ABSTRACT
Background. Epetraborole (EBO) - an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria - is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease. Methods. In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered (n=8/cohort, 3:1 randomization) at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods. Results. A total of 43 subjects were enrolled;the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced >=1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events (48.4% EBO, 41.7% placebo subjects), the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma Cmax and AUC0- of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ~1 h post dose;mean t1/2 ranged from 7.63 to 11.1 h. Conclusion. * Oral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h) * Predictable PK characteristics facilitate its use in MAC lung disease * Further evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is planned.
ABSTRACT
Background. ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods. The QSP model was fit inNONMEMVersion 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE;N=659, IM) and treatment (STAMP;N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/ pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results. The QSP model provided an excellent fit to serum ADI concentrationtime data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion. This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants.
ABSTRACT
Background. ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses with pandemic potential. Our objective was to develop a PPK model that describes the serum ADI concentration time profile following intravenous (IV) and intramuscular (IM) administration. Methods. The ADI PPK model was developed on PK data from a Phase 1 single ascending dose study (24 adults, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE;659 adults, IM) and treatment (STAMP;189 adults, IM) studies. 1,486 PK samples were included in the analysis. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI serum disposition were evaluated. Prediction-corrected visual predictive check (PC-VPC) plots were used to qualify the PPK model. Participant-specific ADI exposure estimates were generated using individual post hoc PK parameters. Results. The PPK model is comprised of 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration and provided a robust fit to the data based on the PC-VPC plots and goodness-of-fit plots (data not shown). Body weight influenced clearance, inter compartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI clearance. The median [range] half-lives in days by study;Phase 1 (alpha1.71 [1.18-2.46];beta 125 [117-149]), Phase 2/3 prevention (alpha 1.86 [0.640-3.13];beta 136 [105-209]), and Phase 2/3 treatment (alpha 1.89 [0.631-3.01];beta 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. The figure shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI dose by study. Conclusion. The PPK model provided a precise and unbiasedfit to the observed ADI concentration-time data and will be useful for future PK-pharmacodynamic analyses. Moreover, ADI demonstrated high IM bioavailability and a median terminal elimination half-life of 125 to 136 days.