Patrick Peter John Phillips

Background: Ethambutol, a longstanding treatment for tuberculosis (TB), lacks comprehensive pharmacokinetic (PK) data, particularly regarding covariates affecting exposure and their link to treatment outcomes. Using the largest data to date from Study 31/AIDS Clinical Trials Group A5349, we aimed to characterize ethambutol PKs, identify risk factors for lower exposure, quantify relationships between exposure and efficacy and safety outcomes, and explore dosing considerations that optimize risks and benefits. Methods: We analyzed ethambutol PK data using nonlinear mixed-effect modeling. We evaluated the contribution of ethambutol exposure to efficacy outcomes using parametric time-to-event modeling and safety outcomes using logistic regression. Results: In 1493 participants with 3077 plasma samples, a one-compartment model with first-order elimination best described ethambutol PKs, with diabetes, higher creatinine clearance, and higher weight linked to increased clearance. Higher ethambutol exposure was modestly associated with grade 3 or higher adverse events and a reduced risk of TB-related unfavorable outcomes. Target exposures for 95% cure were 8.9 µg·h/mL in the 6-month control regimen and 25.6 µg·h/mL in the 4-month rifapentine regimen. Simulations showed that reducing doses in middle (1200 to 1000 mg) and highest (1600 to 1200 mg) weight bands could equalize median exposures, lowering toxicity risk while maintaining efficacy in the control regimen, but might not achieve target exposure in the rifapentine regimen. Conclusions: The contribution of ethambutol exposure is regimen-dependent, with a higher efficacy target required for the 4-month rifapentine regimen. Dose reductions for patients above 55 kg may mitigate toxicity in standard therapy but risk compromising efficacy in the shorter regimen.

Background: Young children with exposure to or infection with Mycobacterium tuberculosis are at high risk of developing tuberculosis disease, and postexposure tuberculosis preventive treatment decreases this risk. Evidence is limited regarding the dosing and safety of the 12-dose once-weekly rifapentine and isoniazid regimen (3HP) for tuberculosis preventive treatment in children younger than 2 years and in children living with HIV. Objective: This protocol describes Tuberculosis Trials Consortium (TBTC) Study 35, which aims to establish practical age- and weight-banded rifapentine doses for 3HP in children aged 0 to 12 years, including children younger than 2 years, and children living with HIV, while assessing safety, tolerability, palatability, and acceptability. Methods: TBTC Study 35 was a phase I/II, open-label, multisite, single-arm, exposure-controlled dose-finding and safety study of 3HP in children aged 0 to 12 years, including children living with HIV. Novel water-dispersible rifapentine and isoniazid formulations were used. Building on TBTC Study 26 data, initial rifapentine doses were selected, and nonlinear mixed-effects modeling was used to analyze the pharmacokinetic data and evaluate subsequent rifapentine doses. Safety was monitored throughout the 12-week treatment period and 12-week posttreatment follow-up. Results: Data collection began with the first recruitment in November 2019. The last participant was enrolled in December 2023, and participant follow-up and data collection were completed in May 2024. As of now, 69 participants were enrolled. The trial was funded throughout this time period. Data analysis is ongoing, and trial results are expected to be disseminated in 2026. Conclusions: TBTC Study 35 is expected to provide pharmacokinetic and safety data to inform practical pediatric 3HP dosing recommendations, including for children younger than 2 years and children living with HIV.

Tuberculosis is the deadliest infectious disease, and treatments for multidrug-resistant tuberculosis are lengthy and toxic. By analyzing a large international database (N = 7,750), we identified patient risk phenotypes linked to unfavorable outcomes. Factors like HIV infection, age, low BMI, smoking, acid-fast bacillus smear positivity, extrapulmonary involvement, and cavitary disease were associated ( p < 0.001) with worse clinical outcomes (ROC AUC 0.728; 95% CI 0.726–0.731) and were used to derive a patient risk score. Low-risk patients had a lower probability of unfavorable outcome over time since treatment initiation compared to high-risk patients ( p < 0.001). External validation with a highly effective 6-month BPaL regimen showed 97% treatment success for low-risk patients and 88% for medium-to-high-risk patients. Stratifying patients by risk phenotype enables more effective, personalized tuberculosis interventions, which are key to improving cure rates.

