TB Alliance

IntroductionThe first-in-class diarylquinoline (DARQ) bedaquiline (BDQ) is in the medicines list for drug-resistant tuberculosis. TBAJ-587 is a next-generation DARQ with improved anti-Mycobacterium tuberculosis (Mtb) activity and reduced cardiac repolarization abnormalities.MethodsThe in vitro efficacy of TBAJ-587 and its main metabolites (M2, M3 and M12) was analyzed under standard (ST) growth conditions and with cholesterol (CHO), or fatty acids (FA) as physiologically relevant alternative carbon sources. Minimal inhibitory concentration (MIC) assays and time-kill assays (TKA) linked to drug measurements in bacterial samples were performed to allow correlation of pharmacodynamics (PD) with actual in vitro pharmacokinetics (PK).ResultsThe most active compounds, TBAJ-587 and its M3 metabolite, exhibited broth media and concentration dependent efficacy showing a bactericidal effect at ≥5x MIC. Bacterial cultures treated with 1x MIC and 2x MIC of TBAJ-587 resumed growth after 28 days and displayed moderate increased MIC values compared to untreated conditions, which were linked to new variants of BDQ resistance mutations in the atpE, atpB, and Rv0678 genes. This study revealed that TBAJ-587 and its metabolites bind to polystyrene plastic-ware, the most commonly used material in antimicrobial research, being the effective unbound drug concentration dependent on the media composition. PKPD analyses determined that Mtb was killed with lower exposures of TBAJ-587 and M3 than expected in ST and FA broth, suggesting previously underestimated potency in these media.DiscussionUnlike commonly performed in in vitro PKPD studies that solely rely on nominal drug concentrations, our work precisely relates compound activity to actual effective concentrations that are measured over time directly in Mtb cultures, providing improved longitudinal data to feed in silico models for translational research.

ABSTRACTSorfequiline is a novel diarylquinoline in development for treatment of tuberculosis. In vitro data suggest metabolism via CYP3A4, carrying the potential for presystemic metabolism and drug–drug interactions. Its major metabolite, M3, is pharmacologically active. We developed a semi‐mechanistic joint population pharmacokinetic model of sorfequiline and M3 in healthy volunteers. Data were pooled from two studies (CL‐001 and CL‐002). CL‐001 comprised a single‐ascending‐dose part (10–800 mg suspension fasted plus 100 mg fed), a multiple‐ascending‐dose part (25, 75, or 200 mg/day for 14 days, fed), and a relative bioavailability assessment including 100 mg in tablet form under fed and fasted conditions. In CL‐002, fed participants received 200 mg/day suspension for 8 days followed by 165 mg/day for 4 days. Plasma concentrations were quantified using HPLC–MS/MS, and pharmacokinetic modeling and simulations were conducted in NONMEM. A three‐compartment disposition model for both analytes, with transit‐compartment absorption, adequately described the data. A fraction of the dose was assumed to be absorbed as M3 due to gut first‐pass metabolism. This fraction was 46% (95% CI: 41%–50%) in fasted and 15% (13%–19%) in fed participants. Overall bioavailability decreased by 46% (32%–61%) at fasted doses ≥ 400 mg. Model‐based simulations showed that exposures for all investigated regimens remained below safety reference values. Food reduced the fraction of sorfequiline dose absorbed as M3, likely due to limited gut first‐pass metabolism. The developed model provides an initial platform for future pharmacokinetic/pharmacodynamic analyses and simulation of both analytes' exposures under drug–drug interaction scenarios.

ABSTRACT TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25–800 mg under fasting conditions and multiple doses of 50–200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.

ABSTRACT Rationale Tuberculosis preventive therapy (TPT) is essential for global tuberculosis control, yet estimated coverage remains well below global targets. Current World Health Organization (WHO)-recommended regimens require 1-9 months of treatment and are associated with suboptimal completion rates. Long-acting injectable (LAI) formulations offer the potential to improve TPT uptake and completion, with ideal products providing "one-and-done" options via a single administration. Sorfequiline, a second-generation diarylquinoline with superior potency over bedaquiline and lower QT prolongation risk, is a promising candidate for LAI TPT. Objectives To experimentally determine exposure-activity relationships for sorfequiline as TPT, estimate target plasma exposures, and characterize the pharmacokinetics (PK), tolerability, and efficacy of sorfequiline LAI formulations. Methods Oral sorfequiline dosing experiments established PK and pharmacodynamic relationships in a validated paucibacillary mouse model of TPT. Three candidate sorfequiline LAI formulations were evaluated for PK and tolerability in uninfected mice, followed by efficacy assessment compared to oral comparators (1HP, bedaquiline, sorfequiline). Measurement and Main Results Oral dosing experiments established a provisional target plasma C min of 35 ng/mL for bactericidal effect. All tested LAI formulations achieved this target for at least 4 weeks post-dose. In efficacy studies, all sorfequiline LAI regimens (62.5-250 mg/kg) and sorfequiline oral regimens demonstrated significantly greater bactericidal activity than 1HP and oral bedaquiline. Among mice receiving ≥125 mg/kg of any sorfequiline LAI, 92% were culture-negative at 12 weeks. Conclusion Superior efficacy of a single-dose sorfequiline LAI injection compared to 1HP indicates the potential to meet the WHO target product profile for an optimal "one-and-done" LAI TPT clinical regimen.

In 2023, tuberculosis (TB) returned to being the world’s leading cause of death from a single infectious agent. Current standard of care for drug-sensitive tuberculosis (DS-TB) treatment has a long duration with risk of poor compliance and outcomes and increased risk of development of resistant strains. Sorfequiline (S) is a second-generation diarylquinoline with the potential to contribute both to increased efficacy and improved safety and to a shorter TB treatment regimen for both DS-TB and drug-resistant DR-TB. NC-009 is a phase 2, multicentre, partially blinded, randomized clinical trial conducted in five treatment arms, including three doses of sorfequiline in combination with pretomanid and linezolid for 8 weeks followed by 7 or 18 weeks of HR depending on the participant meeting criteria to stop treatment at week 15. There is also a BPaL arm and standard of care arm, both for a 26-week treatment duration. The study population is smear-positive, DS-TB. The primary objective of the study is to determine the optimal dose of sorfequiline to move forward to a potential phase 3 study based on efficacy and safety data. The study is being conducted in Georgia, South Africa, Tanzania, Uganda, and the Philippines in accordance with ICH-GCP and after approval of all relevant country health authorities and ethics committees. NC-009 is a first in-patient, dose-ranging, phase 2 trial of sorfequiline, with an innovative design combining ph2a, ph2b, and ph2c elements that simultaneously allow for dose selection, preliminary evaluation of treatment duration, robust collection of safety data, evaluation of drug-drug interaction with antiretroviral medications, and pharmacokinetic assessment of study drugs. The study is currently ongoing. ClinicalTrials.gov NCT 06058299. Registered on 09 September 2023.