Sylvie Retout1, Sébastien Jolivet1, Valérie Cosson1, Marie-Laure Delporte1
1Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel
Objectives: Baloxavir marboxil (Bxm) is an antiviral prodrug that is converted by hydrolysis to the active form baloxavir acid (here referred as baloxavir), which suppresses influenza virus replication by selective inhibition of a virus-specific cap-dependent endonuclease. Bxm is now approved for the treatment and post-exposure prophylaxis of uncomplicated influenza in patients above 1 year in the EU and in patients who are otherwise healthy (OwH) or at high risk of developing influenza-related complications (HR) aged = 5 years in the USA. The time to alleviation of symptoms (TTAS) is an efficacy endpoint used in clinical trials that investigate the efficacy of an antiviral. To support the pediatric development of Bxm, a PK-TTAS model was developed, providing a quantitative characterization of the relationship between baloxavir exposure and the alleviation of influenza symptoms and assessing any covariate impact on that relationship. Methods: Based on placebo- and Bxm-treated pediatric, adolescent and adult patients data, a time-to-event analysis was conducted to model the baloxavir PK-TTAS relationship, using a parametric proportional hazard model to describe the instantaneous risk of symptom alleviation. Since the definition of TTAS was not identical in all pediatric and adult trials, a second TTAS (TTAS2) was derived based on a set of criteria used in all trials (cough, nasal congestion, return to afebrile state). Baloxavir plasma concentrations collected and TTAS2 derived from 7 Bxm studies were pooled with the TTAS2 of placebo-treated pediatric patients from an oseltamivir trial. A placebo model was first developed (from the placebo arm) to characterize the natural TTAS2 distribution without Bxm administration and to identify the potential factors that impact the natural TTAS2 distribution. Then the effect of baloxavir concentrations on the TTAS2 distribution was investigated (data from placebo and Bxm arms) and covariates with significant influence on baloxavir drug effect were identified. The performances of the model to predict the PK-TTAS2 profiles in the different covariate sub-groups (including age) were assessed. Then, PK-TTAS simulations in pediatric, adolescent and adult patients were performed to support extrapolation of baloxavir efficacy in pediatric patients and to provide justification for baloxavir dosing in this patient population. Results: A total of 2216 patients were included in the PK-TTAS2 model development, including 901 placebo-treated and 1315 Bxm-treated patients. The Placebo TTAS2 data were best described using a log-logistic distribution. A clear baloxavir PK effect on the TTAS2 distribution was found, with an increased instantaneous risk of symptom alleviation as baloxavir concentrations increased; the impact of the baloxavir concentrations on the TTAS2 distribution was best described by a sigmoid Emax model, affecting the instantaneous risk of symptom alleviation additively. The covariate investigation determined that a composite cough/nasal congestion symptom score at baseline, the race (Asian or non-Asian) and the disease status at baseline (OwH or HR) influenced the natural TTAS2 distribution, while influenza type (A or B) and the composite cough/nasal congestion symptom score at baseline were the main covariates with significant impact on the drug effect. Notably, age, disease status at baseline and race had no influence on the effect of baloxavir on the hazard ratio function. This indicates a similar impact of baloxavir concentrations on TTAS2, regardless of age, disease status at baseline and race. PK-TTAS2 simulations showed a consistent reduction of one day or more in the predicted median TTAS2 after Bxm treatment at the recommended dose (2 mg/kg for < 20 kg, 40 mg for 20 to < 80 kg, or 80 mg for = 80 kg). The shortening of symptom duration with Bxm was similar across all groups based on age (when comparing patients 1 to <5 years, 5 to <12 years, and =12 years), race and disease status. Conclusions: The results from the PK-TTAS2 model demonstrated, by a clinically meaningful reduction of TTAS2, the benefit of Bxm at the recommended dose across all age groups (from pediatrics to adults), disease status (OwH and HR), and race (Asian and non-Asian populations). The model-based simulations supported the extrapolation of efficacy between populations based on exposure-matching and the pediatric label extensions.
Reference: PAGE 33 (2025) Abstr 11401 [www.page-meeting.org/?abstract=11401]
Poster: Drug/Disease Modelling - Infection