Orestis Papasouliotis (1), David Mitchell (2), Pascal Girard (1), Martin Dyroff (3)
(1) Translational Medicine, Merck Institute for Pharmacometrics, Lausanne, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany); (2) Clinical Pharmacology, Nuventra, Inc., Broomfield, CO, USA; (3) Translational Medicine, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA, Darmstadt, Germany)
Introduction: Evobrutinib is a highly selective Bruton’s tyrosine kinase (BTK) inhibitor currently in development for the treatment of multiple sclerosis (MS) [1]. A placebo-controlled, double-blind, randomised, phase II trial (NCT02975349) has investigated the safety and efficacy of evobrutinib in relapsing MS [2]. Fasted patients were treated with placebo or evobrutinib (25 mg once daily [QD], 75 mg QD, or 75 mg twice daily [BID]) for 24 weeks, followed by a 24-week blinded extension (placebo patients switched to evobrutinib 25mg QD).
Objective: To explore exposure-response (E-R) relationships for key trial endpoints and identify effective evobrutinib dosing regimens for phase III trials in patients with relapsing MS. The endpoints included the total number of gadolinium-enhancing (Gd+) lesions identified on T1-weighted magnetic resonance imaging (MRI) at Weeks 12 to 24, total number of new or enlarging T2 lesions at Weeks 12 to 24 and annualized relapse rate (ARR) at Week 48.
Methods: Data from patients in the phase II trial were used to update evobrutinib population pharmacokinetic (PK) [3] and BTK occupancy (BTKO) models previously identified in healthy participants. Key exposure and occupancy metrics were derived and used to investigate their relationship to MRI and ARR endpoints. E-R was investigated with cross-sectional negative-binomial regression models. The population models were used to simulate PK and BTKO profiles and ARR for alternative dosing regimens (10 to 200 mg QD and BID with or without food). NONMEM® programme (version 7.3) was used for PK and BTKO model fitting. Since slightly more than 20% of the observed PK data were below the limit of quantification, the M3 method was used in the PK modelling. SAS (version 9.04, proc nlmixed) was used for the E-R models.
Results: A two-compartment model with sequential zero first-order absorption and first order elimination described the PK profiles well. Food increased bioavailability by 49% versus a fasted state. Food was also associated with an increase of the duration of the zero-order input. Apparent clearance (CL/F) in MS patients was reduced by 41.6% compared with healthy participants. BTKO profiles were described by an irreversible-binding model. The PK-BTKO relationship was consistent between healthy participants and MS patients, i.e. no indication-related covariates were present in the BTKO model. E-R models showed a significant relationship between evobrutinib exposure (steady state [SS] area under the concentration-time curve over 24 hours [AUC0-24,SS]) and clinical response (total T1 Gd+ and new/enlarging T2 lesions at Week 24, and ARR at Week 48). The E-R relationship with T1 Gd+/T2 lesions was linear, with an AUC0-24,SS of 468 ng/mL*hr, the quintile of the exposure distribution above which a substantially lower number of T1 Gd+ and T2 lesions were observed. A step function E-R curve was identified for the ARR data, with the lower step (associated with ARR improvement) reached at an AUC0-24,SS of 400 ng/mL*hr. These exposures were associated with SS pre-dose BTKO of ≥95%.
An evobrutinib dose of 45 mg BID in fed MS patients is expected to result in similar AUC0-24,SS and SS pre-dose BTKO as the 75 mg BID fasted dose of the phase II trial. It is projected to achieve an AUC0-24,SS >400 ng/mL*hr and SS pre-dose BTKO of >95% in more than 90% of patients. The expected ARR is anticipated to be similar to the one obtained in the 75 mg BID fasted arm of the phase II trial.
Conclusions: A 45 mg BID dose of evobrutinib administered with food should be pharmacologically and clinically effective and is appropriate for clinical use in phase III relapsing MS trials. This dosing regimen, not tested previously in the evobrutinib clinical programme, was selected based on a framework of models and extensive simulations, with the exposure verified in a phase I clinical study.
Funding disclosure: This research was funded by Merck KGaA, Darmstadt, Germany. The authors would like to thank ICON plc for their assistance with portions of this analysis.
References:
[1] Torke S and Weber MS. Inhibition of Bruton´s tyrosine kinase as a novel therapeutic approach in multiple sclerosis. Expert Opin Investig Drugs 2020;29(10):1143–50.
[2] Montalban X, et al. Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis. N Engl J Med 2019;380(25):2406–17.
[3] Papasouliotis O, Mitchell D, Dyroff M and Girard P. Population Pharmacokinetic Model of Evobrutinib, a Bruton Tyrosine Kinase Inhibitor – An Analysis of Two Phase I Clinical Trials in Healthy Subjects. ASCPT 2020 Poster.
Reference: PAGE 29 (2021) Abstr 9801 [www.page-meeting.org/?abstract=9801]
Poster: Drug/Disease Modelling - CNS