Efanesoctocog Alfa Population Pharmacokinetics and Repeated Time-To-Event Analysis of Bleeds in Adults, Adolescents, and Children with Severe Hemophilia A

Abstract

Efanesoctocog alfa is a first-in-class high-sustained factor VIII (HSF) replacement therapy for treatment of hemophilia A. This article presents population pharmacokinetics (PopPK) of efanesoctocog alfa and repeated time-to-event (RTTE) analysis of bleeding episodes in adults/adolescents (≥12 years of age) and children (<12 years). The final PopPK dataset contained pooled data from 277 patients (4405 post-dose factor VIII [FVIII] activity records) from two Phase 1/2a studies (NCT03205163; EudraCT 2018-001535-51), and three Phase 3 studies, XTEND-1 (NCT04161495), XTEND-Kids (NCT04759131), and XTEND-ed (NCT04644575). The PopPK model developed was a linear one-compartment model including body weight effect on clearance and volume of central compartment; Asian race was identified as a statistically significant covariate on clearance. The final PopPK model adequately described the FVIII activity-time profiles in adults, adolescents, and children with once-weekly (QW) efanesoctocog alfa 50 IU/kg, consistent with experience in XTEND-1 and XTEND-Kids. Bleeding episodes in participants in XTEND-1 and XTEND-Kids were characterized by an RTTE model with a Weibull base hazard and effect of FVIII activity modeled by a power effect. The RTTE model showed the probability of being bleed-free in 1 year with efanesoctocog alfa 50 IU/kg QW regimen was >70% across all age groups, consistent with the observed clinical outcomes in the Phase 3 trials of highly effective protection from bleeding episodes in patients with severe hemophilia A, which validates the model's prediction of the long-term bleed hazard.

Keywords: adults; efanesoctocog alfa; hemophilia A; pediatric; population pharmacokinetics; time‐to‐event analyses.

Figure 1

(a) Population predicted and (b) individual predicted versus observed FVIII activity from the final population pharmacokinetic model. The black line is line of unity, and the blue line is loess smoothing line. FVIII, factor VIII; OSA, one‐stage clotting assay.

Figure 2

Distribution of steady‐state C_trough, C_max, and duration of time FVIII activity was ≥40 IU/dL across the baseline bodyweight range for adults, adolescents, and children. The box represents the interquartile range, the horizontal line represents the median value, the vertical lines represent the upper and lower data values, and the individual points represent the outlier values. C_maxss, maximum concentration at steady state; C_troughss, trough at steady state.

Figure 3

Simulated FVIII^a activity for a potential perioperative efanesoctocog alfa regimen in a non‐Asian virtual population of adult and adolescents (a), children 6 to <12 years (b), and children <6 years (c). FVIII, factor VIII. ^aActivity was measured with a one‐stage clotting assay.

Figure 4

Simulated FVIII^a activity for a potential efanesoctocog alfa dosing regimen for major bleed in a virtual population of adult and adolescents (a), children 6 to <12 years (b), and children <6 years (c). FVIII, factor VIII. ^aActivity was measured with a one‐stage clotting assay.

Figure 5

Kaplan–Meier visual predictive checks of the final RTTE models for the prophylaxis arm in XTEND‐1 adult/adolescent patients (a) and XTEND‐Kids^a patients <12 years of age (b), 6 to <12 years of age^b (c), and <6 years of age (d). Red solid line is observed Kaplan–Meier; red dashed lines are 95% confidence interval around the observed Kaplan–Meier. Grey band is the visual predictive check with 95% prediction interval. RTTE, repeated time‐to‐event. ^aRTTE model was re‐estimated for the pediatric (<12 years) dataset. ^bIncluding the outlier patient who was excluded from the sensitivity analysis.