound showed no serious side effects following single or multiple doses and was selected for further clinical studies [ 172 ]. Most recently a series of benzhydrol-oxaborole derivatives were identified that selectively inhibited S. pneumoniae LeuRS and demonstrated anti-pneumococcal activity, with the best compound having a MIC of 4 μg/mL [ 173 ].…”

From Patient to Molecule: In Pursuit of Universal Treatments for TB

“…Early examples of Gates MRI's investment in the model‐informed drug development (MIDD) approach include physiologically‐based pharmacokinetic modeling to inform first‐in‐human dose selection for a phase I trial, population‐pharmacokinetic modeling to inform sampling schemes for a phase II early bactericidal activity trial, and extensive clinical trial simulation to support sample size requirements, subject selection criteria, and evaluate the interferon‐gamma release assay threshold sensitivity on end point determination for our upcoming BCG revaccination trial. There is a clear roadmap for the model‐informed drug development approach laid out by our industrial and academic partners in collaboration with colleagues at the Gates Foundation. Our commitment is to adopt this roadmap with the guidance of global regulatory authorities.…”