Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Children With Chronic HCV: Part 2 of the DORA Study

Abstract

Background and aims: Glecaprevir/pibrentasvir (GLE/PIB) has shown high efficacy and safety in chronic HCV-infected adults and adolescents; data in children were limited. DORA part 2 is a phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics, efficacy, and safety of a pediatric formulation of GLE and PIB in children ages 3 to < 12 years.

Approach and results: Children with chronic HCV infection, genotype 1-6, with or without compensated cirrhosis, were divided into three cohorts by age-cohort 2 (9 to < 12 years), cohort 3 (6 to < 9 years), and cohort 4 (3 to < 6 years)-and given weight-based doses of GLE and PIB for 8, 12, or 16 weeks. Primary endpoints were sustained virologic response at posttreatment week 12 (SVR12) and steady-state exposure; secondary endpoints were rates of persistent viremia, relapse, and reinfection. Safety and laboratory abnormalities were assessed. Final pediatric dosages determined to be efficacious were 250 mg GLE + 100 mg PIB (in children weighing ≥ 30 to < 45 kg), 200 mg GLE + 80 mg PIB (≥ 20 to < 30 kg), and 150 mg GLE + 60 mg PIB (12 to < 20 kg). Of 80 participants enrolled and dosed, 96% (77/80) achieved SVR12. One participant, on the initial dose ratio, relapsed by posttreatment week 4; no participants had virologic failures on the final dose ratio of GLE 50 mg/PIB 20 mg. Two nonresponders prematurely discontinued the study. Most adverse events (AEs) were mild; no drug-related serious AEs occurred. Pharmacokinetic exposures were comparable to those of adults.

Conclusions: A pediatric formulation of GLE/PIB was highly efficacious and well tolerated in chronic HCV-infected children 3 to < 12 years old.

Trial registration: ClinicalTrials.gov NCT03067129.

© 2021 by the American Association for the Study of Liver Diseases.

Figures

Fig. 1

Study schematic depicting cohorts 2‐4 in part 2 of the DORA study, broken down by the PK and efficacy/safety analyses portions for each cohort. In the posttreatment period, participants administered at least one dose of the study drug will be monitored for safety, viral response, emergence and/or persistence of resistance‐associated viral substitutions, growth, and development. *Enrolled and dosed. Abbreviation: PD, pharmacodynamic.

Fig. 2

Distribution of AUC of GLE and PIB (at week 2) in adults and adolescents following the adult formulation of GLE/PIB at 300/120 mg dose and in children following the pediatric formulation of GLE/PIB at final determined doses. Dashed lines show the target GLE AUC range of (2400‐9600) ng • hour/mL and the target PIB AUC range of (715‐2860) ng • hour/mL, which are ± 2‐fold of geometric mean exposures in adults.

Fig. 3

SVR12 rates by age cohort and overall group following treatment with the weight‐based GLE/PIB pediatric formulation in the ITT population. Error bars represent 95% CIs, which were calculated using the Wilson score method. *One participant with premature discontinuation due to drug‐related rash and one participant relapsed by PTW4. †One participant refused to swallow granule formulation and prematurely discontinued study after being partially dosed on Day 1; the participant did not receive subsequent doses.