Culture‐based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non‐culture‐based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB‐MBLA), could represent a solution. Our objectives were to evaluate TB‐MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modeling could provide insight into underlying biological processes. We generated TB‐MBLA (LifeArc) data from sputum samples from all 78 patients from the PanACEA BTZ‐043 Phase Ib/IIa trial and derived a summary measure of the joint distribution of the three TB‐MBLA, colony forming units (CFU), and time‐to‐positivity (TTP) biomarkers as the first principal component derived from a probabilistic principal component analysis (pPCA). With TB‐MBLA marker and the principal component 1 (PC1) values, we reevaluated the original stage IIa dose–response and stages Ib/IIa pharmacokinetics—pharmacodynamics (PK‐PD) exposure‐response analyses, applying linear and non‐linear mixed models, respectively. For TB‐MBLA, we could not detect an exposure‐response effect in the PK‐PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced E _max exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modeling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. In this study, we present novel EBA data for the first‐in‐class antimycobacterial compound BTZ‐043 and contextualize the value of emerging bacteriological markers within the EBA trial framework. Trial Registration: ClinicalTrials.gov identifier: NCT04044001

Tuberculosis treatment trials have used various comparison strategies. To inform trial design for novel tuberculosis regimens, we applied an existing framework for evaluating when uncontrolled trials might be justified. We conclude that the conditions are not met for tuberculosis treatment and that uncontrolled phase 3 trials should not be performed.

Background: A 4-month rifapentine-moxifloxacin regimen showed non-inferior efficacy and comparable safety to the standard 6-month control regimen at 12 months for the treatment of tuberculosis (S31/A5349, NCT02410772). We report the final 18-month outcomes. Methods: In this randomized, open-label, controlled phase 3 non-inferiority trial, two 4-month rifapentine-containing regimens were compared to a standard 6-month control regimen. Both investigational regimens replaced rifampin with rifapentine and, in one, moxifloxacin also replaced ethambutol and was given throughout treatment. All participants were followed for 18 months and whole genome sequencing (WGS) was used to distinguish relapse from reinfections. Findings: At 18 months, the rifapentine-moxifloxacin regimen was non-inferior to control, with a difference in unfavorable outcomes of 1.1% (95% CI -2.4%,4.6%) in the microbiologically eligible primary analysis population, and 1.0% (95% CI -2.0%,4.1%) in the assessable primary analysis population, adjusted for baseline cavitation and HIV status. Although not demonstrated at 12 months, the rifapentine regimen was inferior to control at 18 months in both primary analysis populations with adjusted differences in unfavorable outcomes of 4.1% (95% CI 0.5%,7.8%) and 3.7% (95% CI 0.5%,7.0%) in the microbiologically eligible and assessable analysis populations, respectively. In the microbiologically eligible analysis population, 2 (0.3%), 8 (1.0%), and 19 (2.4%) participants had reinfection in the control, rifapentine-moxifloxacin and rifapentine regimens respectively. The number-needed-to-treat to prevent one unfavorable outcome with the control compared to the 4-month rifapentine-moxifloxacin regimen is 91. Interpretation: At 18 months, a 4-month rifapentine-moxifloxacin regimen had non-inferior efficacy to control, but rifapentine without moxifloxacin had inferior efficacy to control.

Culture-based monitoring of bacterial load is slow and susceptible to missing data, contributing to the length and cost of TB clinical trials. Non-culture-based alternatives, like the Tuberculosis Molecular Load Bacterial Assay (TB-MBLA), could represent a solution. Our objectives were to evaluate TB-MBLA as a biomarker in early bactericidal activity (EBA) studies and explore whether combining biomarkers with joint modelling could provide insight into underlying biological processes and reduce data loss. We generated TB-MBLA (LifeArc ^(R) ) data from sputum samples from all 78 patients from the PanACEA BTZ-043 Phase Ib/IIa trial. In addition, we defined a joint biomarker as the first principal component derived from a probabilistic principal component analysis (pPCA) integrating TB-MBLA, colony forming units (CFU), and time-to-positivity (TTP) data. With TB-MBLA alone and the principal component 1 (PC1) marker we reevaluated the original stage IIa dose-response and stages Ib/IIa pharmacokinetics - pharmacodynamics (PK-PD) exposure-response analyses, applying linear and non-linear mixed models, respectively. For TB-MBLA, we could not detect an exposure-response effect in the PK-PD analysis, in contrast with CFU and TTP. When combining biomarkers, we observed a significant but less pronounced Emax exposure–response between days 0–3 compared with CFU and TTP alone. We also successfully applied pPCA as a modelling framework and show evidence that combining CFU and TTP in a joint latent component can improve detection of treatment effects compared with either biomarker alone. STUDY HIGHLIGHTS: What is the current knowledge on the topic?: BTZ-043 is a first-in-class antimycobacterial compound with promising applications in drug-sensitive pulmonary tuberculosis. TB EBA trials are typically conducted using sputum culture assays for dose-exposure-response modelling, but the technical challenges of these assays limit their effectiveness. What question did this study address?: How does the novel RT-qPCR assay TB-MBLA perform as a dose-exposure response marker for novel antitubercular compound BTZ-043 and what are the effects of joint modelling approaches in EBA modelling tasks? What does this study add to our knowledge?: We did not observe a significant exposure response for BTZ-043 in TB-MBLA over the 14-day treatment window. Joint modelling with pPCA can overcome the issues of missing and contaminated data that are canonical of culture data from TB treatment monitoring cohorts. How might this change drug discovery, development, and/or therapeutics?: Designing EBA trials should consider the drug-bacterial subpopulation axis of the specific study drug to maximise efficiency. Latent variable modelling techniques can be an effective and efficient framework for modelling Mycobacterial tuberculosis load in EBA trials.

