Contributions
Abstract: P551
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Evobrutinib (M2951) is a highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that demonstrated efficacy in preclinical models of autoimmune disease. This first-in-human study investigated the safety, tolerability, and pharmacokinetics (PK) of evobrutinib in healthy subjects, and examined the relationship between evobrutinib exposure and changes in QT interval.
Methods: This was a single-centre, Phase I, double-blind, placebo-controlled trial. In Part 1, 48 healthy participants in six successive dose cohorts (20-fold difference between highest and lowest doses) were randomised to a single oral dose of evobrutinib or placebo (6:2). In Part 2, 36 participants in three ascending dose cohorts were randomised to evobrutinib or placebo (9:3) once daily for 14 days. Safety and tolerability were assessed following single and multiple dosing and PK parameters determined by non-compartmental methods. Change from baseline in QT interval, corrected for heart rate by Fridericia's method (QTcF), in the 24 hours following the first dose was determined by electrocardiography.
Results: Treatment-emergent adverse events (TEAEs) with evobrutinib were mostly mild, occurring in 25% of participants after single, and 48.1% after multiple dosing. Nature and incidence of TEAEs were similar among evobrutinib and placebo groups, with no apparent dose relationship regarding frequency or type of TEAEs among evobrutinib-treated subjects. Absorption of evobrutinib was rapid (tmax ~0.5 h), half-life was short (~2 h), and PK were dose-proportional following single and multiple dosing, with no accumulation or time dependency on repeat dosing. Concentration-QTcF analyses revealed no significant exposure-effect relationship. Based on a linear mixed-effects model for change from baseline in QTcF (ΔQTcF), the slope of the relationship between mean placebo-adjusted ΔQTcF (ΔΔQTcF) and concentration was negative and close to zero (-0.00027 ms/ng per mL; p=0.86). The predicted ΔΔQTcF effect at geometric mean Cmax for the highest dose (1512 ng/mL) was -1.16 ms with an upper limit of 3.26 ms for the 90% two-sided bootstrapped confidence interval, which is well below the 10 ms threshold of regulatory concern (ICH-E14 guidance).
Conclusions: Evobrutinib was well tolerated, with predictable PK and no prolongation of QT interval (ΔΔQTcF) in healthy volunteers, and is suitable for further investigation in patients with autoimmune disease.
Disclosure: Andreas Becker: Employee of Merck KGaA, holds shares in Merck; Emily Martin: Employee of EMD Serono; David Y Mitchell: Clinical pharmacology consultant working with Merck KGaA; Victor Ona: Employee of EMD Serono; Jonathan Willmer: Employee of EMD Serono; Andreas Johne: Employee of Merck KGaA
Abstract: P551
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Background: Evobrutinib (M2951) is a highly selective, irreversible Bruton's tyrosine kinase (BTK) inhibitor that demonstrated efficacy in preclinical models of autoimmune disease. This first-in-human study investigated the safety, tolerability, and pharmacokinetics (PK) of evobrutinib in healthy subjects, and examined the relationship between evobrutinib exposure and changes in QT interval.
Methods: This was a single-centre, Phase I, double-blind, placebo-controlled trial. In Part 1, 48 healthy participants in six successive dose cohorts (20-fold difference between highest and lowest doses) were randomised to a single oral dose of evobrutinib or placebo (6:2). In Part 2, 36 participants in three ascending dose cohorts were randomised to evobrutinib or placebo (9:3) once daily for 14 days. Safety and tolerability were assessed following single and multiple dosing and PK parameters determined by non-compartmental methods. Change from baseline in QT interval, corrected for heart rate by Fridericia's method (QTcF), in the 24 hours following the first dose was determined by electrocardiography.
Results: Treatment-emergent adverse events (TEAEs) with evobrutinib were mostly mild, occurring in 25% of participants after single, and 48.1% after multiple dosing. Nature and incidence of TEAEs were similar among evobrutinib and placebo groups, with no apparent dose relationship regarding frequency or type of TEAEs among evobrutinib-treated subjects. Absorption of evobrutinib was rapid (tmax ~0.5 h), half-life was short (~2 h), and PK were dose-proportional following single and multiple dosing, with no accumulation or time dependency on repeat dosing. Concentration-QTcF analyses revealed no significant exposure-effect relationship. Based on a linear mixed-effects model for change from baseline in QTcF (ΔQTcF), the slope of the relationship between mean placebo-adjusted ΔQTcF (ΔΔQTcF) and concentration was negative and close to zero (-0.00027 ms/ng per mL; p=0.86). The predicted ΔΔQTcF effect at geometric mean Cmax for the highest dose (1512 ng/mL) was -1.16 ms with an upper limit of 3.26 ms for the 90% two-sided bootstrapped confidence interval, which is well below the 10 ms threshold of regulatory concern (ICH-E14 guidance).
Conclusions: Evobrutinib was well tolerated, with predictable PK and no prolongation of QT interval (ΔΔQTcF) in healthy volunteers, and is suitable for further investigation in patients with autoimmune disease.
Disclosure: Andreas Becker: Employee of Merck KGaA, holds shares in Merck; Emily Martin: Employee of EMD Serono; David Y Mitchell: Clinical pharmacology consultant working with Merck KGaA; Victor Ona: Employee of EMD Serono; Jonathan Willmer: Employee of EMD Serono; Andreas Johne: Employee of Merck KGaA