Safety, Tolerability, and Pharmacokinetics of Telacebec (Q203), a New Antituberculosis Agent, in Healthy Subjects

Abstract

Telacebec (Q203) is a potent drug candidate under clinical development for the treatment of drug-naïve and drug-resistant tuberculosis. The first-in-human randomized, placebo-controlled, double-blind, dose-escalation Phase 1A trial (Q203-TB-PI-US001) was conducted to evaluate the safety, tolerability, and pharmacokinetics of telacebec. A total of 56 normal, healthy, male and female subjects (42 active and 14 placebo) were enrolled in the study. The doses of telacebec were 10 mg (Cohort 1), 30 mg (Cohort 2), 50 mg (Cohort 3), 100 mg (Cohort 4), 200 mg (Cohort 5), 400 mg (Cohort 6), and 800 mg (Cohort 7) in a fasted state. Subjects participating in Cohort 4 were also enrolled in Cohort 8 to investigate the food effect on the pharmacokinetics of telacebec after a high-fat meal. In all subjects dosed with telacebec (10 – 800 mg), telacebec was well tolerated and did not lead to any significant or serious adverse events. Following a single oral administration of telacebec (10 – 800 mg), telacebec plasma concentration reached the maximal plasma concentration (C max ) in average 2.0 – 3.5 h and showed multi-exponential decline thereafter. The area under the plasma concentration vs. time curve (AUC) was approximately dose-proportional. A significant increase in plasma concentrations was observed in the fed condition compared with the fasted condition with the geometric mean ratio of 3.93 for C max . Moderate delay in T max (4.5 h) was also observed in the fed condition. These results, combined with the demonstrated activity against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis , support further investigation of telacebec for the treatment of tuberculosis.

Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB)

“…The mean AUC from time zero to last measurement (AUC last ) has a statistically significant dose proportionality relationship. The half-life of telacebec increased with its dosage and ranged from 21.13 h to 150.79 h. A food effect was observed: serum levels of telacebec were significantly higher in a fed state compared to a fasted state [18].…”

“…Finding(s) Phase 1a [11,18]  First-in-human trial  Telacebec was administered as single ascending doses (up to 800 mg)  Food effect was evaluated  No serious adverse events reported  Adverse events did not correlate to drug dosage  Plasma concentration of telacebec was significantly higher when administered in a fed state Phase 1b [11]  Ascending multiple dose trial  Telacebec was administered with food daily for 14 days  No serious adverse events reported  No reports of ECG-related adverse events…”

“…The first-in-human trial was conducted between August 2015 and July 2016. The trial was a randomised, double-blind, placebo-controlled, dose-ascending study designed primarily to evaluate the safety and tolerability of telacebec [18]. The study involved 56 healthy male and female subjects, with 42 subjects receiving a single dose of telacebec at 10 mg, 30 mg, 50 mg, 100 mg, 200 mg, 400 mg, or 800 mg.…”

“…The drug candidate was well-tolerated with no incidences of serious adverse events. In terms of pharmacokinetics, the maximum plasma concentration (C max ) as well as the area under the curve (AUC) increased with the dosage that was administered [18]. The mean AUC from time zero to last measurement (AUC last ) has a statistically significant dose proportionality relationship.…”

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

“…This unique mode of action of telacebec allows MDR- and XDR-TB to be easily targeted. The drug was well tolerated during a phase I trial and there were no serious AEs with single oral doses ranging from 10 to 800 mg [ 171 ]. In the phase IIa study [ 172 ], treatment-naïve patients with pulmonary DS-TB were given 100 mg, 200 mg, or 300 mg of telacebec for 14 days with a reduction in the sputum mycobacterial load proportional to the dose of telacebec, as determined by the time-to-culture positivity in MGIT 960 system liquid media [ 173 ].…”