Background: Accurate nonsputum tests are essential for improving tuberculosis (TB) detection. We report the first evaluation of the Xpert TB/LTBI assay (research-use-only; Cepheid, USA), which detects 9 Mycobacterium tuberculosis antigen-stimulated mRNA targets from blood. Methods: We enrolled individuals ≥12 years with presumptive TB from clinics in Uganda and Vietnam. All participants underwent sputum- (liquid culture; Xpert MTB/RIF Ultra) and blood-based (Xpert TB/LTBI; QuantiFERON-TB Gold Plus [QFT-Plus]) testing. Participants were classified as having active TB (positive sputum results), latent TB infection (LTBI; positive QFT-Plus with negative sputum results), or no TB infection. Diagnostic accuracy for active TB (primary analysis) and of a 2-step algorithm that first predicted TB infection (active TB or LTBI) and then distinguished active TB from LTBI was assessed using logistic regression and receiver operating characteristic analysis. Results: Among 214 participants included, 56.5% were male, 9.3% were living with HIV, 29.0% had active TB, and 31.8% had LTBI. Xpert TB/LTBI area under the curve (AUC) was 0.92 (95% CI: .88–.96) for identifying active TB, and sensitivity was 93.5% (95% CI: 84.6–97.5) and specificity 76.3% (95% CI: 69.0–82.4) at a cut-point that achieved ≥90% sensitivity. In the 2-step algorithm, Xpert TB/LTBI had high accuracy for identifying TB infection in the first step, but accuracy was lower for distinguishing active TB from LTBI in the second step. Conclusions: Xpert TB/LTBI exceeded World Health Organization (WHO)-recommended minimum accuracy targets for a TB screening test. However, further refinement is needed to improve its ability to distinguish active TB from LTBI.

Rationale: Evaluation of optimal dosing has generally been inadequate during tuberculosis (TB) drug development. Fluoroquinolones are central to TB treatment. Objectives: To determine the dose of levofloxacin needed to achieve maximal efficacy and acceptable safety and tolerability as part of a multidrug TB regimen. Methods: Opti-Q was an international, multicenter, randomized, placebo-controlled phase II trial. Eligible participants with TB resistant to isoniazid and rifampicin but susceptible to fluoroquinolones were randomized to receive one of four weight-adjusted once-daily doses of levofloxacin for 24 weeks (168 doses) alongside a multidrug regimen: 11 mg/kg (750 mg), 14 mg/kg (750 mg/1,000 mg), 17 mg/kg (1,000 mg/1,250 mg) or 20 mg/kg (1,250 mg/1,500 mg). The primary efficacy outcome was time to sputum culture conversion, and the primary safety outcome was grade ≥3 adverse events (AEs). Measurements and Main Results: A total of 111 participants were randomized from three sites in South Africa and Peru. Eighty-three (75%) had cavities on chest X-ray, 55 (50%) had a smear grading of 3+, and the median body mass index was 20.4 kg/m2. Median levofloxacin areas under the curve (AUCs)/minimum inhibitory concentrations were 573, 633, 918, and 1,343 across the four treatment arms. There was no difference in time to culture conversion on solid or liquid media by treatment arm (stratified log-rank P = 0.282), by tertile of AUC/minimum inhibitory concentration (P = 0.350), or by dose received (P = 0.723); 69.3%, 74.8%, 70.6%, and 78.3% exhibited culture conversion after 8 weeks on solid media, respectively, across the treatment arms; along with 64.6%, 69.5%, 52.6%, and 69.6% on liquid culture. More participants experienced a grade 3–5 AE at higher doses (37.0% and 16.0% in the highest and lowest dose groups, respectively; P = 0.042, Cochran-Armitage test for trend) and higher tertiles of AUC (P = 0.011). Conclusions: As part of a multidrug regimen, doses of levofloxacin >1,000 mg/d resulted in greater exposures and increased frequency of AEs but did not result in faster time to sputum culture conversion. A dose of 1,000 mg/d can achieve the target exposure in nearly all adults and was well tolerated.